| model | NAME | NOF_TMPLCL | NOF_LIG | AUC | ClassAUC | pKdAUC | Q2 | R2pkd | RMSE | tag | Species | Tissue | ADR | Category | Disease | Function | Drug_Mechanism | version |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| dfa5HT1A | 5-hydroxytryptamine receptor 1A | 2 | 5502 | 93.74 | 89.67 | ND | 0.44 | 0.44 | 0.8 | Nature11159 | Mammalian | Detected in lymph nodes, thymus and spleen. Detected in activated T-cells, but not in resting T-cells. {ECO:0000269|PubMed:3041227, ECO:0000269|PubMed:8393041}. | Asthenia Cardiac failure congestive Dry eye Dry mouth Insomnia Orthostatic hypotension Peripheral coldness Priapism Psychotic disorder Raynaud's phenomenon | Family A G protein-coupled receptor | Periodic fever, menstrual cycle-dependent (PFMC) [MIM:614674]: A condition characterized by recurrent fevers up to 40 degrees Celsius associated with the luteal phase of the menstrual cycle. Women show menstrual cycle-dependent physiologic changes in relation to sex hormone levels. Because ovulation triggers a significant change in the hormonal milieu that is similar to local inflammation, a 0.5 to 1.0 degree Celsius increase in basal body temperature after ovulation is commonly associated with progesterone secretion and is believed to be triggered by the induction of several inflammatory cytokines. {ECO:0000269|PubMed:21990073}. Note=The disease is caused by mutations affecting the gene represented in this entry. | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of 5- hydroxytryptamine release and in the regulation of dopamine and 5- hydroxytryptamine metabolism. Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior. Plays a role in the response to anxiogenic stimuli. {ECO:0000269|PubMed:22957663, ECO:0000269|PubMed:3138543, ECO:0000269|PubMed:8138923, ECO:0000269|PubMed:8393041}. | 5-hydroxytryptamine receptor 1A : Bopindolol 5-hydroxytryptamine receptor 1A activator: Imipramine 5-hydroxytryptamine receptor 1A agonist: Apomorphine, Brexpiprazole, Bromocriptine, Cabergoline, Cariprazine, Cinitapride, Eletriptan, Ergotamine, Flibanserin, Lisuride, Methysergide, Naratriptan, Pergolide, Ropinirole, Rotigotine, Sumatriptan, Vilazodone, Vortioxetine, Zolmitriptan 5-hydroxytryptamine receptor 1A antagonist: Acepromazine, Alprenolol, Alverine, Amoxapine, Aripiprazole, Asenapine, Chlorpromazine, Clozapine, Doxepin, Ergoloid mesylate, Iloperidone, Ketamine, Lurasidone, Molindone, Nefazodone, Nortriptyline, Olanzapine, Paliperidone, Penbutolol, Pindolol, Pipotiazine, Quetiapine, Risperidone, Thioproperazine, Trimipramine, Ziprasidone 5-hydroxytryptamine receptor 1A binder: Desipramine, Dopamine, Loxapine 5-hydroxytryptamine receptor 1A blocker: Mianserin 5-hydroxytryptamine receptor 1A inhibitor: Amitriptyline 5-hydroxytryptamine receptor 1A other/unknown: Ondansetron, Propranolol 5-hydroxytryptamine receptor 1A partial agonist: Buspirone, Trazodone, Yohimbine 5-hydroxytryptamine receptor 1A unknown: Pramipexole | 16.04 |
| dfa5HT1B | 5-hydroxytryptamine receptor 1B | 1 | 1185 | 94.37 | 89.71 | ND | 0.69 | 0.62 | 0.7 | Mammalian | Detected in cerebral artery smooth muscle cells (at protein level). Detected in brain cortex, striatum, amygdala, medulla, hippocampus, caudate nucleus and putamen. {ECO:0000269|PubMed:1348246, ECO:0000269|PubMed:1351684, ECO:0000269|PubMed:15853772}. | Gestational hypertension Orthostatic hypotension Psychotic disorder | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Migraine Obsessive-compulsive disorder Pulmonary hypertension | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries. {ECO:0000269|PubMed:10452531, ECO:0000269|PubMed:1315531, ECO:0000269|PubMed:1328844, ECO:0000269|PubMed:1348246, ECO:0000269|PubMed:1351684, ECO:0000269|PubMed:1559993, ECO:0000269|PubMed:1565658, ECO:0000269|PubMed:15853772, ECO:0000269|PubMed:1610347, ECO:0000269|PubMed:23519210, ECO:0000269|PubMed:23519215, ECO:0000269|PubMed:8218242}. | 5-hydroxytryptamine receptor 1B agonist: Almotriptan, Apomorphine, Bromocriptine, Cabergoline, Dihydroergotamine, Eletriptan, Ergotamine, Frovatriptan, Lisuride, Naratriptan, Pergolide, Rizatriptan, Ropinirole, Sumatriptan, Zolmitriptan 5-hydroxytryptamine receptor 1B antagonist: Amoxapine, Aripiprazole, Asenapine, Clozapine, Ergoloid mesylate, Ketamine, Olanzapine, Penbutolol, Yohimbine, Ziprasidone 5-hydroxytryptamine receptor 1B binder: Amitriptyline, Loxapine, Methysergide 5-hydroxytryptamine receptor 1B other/unknown: Ondansetron, Pindolol, Propranolol, Quetiapine 5-hydroxytryptamine receptor 1B unknown: Bopindolol, Pramipexole | 15.11 | |
| dfa5HT1D | 5-hydroxytryptamine receptor 1D | 1 | 1071 | 95.58 | 86.94 | ND | 0.73 | 0.72 | 0.8 | Mammalian | Detected in brain neocortex and caudate nucleus (at protein level). {ECO:0000269|PubMed:1828434}. | Dyskinesia Gestational hypertension Orthostatic hypotension Somnolence Tachycardia | Family A G protein-coupled receptor | Migraine
Obsessive-compulsive disorder Vascular headache Vomiting | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Regulates the release of 5-hydroxytryptamine in the brain, and thereby affects neural activity. May also play a role in regulating the release of other neurotransmitters. May play a role in vasoconstriction. {ECO:0000269|PubMed:10452531, ECO:0000269|PubMed:1565658, ECO:0000269|PubMed:1652050}. | 5-hydroxytryptamine receptor 1D agonist: Almotriptan, Apomorphine, Bromocriptine, Cabergoline, Dihydroergotamine, Eletriptan, Ergotamine, Frovatriptan, Lisuride, Naratriptan, Pergolide, Rizatriptan, Ropinirole, Sumatriptan, Zolmitriptan 5-hydroxytryptamine receptor 1D antagonist: Aripiprazole, Clozapine, Olanzapine, Paliperidone, Risperidone, Yohimbine, Ziprasidone 5-hydroxytryptamine receptor 1D binder: Amitriptyline, Loxapine, Trimipramine 5-hydroxytryptamine receptor 1D other/unknown: Quetiapine 5-hydroxytryptamine receptor 1D unknown: Pramipexole | 16.04 | |
| dfa5HT1E | 5-hydroxytryptamine receptor 1E | 4 | 97 | 86.42 | 82.41 | ND | 0.15 | 0.66 | 0.8 | Mammalian | Detected in brain. {ECO:0000269|PubMed:14744596}. | Ejaculation disorder Orthostatic hypotension | Family A G protein-coupled receptor | Neurologic and psychiatric diseases | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various alkaloids and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:14744596, ECO:0000269|PubMed:1513320, ECO:0000269|PubMed:1608964, ECO:0000269|PubMed:1733778, ECO:0000269|PubMed:21422162}. | 5-hydroxytryptamine receptor 1E agonist: Eletriptan 5-hydroxytryptamine receptor 1E antagonist: Aripiprazole, Clozapine, Olanzapine, Ziprasidone 5-hydroxytryptamine receptor 1E binder: Loxapine, Methysergide 5-hydroxytryptamine receptor 1E other/unknown: Quetiapine | 16.04 | |
| dfa5HT1F | 5-hydroxytryptamine receptor 1F | 1 | 91 | 99.85 | 99.27 | ND | 0.59 | 0.04 | 0.5 | Mammalian | Family A G protein-coupled receptor | Migraine | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various alkaloids and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:21422162, ECO:0000269|PubMed:8380639, ECO:0000269|PubMed:8384716}. | 5-hydroxytryptamine receptor 1F agonist: Eletriptan, Ergotamine, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan 5-hydroxytryptamine receptor 1F binder: Methysergide, Mianserin | 16.04 | |||
| dfa5HT2A | 5-hydroxytryptamine receptor 2A | 2 | 3654 | 91.67 | 82.43 | ND | 0.56 | 0.56 | 0.7 | Nature11159 | Mammalian | Detected in brain cortex (at protein level). Detected in blood platelets. {ECO:0000269|PubMed:18297054}. | Akathisia Anticholinergic syndrome Corneal pigmentation Dermatitis allergic Dry mouth Dystonia Ejaculation disorder Electrocardiogram change Erectile dysfunction Extrapyramidal disorder Fibrocystic breast disease Galactorrhoea Gynaecomastia Hypercholesterolaemia Hyperprolactinaemia Hyperthermia Insomnia Lenticular opacities Lipid metabolism disorder Mania Miosis Mydriasis Nasal congestion Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tachycardia Tardive dyskinesia Weight increased | Family A G protein-coupled receptor | Acute ureteric colic
Anxiety disorder, unspecified Arterial embolism and thrombosis Cocaine dependence Depression Diabetic nephropathy Diabetic neuropathy Essential (primary) hypertension Migraine Schizophrenia | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5- dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores. Affects neural activity, perception, cognition and mood. Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction. {ECO:0000269|PubMed:1330647, ECO:0000269|PubMed:18297054, ECO:0000269|PubMed:18703043, ECO:0000269|PubMed:19057895, ECO:0000269|PubMed:21645528, ECO:0000269|PubMed:22300836}. (Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV. {ECO:0000269|PubMed:24089568}. | 5-hydroxytryptamine receptor 2A agonist: Apomorphine, Bromocriptine, Cabergoline, Cisapride, Ergotamine, Lisuride, Pergolide, Ropinirole, Trimipramine 5-hydroxytryptamine receptor 2A antagonist: Acepromazine, Amisulpride, Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Brexpiprazole, Butriptyline, Cariprazine, Chlorpromazine, Chlorprothixene, Cinitapride, Clomipramine, Clozapine, Cyclobenzaprine, Cyproheptadine, Desipramine, Doxepin, Epinastine, Flibanserin, Flupentixol, Fluspirilene, Iloperidone, Imipramine, Ketamine, Loxapine, Lurasidone, Mesoridazine, Methotrimeprazine, Methysergide, Mianserin, Minaprine, Mirtazapine, Molindone, Nefazodone, Nortriptyline, Olanzapine, Paliperidone, Pipotiazine, Promazine, Promethazine, Propiomazine, Quetiapine, Risperidone, Sertindole, Thioproperazine, Thioridazine, Thiothixene, Trazodone, Yohimbine, Ziprasidone, Zuclopenthixol 5-hydroxytryptamine receptor 2A binder: Maprotiline 5-hydroxytryptamine receptor 2A other/unknown: Donepezil, Haloperidol, Paroxetine, Remoxipride 5-hydroxytryptamine receptor 2A unknown: Pramipexole | 16.04 |
| dfa5HT2C | 5-hydroxytryptamine receptor 2C | 7 | 2538 | 86.94 | 83.84 | ND | 0.56 | 0.61 | 0.7 | Nature11159 | Mammalian | Detected in brain. {ECO:0000269|PubMed:8812491}. | Akathisia Dermatitis allergic Dry mouth Dystonia Ejaculation disorder Extrapyramidal disorder Galactorrhoea Hypercholesterolaemia Hyperthermia Insomnia Lipid metabolism disorder Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Psychotic disorder Tachycardia Tardive dyskinesia | Family A G protein-coupled receptor | Acute ureteric colic
Cocaine dependence Motor disorder Schizophrenia | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1- 2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis. {ECO:0000269|PubMed:12970106, ECO:0000269|PubMed:18703043, ECO:0000269|PubMed:19057895, ECO:0000269|PubMed:7895773}. | 5-hydroxytryptamine receptor 2C : Lorcaserin 5-hydroxytryptamine receptor 2C agonist: Apomorphine, Bromocriptine, Cabergoline, Dexfenfluramine, Ergotamine, Lisuride, Pergolide, Ropinirole, Trazodone 5-hydroxytryptamine receptor 2C antagonist: Agomelatine, Amoxapine, Aripiprazole, Asenapine, Captodiame, Chlorprothixene, Clomipramine, Clozapine, Cyproheptadine, Doxepin, Imipramine, Loxapine, Methotrimeprazine, Methysergide, Mianserin, Minaprine, Mirtazapine, Nefazodone, Nortriptyline, Olanzapine, Paliperidone, Promazine, Propiomazine, Quetiapine, Risperidone, Sertindole, Tramadol, Trimipramine, Yohimbine, Ziprasidone 5-hydroxytryptamine receptor 2C binder: Amitriptyline, Chlorpromazine, Desipramine, Maprotiline 5-hydroxytryptamine receptor 2C unknown: Pramipexole | 16.04 |
| dfa5HT3A | 5-hydroxytryptamine receptor 3A | 1 | 567 | 93.96 | 87.60 | ND | 0.79 | 0.80 | 0.6 | Nature11159 | Mammalian | Expressed in cerebral cortex, amygdala, hippocampus, and testis. Detected in monocytes of the spleen and tonsil, in small and large intestine, uterus, prostate, ovary and placenta. {ECO:0000269|PubMed:10521471}. | Ligand-gated ion channel | Alcohol dependence
Alcoholism Irritable bowel syndrome Nausea and vomiting Pruritus | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel. {ECO:0000269|PubMed:12867984, ECO:0000269|PubMed:9950429}. | 5-hydroxytryptamine receptor 3A : Ethanol, Tapentadol 5-hydroxytryptamine receptor 3A agonist: Cisapride, Metoclopramide 5-hydroxytryptamine receptor 3A antagonist: Alosetron, Amoxapine, Aripiprazole, Chloroprocaine, Clozapine, Dolasetron, Granisetron, Memantine, Methadone, Mirtazapine, Olanzapine, Ondansetron, Palonosetron, Procaine, Rocuronium, Tubocurarine, Vortioxetine, Ziprasidone 5-hydroxytryptamine receptor 3A binder: Loxapine, Trimipramine 5-hydroxytryptamine receptor 3A other/unknown: Quetiapine | 16.04 | |
| dfa5HT4R | 5-hydroxytryptamine receptor 4 | 1 | 604 | 96.96 | 95.56 | ND | 0.68 | 0.61 | 0.6 | Mammalian | Isoform 5-HT4(A) is expressed in ileum, brain, and atrium, but not in the ventricle. {ECO:0000269|PubMed:15118808}. | Family A G protein-coupled receptor | Alzheimer's disease
Cardiac arrhythmias Dementia Diarrhoea-predominant irritable bowel syndrome Drug dependence Irritable bowel syndrome Psychiatric illness | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. | 5-hydroxytryptamine receptor 4 agonist: Cinitapride, Cisapride, Metoclopramide, Ondansetron, Prucalopride | 16.04 | ||
| dfa5HT6R | 5-hydroxytryptamine receptor 6 | 2 | 1911 | 96.01 | 93.51 | ND | 0.65 | 0.66 | 0.6 | Mammalian | Expressed in several human brain regions, most prominently in the caudate nucleus. | Akathisia Dry mouth Dystonia Extrapyramidal disorder Galactorrhoea Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tardive dyskinesia | Family A G protein-coupled receptor | Irritable bowel syndrome
Nausea and vomiting Pruritus in chronic liver disease Schizophrenia | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. It has a high affinity for tricyclic psychotropic drugs (By similarity). Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity (By similarity). Is an activator of TOR signaling (PubMed:23027611). {ECO:0000250|UniProtKB:P31388, ECO:0000250|UniProtKB:Q9R1C8, ECO:0000269|PubMed:23027611}. | 5-hydroxytryptamine receptor 6 antagonist: Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Clozapine, Iloperidone, Olanzapine, Sertindole, Ziprasidone 5-hydroxytryptamine receptor 6 binder: Chlorpromazine, Doxepin, Imipramine, Loxapine, Mianserin, Nortriptyline 5-hydroxytryptamine receptor 6 other/unknown: Quetiapine | 16.04 | |
| dfa5HT7R | 5-hydroxytryptamine receptor 7 | 5 | 1301 | 87.60 | 91.63 | ND | 0.56 | 0.00 | 0.6 | Mammalian | Isoform A is the predominant isoform in spleen, caudate and hippocampus. Isoform B is expressed at lower levels. Isoform D is a minor isoform in term of expression. {ECO:0000269|PubMed:9084407}. | Akathisia Dystonia Ejaculation disorder Hyperthermia Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tardive dyskinesia | Family A G protein-coupled receptor | Migraine
Neuropsychiatric disorders | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. | 5-hydroxytryptamine receptor 7 agonist: Eletriptan 5-hydroxytryptamine receptor 7 antagonist: Amisulpride, Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Bromocriptine, Cabergoline, Clozapine, Epinastine, Iloperidone, Imipramine, Lurasidone, Maprotiline, Methysergide, Mianserin, Olanzapine, Quetiapine, Vortioxetine, Ziprasidone 5-hydroxytryptamine receptor 7 binder: Chlorpromazine, Dopamine, Loxapine 5-hydroxytryptamine receptor 7 binding: Mirtazapine | 16.04 | |
| dfa5NTD | 5'-nucleotidase | 3 | 44 | 98.70 | 96.74 | ND | 0.05 | 0.69 | 0.4 | Mammalian | Enzyme | Calcification of joints and arteries (CALJA) [MIM:211800]: A condition characterized by adult-onset calcification of the lower extremity arteries, including the iliac, femoral and tibial arteries, and hand and foot capsule joints. Age of onset has been reported as early as the second decade of life, usually involving intense joint pain or calcification in the hands. {ECO:0000269|PubMed:21288095}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Hydrolyzes extracellular nucleotides into membrane permeable nucleosides. Exhibits AMP-, NAD-, and NMN-nucleosidase activities. {ECO:0000269|PubMed:21933152}. | 5'-nucleotidase inhibitor: Pentoxifylline 5'-nucleotidase substrate: Cytarabine | 15.11 | |||
| dfaA4 | Amyloid beta A4 protein | 4 | 236 | 92.66 | 90.67 | ND | 0.59 | 0.75 | 0.9 | Mammalian | Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex- opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra- striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non- neuronal cells. Isoform APP751 is the most abundant form in T- lymphocytes. Appican is expressed in astrocytes. {ECO:0000269|PubMed:12859342, ECO:0000269|PubMed:1406936}. | Membrane receptor | Alzheimer disease 1 (AD1) [MIM:104300]: A familial early- onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. {ECO:0000269|PubMed:10097173, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10665499, ECO:0000269|PubMed:10867787, ECO:0000269|PubMed:11063718, ECO:0000269|PubMed:11528419, ECO:0000269|PubMed:12034808, ECO:0000269|PubMed:1302033, ECO:0000269|PubMed:1303239, ECO:0000269|PubMed:1303275, ECO:0000269|PubMed:1415269, ECO:0000269|PubMed:15201367, ECO:0000269|PubMed:15365148, ECO:0000269|PubMed:15668448, ECO:0000269|PubMed:1671712, ECO:0000269|PubMed:1678058, ECO:0000269|PubMed:1908231, ECO:0000269|PubMed:1925564, ECO:0000269|PubMed:1944558, ECO:0000269|PubMed:8267572, ECO:0000269|PubMed:8290042, ECO:0000269|PubMed:8476439, ECO:0000269|PubMed:8577393, ECO:0000269|PubMed:9328472, ECO:0000269|PubMed:9754958}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cerebral amyloid angiopathy, APP-related (CAA-APP) [MIM:605714]: A hereditary localized amyloidosis due to amyloid- beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque- like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. {ECO:0000269|PubMed:11409420, ECO:0000269|PubMed:12654973, ECO:0000269|PubMed:16178030, ECO:0000269|PubMed:20697050, ECO:0000269|PubMed:2111584}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER- dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1. {ECO:0000250}. Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Also binds GPC1 in lipid rafts. Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain. {ECO:0000250}. The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis. N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6). | 16.04 | |||
| dfaAA1R | Adenosine receptor A1 | 5 | 5507 | 96.13 | 91.03 | ND | 0.60 | 0.00 | 0.6 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Analgesics
Asthma Cardiac arrhythmias Chronic ileitis Inflammation Inflammatory bowel disease Insulin resistance (obesity-related) Noninsulin-dependent diabetes mellitus Pain Renal failure | Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. | Adenosine receptor A1 : Defibrotide, Enprofylline Adenosine receptor A1 agonist: Adenosine, Gabapentin Adenosine receptor A1 antagonist: Aminophylline, Caffeine, Dyphylline, Oxtriphylline, Pentoxifylline, Theobromine, Theophylline Adenosine receptor A1 multitarget: | 16.04 | ||
| dfaAA2AR | Adenosine receptor A2a | 1 | 4634 | 96.50 | 86.31 | ND | 0.68 | 0.63 | 0.7 | Nature11159 | Mammalian | Angina pectoris Flushing Palpitations | Family A G protein-coupled receptor | Analgesics
Brain injury Depression Dyskinesia Inflammation Ischemia reperfusion injuries Neurodegenerative diseases Neuropsychiatric disorders Oxygen-induced retinopathy Pain Parkinson's disease Renal diseases | Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. | Adenosine receptor A2a agonist: Adenosine, Regadenoson Adenosine receptor A2a antagonist: Dyphylline, Mefloquine, Oxtriphylline, Pentoxifylline, Theobromine, Theophylline Adenosine receptor A2a antagonist;multitarget: Caffeine Adenosine receptor A2a unknown: Enprofylline | 15.11 | |
| dfaAA2BR | Adenosine receptor A2b | 1 | 1903 | 97.42 | 83.22 | ND | 0.77 | 0.68 | 0.5 | Mammalian | Palpitations | Family A G protein-coupled receptor | Asthma | Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. | Adenosine receptor A2b agonist: Adenosine Adenosine receptor A2b antagonist: Enprofylline, Theophylline | 16.04 | ||
| dfaAA3R | Adenosine receptor A3 | 4 | 3021 | 94.86 | 91.51 | ND | 0.64 | 0.61 | 0.7 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Cancer, unspecific
Chronic ileitis Depression Inflammatory bowel disease Myocardial ischemia and reperfusion injury | Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. Possible role in reproduction. | Adenosine receptor A3 : Enprofylline Adenosine receptor A3 agonist: Adenosine Adenosine receptor A3 antagonist: Aminophylline | 16.04 | ||
| dfaAAPK1 | 5'-AMP-activated protein kinase catalytic subunit alpha-1 | 3 | 307 | 87.03 | 90.48 | ND | 0.28 | 0.80 | 0.6 | Mammalian | Kinase | Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. {ECO:0000269|PubMed:11518699, ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:18439900, ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641}. | 5'-AMP-activated protein kinase catalytic subunit alpha-1 activator: Acetylsalicylic acid, Adenosine monophosphate, Phenformin 5'-AMP-activated protein kinase catalytic subunit alpha-1 unknown: Adenosine triphosphate | 15.11 | ||||
| dfaAAPK2 | 5'-AMP-activated protein kinase catalytic subunit alpha-2 | 4 | 68 | 99.80 | 98.52 | ND | 0.71 | 0.93 | 0.5 | Mammalian | Kinase | Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. Involved in insulin receptor/INSR internalization (PubMed:25687571). AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (By similarity). {ECO:0000250|UniProtKB:Q8BRK8, ECO:0000269|PubMed:11518699, ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:25687571, ECO:0000269|PubMed:7959015}. | 16.04 | |||||
| dfaABCC9 | ATP-binding cassette sub-family C member 9 | 2 | 47 | 99.58 | 99.96 | ND | 0.76 | 0.45 | 0.2 | Mammalian | Primary active transporter | Cardiomyopathy, dilated 1O (CMD1O) [MIM:608569]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:15034580}. Note=The disease is caused by mutations affecting the gene represented in this entry. Atrial fibrillation, familial, 12 (ATFB12) [MIM:614050]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:17245405}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypertrichotic osteochondrodysplasia (HTOCD) [MIM:239850]: A rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The hypertrichosis leads to thick scalp hair, which extends onto the forehead, and a general increase in body hair. In addition, macrocephaly and coarse facial features, including a broad nasal bridge, epicanthal folds, a wide mouth, and full lips, can be suggestive of a storage disorder. About half of affected individuals are macrosomic and edematous at birth, whereas in childhood they usually have a muscular appearance with little subcutaneous fat. Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones have been reported. Cardiac manifestations such as patent ductus arteriosus, ventricular hypertrophy, pulmonary hypertension, and pericardial effusions are present in approximately 80% of cases. Motor development is usually delayed due to hypotonia. Most patients have a mild speech delay, and a small percentage have learning difficulties or intellectual disability. {ECO:0000269|PubMed:22608503, ECO:0000269|PubMed:22610116, ECO:0000269|PubMed:26621776}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation. {ECO:0000269|PubMed:9831708}. | ATP-binding cassette sub-family C member 9 : Adenosine triphosphate ATP-binding cassette sub-family C member 9 modulator: Glyburide | 16.04 | |||
| dfaABCG2 | ATP-binding cassette sub-family G member 2 | 1 | 353 | 90.02 | 82.64 | ND | 0.35 | 0.40 | 0.6 | Mammalian | Highly expressed in placenta. Low expression in small intestine, liver and colon. {ECO:0000269|PubMed:9850061, ECO:0000269|PubMed:9861027}. | Anaemia Thrombocytopenia | Primary active transporter | High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin. {ECO:0000269|PubMed:12958161, ECO:0000269|PubMed:20705604, ECO:0000269|PubMed:22132962, ECO:0000269|PubMed:23189181}. | ATP-binding cassette sub-family G member 2 Antagonist: ATP-binding cassette sub-family G member 2 inducer: Venlafaxine ATP-binding cassette sub-family G member 2 inhibitor: Alectinib, Buprenorphine, Cabazitaxel, Cobicistat, Cyclosporine, Daclatasvir, Dexamethasone, Diethylstilbestrol, Dronabinol, Erlotinib, Estradiol, Estrone, Hesperetin, Hydrocortisone, Lansoprazole, Nelfinavir, Novobiocin, Omeprazole, Pantoprazole, Rabeprazole, Regorafenib, Rilpivirine, Ritonavir, Rolapitant, Saquinavir, Sunitinib, Telmisartan, Vandetanib, Verapamil, Vismodegib ATP-binding cassette sub-family G member 2 substrate: Afatinib, Apixaban, Carboplatin, Cisplatin, Cladribine, Clofarabine, Conjugated Estrogens, Dabrafenib, Dactinomycin, Dasatinib, Daunorubicin, Docetaxel, Doxorubicin, Etoposide, Ezetimibe, Fluorouracil, Folic Acid, Gefitinib, Glyburide, Idelalisib, Imatinib, Irinotecan, Ivermectin, Lamivudine, Leflunomide, Lenvatinib, Methotrexate, Mitoxantrone, Mycophenolate mofetil, Nilotinib, Nitrofurantoin, Osimertinib, Oxaliplatin, Paclitaxel, Pazopanib, Pitavastatin, Ponatinib, Pravastatin, Prazosin, Riluzole, Rosuvastatin, Sofosbuvir, Sorafenib, Sulfasalazine, Sumatriptan, Tamoxifen, Teniposide, Teriflunomide, Testosterone, Topotecan, Vemurafenib, Vincristine, Zidovudine ATP-binding cassette sub-family G member 2 weak inhibitor: Cobimetinib | 16.04 | ||
| dfaABL1 | Tyrosine-protein kinase ABL1 | 1 | 1065 | 89.59 | 85.84 | ND | 0.55 | 0.00 | 0.7 | Mammalian | Widely expressed. | Kinase | Leukemia, chronic myeloid (CML) [MIM:608232]: A clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B-lymphoid, and sometimes T-lymphoid cells, but not marrow fibroblasts. Note=The gene represented in this entry is involved in disease pathogenesis. Note=A chromosomal aberration involving ABL1 has been found in patients with chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). | Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage- induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin- associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. {ECO:0000269|PubMed:10391250, ECO:0000269|PubMed:11971963, ECO:0000269|PubMed:12379650, ECO:0000269|PubMed:12531427, ECO:0000269|PubMed:12672821, ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:15556646, ECO:0000269|PubMed:15657060, ECO:0000269|PubMed:15886098, ECO:0000269|PubMed:16424036, ECO:0000269|PubMed:16678104, ECO:0000269|PubMed:16943190, ECO:0000269|PubMed:17306540, ECO:0000269|PubMed:17623672, ECO:0000269|PubMed:18328268, ECO:0000269|PubMed:18945674, ECO:0000269|PubMed:19891780, ECO:0000269|PubMed:20357770, ECO:0000269|PubMed:20417104, ECO:0000269|PubMed:9037071, ECO:0000269|PubMed:9144171, ECO:0000269|PubMed:9461559}. | Tyrosine-protein kinase ABL1 inhibitor: Adenosine triphosphate, Bosutinib, Imatinib, Nilotinib, Ponatinib, Regorafenib Tyrosine-protein kinase ABL1 multitarget: Dasatinib | 15.11 | ||
| dfaABL2 | Abelson tyrosine-protein kinase 2 | 5 | 81 | 98.89 | 97.71 | ND | 0.91 | 0.92 | 0.3 | Mammalian | Widely expressed. | Kinase | Non-receptor tyrosine-protein kinase that plays an ABL1- overlapping role in key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion and receptor endocytosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like MYH10 (involved in movement); CTTN (involved in signaling); or TUBA1 and TUBB (microtubule subunits). Binds directly F-actin and regulates actin cytoskeletal structure through its F-actin- bundling activity. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as CRK, CRKL, DOK1 or ARHGAP35. Adhesion-dependent phosphorylation of ARHGAP35 promotes its association with RASA1, resulting in recruitment of ARHGAP35 to the cell periphery where it inhibits RHO. Phosphorylates multiple receptor tyrosine kinases like PDGFRB and other substrates which are involved in endocytosis regulation such as RIN1. In brain, may regulate neurotransmission by phosphorylating proteins at the synapse. ABL2 acts also as a regulator of multiple pathological signaling cascades during infection. Pathogens can highjack ABL2 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. {ECO:0000269|PubMed:15735735, ECO:0000269|PubMed:15886098, ECO:0000269|PubMed:16678104, ECO:0000269|PubMed:17306540, ECO:0000269|PubMed:18945674}. | Abelson tyrosine-protein kinase 2 inhibitor: Adenosine triphosphate Abelson tyrosine-protein kinase 2 multitarget: Dasatinib | 15.11 | |||
| dfaACACA | Acetyl-CoA carboxylase 1 | 2 | 321 | 98.32 | 95.68 | ND | 0.49 | 0.70 | 0.7 | Mammalian | Expressed in brain, placental, skeletal muscle, renal, pancreatic and adipose tissues; expressed at low level in pulmonary tissue; not detected in the liver. | Enzyme | Acetyl-CoA carboxylase 1 deficiency (ACACAD) [MIM:613933]: An inborn error of de novo fatty acid synthesis associated with severe brain damage, persistent myopathy and poor growth. {ECO:0000269|PubMed:6114432}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the rate-limiting reaction in the biogenesis of long-chain fatty acids. Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. {ECO:0000269|PubMed:20952656}. | 16.04 | |||
| dfaACACB | Acetyl-CoA carboxylase 2 | 4 | 307 | 97.34 | 99.62 | ND | 0.35 | 0.47 | 0.5 | Mammalian | Widely expressed with highest levels in heart, skeletal muscle, liver, adipose tissue, mammary gland, adrenal gland and colon (PubMed:9099716). Isoform 3 is expressed in skeletal muscle, adipose tissue and liver (at protein level) (PubMed:19190759). Isoform 3 is detected at high levels in adipose tissue with lower levels in heart, liver, skeletal muscle and testis (PubMed:19190759). {ECO:0000269|PubMed:19190759, ECO:0000269|PubMed:9099716}. | Enzyme | Obesity | Catalyzes the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA. Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. Involved in inhibition of fatty acid and glucose oxidation and enhancement of fat storage (By similarity). May play a role in regulation of mitochondrial fatty acid oxidation through malonyl- CoA-dependent inhibition of carnitine palmitoyltransferase 1 (By similarity). {ECO:0000250|UniProtKB:E9Q4Z2, ECO:0000269|PubMed:20952656}. | Acetyl-CoA carboxylase 2 unknown: Adenine, Biotin | 15.11 | ||
| dfaACE | Angiotensin-converting enzyme | 1 | 1219 | 97.89 | 97.15 | ND | 0.33 | 0.47 | 0.7 | Mammalian | Ubiquitously expressed, with highest levels in lung, kidney, heart, gastrointestinal system and prostate. Isoform Testis-specific is expressed in spermatocytes and adult testis. {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:12459472, ECO:0000269|PubMed:15671045}. | Angioedema Cough Dysgeusia Palpitations Pancreatitis | Protease | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry. Microvascular complications of diabetes 3 (MVCD3) [MIM:612624]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end- stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Intracerebral hemorrhage (ICH) [MIM:614519]: A pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke. {ECO:0000269|PubMed:15277638}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. | Angiotensin-converting enzyme inhibitor: Benazepril, Candoxatril, Captopril, Cilazapril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Rescinnamine, Spirapril, Trandolapril | 15.11 | |
| dfaACE2 | Angiotensin-converting enzyme 2 | 1 | 57 | 99.36 | 96.98 | ND | 0.81 | 0.65 | 0.6 | Mammalian | Expressed in endothelial cells from small and large arteries, and in arterial smooth muscle cells. Expressed in lung alveolar epithelial cells, enterocytes of the small intestine, Leydig cells and Sertoli cells (at protein level). Expressed in heart, kidney, testis, and gastrointestinal system. {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:12459472, ECO:0000269|PubMed:15141377, ECO:0000269|PubMed:15231706, ECO:0000269|PubMed:15671045}. | Protease | Cardiovascular disease, unspecified | Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin- 13 and dynorphin-13 with high efficiency. May be an important regulator of heart function. {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:14647384, ECO:0000269|PubMed:24227843}. (Microbial infection) Acts as a receptor for SARS coronavirus/SARS-CoV and human coronavirus NL63/HCoV-NL63. {ECO:0000269|PubMed:14647384, ECO:0000269|PubMed:15452268, ECO:0000269|PubMed:15791205, ECO:0000269|PubMed:15897467}. | Angiotensin-converting enzyme 2 inhibitor: Lisinopril, Moexipril | 16.04 | ||
| dfaACES | Acetylcholinesterase | 5 | 3484 | 92.26 | 85.24 | ND | 0.65 | 0.00 | 0.8 | Mammalian | Isoform H is highly expressed in erythrocytes. {ECO:0000269|PubMed:2714437}. | Diarrhoea Nausea Salivary hypersecretion | Hydrolase | Alzheimer's disease
Cognitive deficits Hypoxic-ischemic encephalopathy Motor neurone disease Parkinson's disease | Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis. {ECO:0000269|PubMed:11985878, ECO:0000269|PubMed:1517212, ECO:0000269|PubMed:1748670, ECO:0000269|PubMed:2714437}. | Acetylcholinesterase activator: Pralidoxime Acetylcholinesterase antagonist: Dimetacrine Acetylcholinesterase antagonist;inhibitor: Pyridostigmine Acetylcholinesterase inhibitor: Ambenonium, Decamethonium, Demecarium, Donepezil, Edrophonium, Galantamine, Gallamine Triethiodide, Isoflurophate, Mefloquine, Minaprine, Neostigmine, Physostigmine, Rivastigmine, Tubocurarine Acetylcholinesterase product of: Choline Acetylcholinesterase unknown: Dipivefrin, Ephedrine | 15.11 | |
| dfaACH10 | Neuronal acetylcholine receptor subunit alpha-10 | 1 | 50 | 98.82 | 99.52 | ND | 0.39 | 0.54 | 0.7 | Nature11159 | Mammalian | Expressed in inner-ear tissue, tonsil, immortalized B-cells, cultured T-cells and peripheral blood lymphocytes. {ECO:0000269|PubMed:11752216, ECO:0000269|PubMed:15531379}. | Apnoea Bradycardia Bronchospasm Cardiac arrest Death Hypotension Lung disorder Muscle twitching Respiratory disorder Respiratory failure Salivary hypersecretion | Ligand-gated ion channel | Analgesics
Neuropathic pain | Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane. In the ear, this may lead to a reduction in basilar membrane motion, altering the activity of auditory nerve fibers and reducing the range of dynamic hearing. This may protect against acoustic trauma. {ECO:0000269|PubMed:11752216}. | Neuronal acetylcholine receptor subunit alpha-10 : Ethanol Neuronal acetylcholine receptor subunit alpha-10 agonist: Nicotine, Succinylcholine Neuronal acetylcholine receptor subunit alpha-10 allosteric modulator: Galantamine Neuronal acetylcholine receptor subunit alpha-10 antagonist: Chloroprocaine, Methadone, Pentolinium, Trimethaphan | 16.04 |
| dfaACHA3 | Neuronal acetylcholine receptor subunit alpha-3 | 2 | 130 | 92.07 | 92.36 | ND | 0.69 | 0.00 | 0.8 | Mammalian | Ligand-gated ion channel | After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. | Neuronal acetylcholine receptor subunit alpha-3 : Ethanol Neuronal acetylcholine receptor subunit alpha-3 agonist: Cytisine, Nicotine Neuronal acetylcholine receptor subunit alpha-3 allosteric modulator: Galantamine Neuronal acetylcholine receptor subunit alpha-3 antagonist: Bupropion, Dextromethorphan, Levomethadyl Acetate, Pentolinium Neuronal acetylcholine receptor subunit alpha-3 partial agonist: Varenicline | 16.04 | ||||
| dfaACHA4 | Neuronal acetylcholine receptor subunit alpha-4 | 3 | 273 | 94.24 | 90.66 | ND | 0.66 | 0.76 | 0.9 | Mammalian | Agitation Apnoea Bradycardia Bronchospasm Death Hypotension Irritability Laryngospasm Lung disorder Nystagmus Respiratory depression Respiratory disorder Respiratory failure Salivary hypersecretion Shock | Ligand-gated ion channel | Epilepsy, nocturnal frontal lobe, 1 (ENFL1) [MIM:600513]: An autosomal dominant focal epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements. {ECO:0000269|PubMed:10563623, ECO:0000269|PubMed:14623738, ECO:0000269|PubMed:7550350}. Note=The disease is caused by mutations affecting the gene represented in this entry. | After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions. {ECO:0000269|PubMed:22361591}. | Neuronal acetylcholine receptor subunit alpha-4 : Ethanol Neuronal acetylcholine receptor subunit alpha-4 agonist: Cytisine, Nicotine Neuronal acetylcholine receptor subunit alpha-4 allosteric modulator: Galantamine Neuronal acetylcholine receptor subunit alpha-4 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Dextromethorphan, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Talbutal, Thiopental Neuronal acetylcholine receptor subunit alpha-4 partial agonist: Varenicline | 16.04 | ||
| dfaACHA7 | Neuronal acetylcholine receptor subunit alpha-7 | 5 | 1394 | 89.90 | 84.47 | ND | 0.65 | 0.00 | 0.7 | Mammalian | Agitation Apnoea Bradycardia Bronchospasm Irritability Laryngospasm Nystagmus Respiratory depression Respiratory disorder Salivary hypersecretion Shock | Ligand-gated ion channel | Alzheimer's disease
Analgesics Drug dependence Neuropsychiatric disorders Pain Schizophrenia | After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is blocked by alpha-bungarotoxin. | Neuronal acetylcholine receptor subunit alpha-7 : Ethanol Neuronal acetylcholine receptor subunit alpha-7 agonist: Cytisine, Nicotine, Varenicline Neuronal acetylcholine receptor subunit alpha-7 allosteric modulator: Galantamine Neuronal acetylcholine receptor subunit alpha-7 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Dextromethorphan, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Talbutal, Thiopental | 16.04 | ||
| dfaACK1 | Activated CDC42 kinase 1 | 6 | 288 | 92.99 | 92.32 | ND | 0.66 | 0.75 | 0.6 | Mammalian | The Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. It also shows a significant increase in expression in prostate cancers during the progressive stages. {ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20623637}. | Kinase | Non-receptor tyrosine-protein and serine/threonine- protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr- 287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. {ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:11278436, ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:18262180, ECO:0000269|PubMed:18435854, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20383201}. | Activated CDC42 kinase 1 unknown: Adenosine triphosphate | 15.11 | |||
| dfaACLY | ATP-citrate synthase | 4 | 72 | 99.01 | 98.48 | ND | 0.67 | 0.54 | 0.4 | Mammalian | Enzyme | Hyperlipidemia
Obesity | ATP-citrate synthase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine. {ECO:0000269|PubMed:23932781}. | 16.04 | ||||
| dfaACM2 | Muscarinic acetylcholine receptor M2 | 4 | 1670 | 89.53 | 86.69 | ND | 0.72 | 0.00 | 0.7 | Nature11159 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Diabetic eye disease Dry mouth Dry skin Extrapyramidal disorder Gastric hypomotility Hyperpyrexia Intraocular pressure increased Mydriasis Salivary hypersecretion Tachycardia Urinary incontinence Urinary retention Vision blurred | Family A G protein-coupled receptor | Major depressive disorder (MDD) [MIM:608516]: A common psychiatric disorder. It is a complex trait characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is characterized by at least 2 weeks during which there is a new onset or clear worsening of either depressed mood or loss of interest or pleasure in nearly all activities. Four additional symptoms must also be present including changes in appetite, weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. The episode must be accompanied by distress or impairment in social, occupational, or other important areas of functioning. {ECO:0000269|PubMed:15229186}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol. {ECO:0000269|PubMed:24256733, ECO:0000269|PubMed:3443095}. | Muscarinic acetylcholine receptor M2 agonist: Bethanechol, Carbachol, Pilocarpine, Succinylcholine Muscarinic acetylcholine receptor M2 antagonist: Aclidinium, Amitriptyline, Amoxapine, Anisotropine Methylbromide, Aripiprazole, Atropine, Brompheniramine, Chlorprothixene, Clozapine, Cocaine, Cyproheptadine, Darifenacin, Desipramine, Dicyclomine, Dimetindene, Diphenidol, Disopyramide, Doxacurium chloride, Doxepin, Ethopropazine, Fesoterodine, Flavoxate, Gallamine Triethiodide, Homatropine Methylbromide, Hyoscyamine, Imipramine, Ipratropium bromide, Maprotiline, Methotrimeprazine, Methylscopolamine bromide, Metixene, Metocurine, Nicardipine, Nortriptyline, Olanzapine, Oxybutynin, Oxyphencyclimine, Pancuronium, Paroxetine, Pipecuronium, Procyclidine, Promazine, Promethazine, Propiomazine, Quetiapine, Rocuronium, Scopolamine, Solifenacin, Tiotropium, Tolterodine, Triflupromazine, Trihexyphenidyl, Tropicamide, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M2 antagonist;partial agonist: Mivacurium Muscarinic acetylcholine receptor M2 binder: Cinnarizine, Glycopyrrolate, Ketamine, Loxapine, Pethidine, Trimipramine | 15.11 | |
| dfaACM3 | Muscarinic acetylcholine receptor M3 | 2 | 1372 | 92.98 | 85.56 | ND | 0.75 | 0.67 | 0.8 | Nature11159 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Diabetic eye disease Dry mouth Dry skin Dysphagia Extrapyramidal disorder Hyperpyrexia Intraocular pressure increased Mydriasis Salivary hypersecretion Tachycardia Urinary retention Vision blurred | Family A G protein-coupled receptor | Prune belly syndrome (PBS) [MIM:100100]: A syndrome characterized by thin abdominal musculature with overlying lax skin, cryptorchism, megacystis with disorganized detrusor muscle, and urinary tract abnormalities. {ECO:0000269|PubMed:22077972}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover. {ECO:0000269|PubMed:7565628}. | Muscarinic acetylcholine receptor M3 : Chlorpromazine Muscarinic acetylcholine receptor M3 agonist: Cevimeline, Methacholine, Pilocarpine, Succinylcholine Muscarinic acetylcholine receptor M3 antagonist: Aclidinium, Amitriptyline, Anisotropine Methylbromide, Aripiprazole, Atropine, Brompheniramine, Chlorprothixene, Clozapine, Cryptenamine, Cyproheptadine, Darifenacin, Desipramine, Diphemanil Methylsulfate, Diphenidol, Disopyramide, Doxepin, Fesoterodine, Glycopyrrolate, Homatropine Methylbromide, Hyoscyamine, Imipramine, Ipratropium bromide, Isopropamide, Maprotiline, Mepenzolate, Methotrimeprazine, Methylscopolamine bromide, Metixene, Mivacurium, Nicardipine, Nortriptyline, Olanzapine, Oxybutynin, Oxyphencyclimine, Pancuronium, Paroxetine, Pipecuronium, Procyclidine, Promazine, Promethazine, Propiomazine, Quetiapine, Scopolamine, Solifenacin, Tiotropium, Tolterodine, Tramadol, Trihexyphenidyl, Tropicamide, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M3 binder: Loxapine | 16.04 | |
| dfaACM4 | Muscarinic acetylcholine receptor M4 | 7 | 581 | 82.55 | 81.79 | ND | 0.70 | 0.65 | 0.6 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Dry mouth Dysphagia Extrapyramidal disorder Mydriasis Salivary hypersecretion Tachycardia Throat irritation Urinary incontinence Urinary retention Vision blurred | Family A G protein-coupled receptor | Analgesics
Manic disorder Neurologic and psychiatric diseases Pain, unspecified Parkinsonian symptoms | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase. | Muscarinic acetylcholine receptor M4 antagonist: Aclidinium, Amitriptyline, Aripiprazole, Atropine, Brompheniramine, Chlorprothixene, Clozapine, Cryptenamine, Darifenacin, Desipramine, Doxepin, Fesoterodine, Homatropine Methylbromide, Hyoscyamine, Imipramine, Isopropamide, Maprotiline, Methotrimeprazine, Metixene, Nicardipine, Nortriptyline, Olanzapine, Paroxetine, Procyclidine, Promazine, Promethazine, Propiomazine, Quetiapine, Scopolamine, Solifenacin, Tolterodine, Trihexyphenidyl, Tropicamide, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M4 binder: Loxapine | 16.04 | ||
| dfaACM5 | Muscarinic acetylcholine receptor M5 | 7 | 541 | 82.72 | 84.60 | ND | 0.68 | 0.56 | 0.6 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Dry mouth Dry skin Extrapyramidal disorder Mydriasis Orthostatic hypotension Tachycardia Urinary incontinence Urinary retention | Family A G protein-coupled receptor | Opioid dependence
Schizophrenia | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover. | Muscarinic acetylcholine receptor M5 antagonist: Aclidinium, Amitriptyline, Aripiprazole, Atropine, Brompheniramine, Chlorprothixene, Clozapine, Cryptenamine, Darifenacin, Desipramine, Doxepin, Fesoterodine, Homatropine Methylbromide, Imipramine, Maprotiline, Methotrimeprazine, Metixene, Nicardipine, Nortriptyline, Olanzapine, Paroxetine, Promazine, Promethazine, Propiomazine, Quetiapine, Scopolamine, Solifenacin, Tolterodine, Trihexyphenidyl, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M5 binder: Loxapine | 16.04 | ||
| dfaACOD | Acyl-CoA desaturase | 7 | 324 | 97.83 | 99.21 | ND | 0.44 | 0.51 | 0.7 | Mammalian | Detected in fetal liver, lung and brain. Highly expressed in adult adipose tissue, and at lower levels in adult brain and lung. {ECO:0000269|PubMed:15907797}. | Enzyme | Stearyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates (PubMed:15907797, PubMed:18765284). Catalyzes the insertion of a cis double bond at the delta-9 position into fatty acyl-CoA substrates including palmitoyl-CoA and stearoyl-CoA (PubMed:15907797, PubMed:18765284). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:15610069). Plays an important role in lipid biosynthesis. Plays an important role in regulating the expression of genes that are involved in lipogenesis and in regulating mitochondrial fatty acid oxidation (By similarity). Plays an important role in body energy homeostasis (By similarity). Contributes to the biosynthesis of membrane phospholipids, cholesterol esters and triglycerides (By similarity). {ECO:0000250|UniProtKB:P13516, ECO:0000269|PubMed:15610069, ECO:0000269|PubMed:15907797, ECO:0000269|PubMed:18765284}. | 16.04 | ||||
| dfaACOD1 | Acyl-CoA desaturase 1 {ECO:0000305} | 4 | 532 | 99.28 | 99.10 | ND | 0.34 | 0.47 | 0.6 | Mammalian | Detected in liver (at protein level) (PubMed:10899171, PubMed:11533264). Detected in skin and liver (PubMed:10545940, PubMed:11161812, PubMed:11441127, PubMed:11533264). Detected in sebaceous gland, but not in hair follicle (PubMed:10545940). Detected in white and brown adipose tissue, eyelid, Harderian gland, and at lower levels in Meibomian gland, eyeball and adrenal gland (PubMed:11500518, PubMed:11533264). Highly expressed in liver, and detected at low levels in brain, heart, lung, stomach, skeletal muscle and kidney (PubMed:11161812, PubMed:12815040). {ECO:0000269|PubMed:10545940, ECO:0000269|PubMed:10899171, ECO:0000269|PubMed:11441127, ECO:0000269|PubMed:11500518, ECO:0000269|PubMed:11533264, ECO:0000269|PubMed:12815040}. | Enzyme | Note=Defects is Scd1 are the cause of asebia (ab) (PubMed:17738154, PubMed:10545940, PubMed:10854228, PubMed:10899171, PubMed:15278437). The trait is due to spontaneous autosomal recessive mutations that give rise to deletions or point mutations in Scd1. The ab trait has complete penetrance (PubMed:17738154). Ab mice are characterized by reduced body weight, extreme sebaceous gland hypoplasia leading to nearly complete absence of sebaceous glands, and thickened, scaly skin with hyperkeratosis and alopecia (PubMed:17738154, PubMed:10854228, PubMed:15278437). The hair follicles are abnormally long and extend at a sharp angle into the subcutis, probably due to abnormal persistence of inner root sheath. Frequently the hair shaft ruptures through the base of the hair follicle, giving rise to inflammation that results in scarring alopecia (PubMed:10854228, PubMed:15278437). Besides, ab mice display increased transepithelial water loss (PubMed:10854228). Ab mice present a narrow eye fissure and their eyes are nearly closed (PubMed:10854228, PubMed:15278437). Older mice develop blindness (PubMed:17738154). Scd1 activity is almost absent in liver, and is not compensated by expression of another family member (PubMed:10899171). Liver levels of total cholesterol esters are decreased by 87%, while plasma cholesterol levels are increased by 35% (PubMed:10899171). Likewise, skin sterol esters and diol diesters are strongly reduced (PubMed:10854228). Liver triglyceride levels are decreased by 62%, while plasma triglyceride levels are decreased by 67% (PubMed:10899171). The fatty acid composition of liver triglycerides is altered, with a decrease of about 85% in palmitoleate (C16:1) and oleate (C18:1) levels (PubMed:10899171). These defects cannot be compensated by a diet enriched in unsaturated fatty acids (PubMed:10899171, PubMed:11441127). {ECO:0000269|PubMed:10545940, ECO:0000269|PubMed:10854228, ECO:0000269|PubMed:10899171, ECO:0000269|PubMed:11441127, ECO:0000269|PubMed:11533264, ECO:0000269|PubMed:15278437, ECO:0000269|PubMed:17738154}. | Stearyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates. Catalyzes the insertion of a cis double bond at the delta-9 position into fatty acyl-CoA substrates including palmitoyl-CoA and stearoyl-CoA (PubMed:11500518, PubMed:11533264, PubMed:16275639, PubMed:16443825, PubMed:26098370). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:11500518, PubMed:11533264, PubMed:16443825, PubMed:26098370). Plays an important role in lipid biosynthesis (PubMed:17127673, PubMed:10899171, PubMed:11500518, PubMed:11441127, PubMed:11533264, PubMed:12177411, PubMed:26098370). Plays an important role in regulating the expression of genes that are involved in lipogenesis and in regulating mitochondrial fatty acid oxidation (PubMed:12177411, PubMed:17127673, PubMed:24356954, PubMed:24295027). Plays an important role in body energy homeostasis (PubMed:17127673, PubMed:15210843, PubMed:24295027, PubMed:24356954). Contributes to the biosynthesis of membrane phospholipids, cholesterol esters and triglycerides (PubMed:10899171, PubMed:11500518, PubMed:11441127, PubMed:11533264, PubMed:12177411, PubMed:15210843, PubMed:26098370). Required for normal development of sebaceous glands (PubMed:17738154, PubMed:11533264). Required for the biosynthesis of normal levels of delta-9 unsaturated fatty acids and 1-alkyl-2,3-diacylglycerol in the Harderian gland (PubMed:11500518). Required for normal production of meibum, an oily material that prevents drying of the cornea (PubMed:11533264). {ECO:0000269|PubMed:10899171, ECO:0000269|PubMed:11441127, ECO:0000269|PubMed:11500518, ECO:0000269|PubMed:11533264, ECO:0000269|PubMed:12177411, ECO:0000269|PubMed:15210843, ECO:0000269|PubMed:16275639, ECO:0000269|PubMed:16443825, ECO:0000269|PubMed:17127673, ECO:0000269|PubMed:26098370, ECO:0000305|PubMed:24295027, ECO:0000305|PubMed:24356954}. | 16.04 | |||
| dfaACOX1 | Peroxisomal acyl-coenzyme A oxidase 1 | 1 | 51 | 100.00 | 99.94 | ND | 0.71 | 0.36 | 0.2 | Mammalian | Widely expressed with highest levels of isoform 1 and isoform 2 detected in testis. Isoform 1 is expressed at higher levels than isoform 2 in liver and kidney while isoform 2 levels are higher in brain, lung, muscle, white adipose tissue and testis. Levels are almost equal in heart. {ECO:0000269|PubMed:17603022, ECO:0000269|PubMed:20195242}. | Adrenoleukodystrophy, pseudoneonatal (Pseudo-NALD) [MIM:264470]: A peroxisomal single-enzyme disorder of fatty acid beta-oxidation, resulting in clinical manifestations that remind neonatal adrenoleukodystrophy. Clinical features include mental retardation, leukodystrophy, seizures, mild hepatomegaly, hearing deficit. Pseudo-NALD is characterized by increased plasma levels of very-long chain fatty acids, due to decreased or absent peroxisome acyl-CoA oxidase activity. Peroxisomes are intact and functioning. {ECO:0000269|PubMed:11815777, ECO:0000269|PubMed:17458872, ECO:0000269|PubMed:8040306}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the desaturation of acyl-CoAs to 2-trans- enoyl-CoAs. Isoform 1 shows highest activity against medium-chain fatty acyl-CoAs and activity decreases with increasing chain length. Isoform 2 is active against a much broader range of substrates and shows activity towards very long-chain acyl-CoAs. Isoform 2 is twice as active as isoform 1 against 16-hydroxy- palmitoyl-CoA and is 25% more active against 1,16-hexadecanodioyl- CoA. {ECO:0000269|PubMed:17458872, ECO:0000269|PubMed:17603022}. | 16.04 | ||||
| dfaACRO | Acrosin | 1 | 85 | 99.92 | 99.87 | ND | 0.90 | 0.86 | 0.4 | Mammalian | Protease | Acrosin is the major protease of mammalian spermatozoa. It is a serine protease of trypsin-like cleavage specificity, it is synthesized in a zymogen form, proacrosin and stored in the acrosome. | 16.04 | |||||
| dfaACV1B | Activin receptor type-1B | 3 | 79 | 89.89 | 90.38 | ND | 0.56 | 0.93 | 0.3 | Mammalian | Expressed in many tissues, most strongly in kidney, pancreas, brain, lung, and liver. | Kinase | Note=ACVRIB is abundantly expressed in systemic sclerosis patient fibroblasts and production of collagen is also induced by activin-A/INHBA. This suggests that the activin/ACRV1B signaling mechanism is involved in systemic sclerosis. {ECO:0000269|PubMed:21377836}. | Transmembrane serine/threonine kinase activin type-1 receptor forming an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating a many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, type-2 receptors (ACVR2A and/or ACVR2B) act as a primary activin receptors whereas the type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine- threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor such as ACVR1B. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C- terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor. ACVR1B also phosphorylates TDP2. {ECO:0000269|PubMed:12364468, ECO:0000269|PubMed:12639945, ECO:0000269|PubMed:18039968, ECO:0000269|PubMed:20226172, ECO:0000269|PubMed:8196624, ECO:0000269|PubMed:9032295, ECO:0000269|PubMed:9892009}. | 16.04 | |||
| dfaACVL1 | Serine/threonine-protein kinase receptor R3 | 5 | 76 | 99.16 | 96.46 | ND | 0.73 | 0.96 | 0.5 | Mammalian | Kinase | Telangiectasia, hereditary hemorrhagic, 2 (HHT2) [MIM:600376]: A multisystemic vascular dysplasia leading to dilation of permanent blood vessels and arteriovenous malformations of skin, mucosa, and viscera. The disease is characterized by recurrent epistaxis and gastro-intestinal hemorrhage. Visceral involvement includes arteriovenous malformations of the lung, liver, and brain. {ECO:0000269|PubMed:10694922, ECO:0000269|PubMed:10767348, ECO:0000269|PubMed:11170071, ECO:0000269|PubMed:11484689, ECO:0000269|PubMed:14684682, ECO:0000269|PubMed:15024723, ECO:0000269|PubMed:15712270, ECO:0000269|PubMed:16525724, ECO:0000269|PubMed:16752392, ECO:0000269|PubMed:20414677, ECO:0000269|PubMed:26176610, ECO:0000269|PubMed:8640225, ECO:0000269|PubMed:9245985}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. May bind activin as well. {ECO:0000269|PubMed:22718755, ECO:0000269|PubMed:22799562, ECO:0000269|PubMed:26176610}. | 16.04 | ||||
| dfaACVR1 | Activin receptor type-1 | 6 | 188 | 92.32 | 89.45 | ND | 0.58 | 0.76 | 0.5 | Mammalian | Expressed in normal parenchymal cells, endothelial cells, fibroblasts and tumor-derived epithelial cells. | Kinase | Fibrodysplasia ossificans progressiva (FOP) [MIM:135100]: A rare autosomal dominant connective tissue disorder resulting in skeletal malformations and progressive extraskeletal ossification. Heterotopic ossification begins in childhood and can be induced by trauma or may occur without warning. Bone formation is episodic and progressive, leading to a debilitating ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible. {ECO:0000269|PubMed:16642017, ECO:0000269|PubMed:19085907, ECO:0000269|PubMed:19330033}. Note=The disease is caused by mutations affecting the gene represented in this entry. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin. May be involved for left-right pattern formation during embryogenesis (By similarity). {ECO:0000250}. | Activin receptor type-1 unknown: Adenosine triphosphate | 15.11 | ||
| dfaADA | Adenosine deaminase | 2 | 437 | 93.66 | 96.44 | ND | 0.66 | 0.72 | 0.7 | Mammalian | Found in all tissues, occurs in large amounts in T-lymphocytes and, at the time of weaning, in gastrointestinal tissues. | Hydrolase | Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-negative/NK-cell-negative due to adenosine deaminase deficiency (ADASCID) [MIM:102700]: An autosomal recessive disorder accounting for about 50% of non-X-linked SCIDs. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell- mediated cellular immunity due to a defect in T-cell development. ADA deficiency has been diagnosed in chronically ill teenagers and adults (late or adult onset). Population and newborn screening programs have also identified several healthy individuals with normal immunity who have partial ADA deficiency. {ECO:0000269|PubMed:10200056, ECO:0000269|PubMed:1284479, ECO:0000269|PubMed:2166947, ECO:0000269|PubMed:2783588, ECO:0000269|PubMed:3182793, ECO:0000269|PubMed:3839802, ECO:0000269|PubMed:6208479, ECO:0000269|PubMed:7599635, ECO:0000269|PubMed:8227344, ECO:0000269|PubMed:8299233}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the hydrolytic deamination of adenosine and 2- deoxyadenosine. Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4. Its interaction with DPP4 regulates lymphocyte- epithelial cell adhesion. {ECO:0000269|PubMed:11772392}. | Adenosine deaminase inhibitor: Dipyridamole, Edetic Acid, Pentostatin Adenosine deaminase inhibitor;inducer: Theophylline Adenosine deaminase substrate: Adenosine, Nelarabine, Vidarabine | 15.11 | ||
| dfaADA10 | Disintegrin and metalloproteinase domain-containing protein 10 | 1 | 112 | 99.76 | 97.97 | ND | 0.25 | 0.54 | 0.6 | Mammalian | Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver. {ECO:0000269|PubMed:11511685, ECO:0000269|PubMed:9016778}. | Protease | Reticulate acropigmentation of Kitamura (RAK) [MIM:615537]: A rare cutaneous pigmentation disorder characterized by reticulate, slightly depressed, sharply demarcated brown macules without hypopigmentation, affecting the dorsa of the hands and feet and appearing in the first or second decade of life. The macules gradually darken and extend to the proximal regions of the extremities. The manifestations tend to progress until middle age, after which progression of the eruptions stops. The pigmentary augmentation is found on the flexor aspects of the wrists, neck, patella and olecranon. Other features include breaks in the epidermal ridges on the palms and fingers, palmoplantar pits, occasionally plantar keratoderma, and partial alopecia. {ECO:0000269|PubMed:23666529}. Note=The disease is caused by mutations affecting the gene represented in this entry. Alzheimer disease 18 (AD18) [MIM:615590]: A late-onset form of Alzheimer disease, a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. {ECO:0000269|PubMed:19608551}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth- like factor, ephrin-A2 and for constitutive and regulated alpha- secretase cleavage of amyloid precursor protein (APP). Contributes to the normal cleavage of the cellular prion protein. Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity. Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis. Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form. Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B. May regulate the EFNA5-EPHA3 signaling. {ECO:0000269|PubMed:11477090, ECO:0000269|PubMed:11786905, ECO:0000269|PubMed:12475894, ECO:0000269|PubMed:16239146, ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:19114711, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:21288900}. | 16.04 | |||
| dfaADA17 | Disintegrin and metalloproteinase domain-containing protein 17 | 5 | 1423 | 95.53 | 98.85 | ND | 0.73 | 0.70 | 0.5 | Mammalian | Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney. | Protease | Inflammatory skin and bowel disease, neonatal, 1 (NISBD1) [MIM:614328]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269|PubMed:22010916}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2. {ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:24226769, ECO:0000269|PubMed:24227843}. | 15.11 | |||
| dfaADA1A | Alpha-1A adrenergic receptor | 4 | 1565 | 93.17 | 87.84 | ND | 0.65 | 0.68 | 0.7 | Nature11159 | Mammalian | Expressed in heart, brain, liver and prostate, but not in kidney, lung, adrenal, aorta and pituitary. Within the prostate, expressed in the apex, base, periurethral and lateral lobe. Isoform 4 is the most abundant isoform expressed in the prostate with high levels also detected in liver and heart. {ECO:0000269|PubMed:7737411, ECO:0000269|PubMed:8196478, ECO:0000269|PubMed:9490024}. | Anxiety Bradycardia Carbohydrate metabolism disorder Cerebral haemorrhage Dyskinesia Dysuria Ejaculation disorder Fear Gangrene Gestational hypertension Hyperhidrosis Hypertension Insomnia Intranasal paraesthesia Irritability Nasal congestion Nasal discomfort Nasal dryness Nervous system disorder Orthostatic hypotension Pallor Palpitations Psychotic disorder Pulmonary oedema Restlessness Sleep disorder Sneezing Sudden death Tachycardia Vasoconstriction Ventricular arrhythmia | Family A G protein-coupled receptor | Benign prostate hyperplasia
Hypertrophic vascular disease | This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes. {ECO:0000269|PubMed:18802028, ECO:0000269|PubMed:22120526}. | Alpha-1A adrenergic receptor : Chlorpromazine, Dextroamphetamine, Ephedrine, Fenoldopam, Phenylephrine, Sertindole Alpha-1A adrenergic receptor agonist: Amphetamine, Apraclonidine, Benzphetamine, Bromocriptine, Clonidine, Dipivefrin, Droxidopa, Epinephrine, Ergonovine, Isometheptene, Levonordefrin, Mephentermine, Metaraminol, Methoxamine, Midodrine, Naphazoline, Norepinephrine, Oxymetazoline, Pergolide, Phendimetrazine, Phenylpropanolamine, Pseudoephedrine, Tetryzoline, Xylometazoline Alpha-1A adrenergic receptor antagonist: Acepromazine, Alfuzosin, Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Bevantolol, Carvedilol, Clozapine, Dapiprazole, Desipramine, Doxazosin, Doxepin, Dronedarone, Droperidol, Ergoloid mesylate, Escitalopram, Flupentixol, Iloperidone, Imipramine, Labetalol, Maprotiline, Methotrimeprazine, Mianserin, Nefazodone, Nicardipine, Nicergoline, Nortriptyline, Olanzapine, Paliperidone, Phenoxybenzamine, Phentolamine, Prazosin, Promazine, Propiomazine, Quetiapine, Risperidone, Silodosin, Tamsulosin, Terazosin, Thioproperazine, Thioridazine, Tolazoline, Trazodone, Trifluoperazine, Trimipramine, Ziprasidone, Zuclopenthixol Alpha-1A adrenergic receptor binder: Cabergoline, Citalopram, Loxapine, Mirtazapine Alpha-1A adrenergic receptor partial agonist: Ergotamine Alpha-1A adrenergic receptor unknown: Epinastine, Promethazine | 16.04 |
| dfaADA1B | Alpha-1B adrenergic receptor | 1 | 1126 | 92.18 | 87.51 | ND | 0.67 | 0.56 | 0.6 | Mammalian | Anxiety Bradycardia Cerebral haemorrhage Depressed level of consciousness Dyskinesia Ejaculation disorder Fear Gangrene Gestational hypertension Hyperhidrosis Intranasal paraesthesia Nasal congestion Nasal discomfort Nasal dryness Nervous system disorder Orthostatic hypotension Pallor Palpitations Pulmonary oedema Respiration abnormal Sneezing Tachycardia Vasoconstriction | Family A G protein-coupled receptor | Shy-Drager syndrome | This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine (PE)-stimulated ERK signaling in cardiac myocytes. {ECO:0000269|PubMed:18802028, ECO:0000269|PubMed:22120526}. | Alpha-1B adrenergic receptor : Fenoldopam, Phenylephrine, Sertindole Alpha-1B adrenergic receptor agonist: Bromocriptine, Clonidine, Droxidopa, Epinephrine, Methoxamine, Midodrine, Norepinephrine, Oxymetazoline, Pergolide, Phendimetrazine, Xylometazoline Alpha-1B adrenergic receptor antagonist: Acepromazine, Alfuzosin, Amitriptyline, Aripiprazole, Brexpiprazole, Carvedilol, Chlorpromazine, Clozapine, Dapiprazole, Dextroamphetamine, Doxazosin, Doxepin, Dronedarone, Imipramine, Lisdexamfetamine, Methotrimeprazine, Nicardipine, Nortriptyline, Olanzapine, Paliperidone, Phenoxybenzamine, Prazosin, Promazine, Propericiazine, Propiomazine, Quetiapine, Risperidone, Silodosin, Tamsulosin, Terazosin, Thioproperazine, Thioridazine, Trimipramine, Ziprasidone Alpha-1B adrenergic receptor binder: Cabergoline, Loxapine Alpha-1B adrenergic receptor other/unknown: Nefazodone Alpha-1B adrenergic receptor partial agonist: Ergotamine, Modafinil | 16.04 | ||
| dfaADA1D | Alpha-1D adrenergic receptor | 6 | 1139 | 90.38 | 92.80 | ND | 0.77 | 0.70 | 0.6 | Mammalian | Anxiety Bradycardia Cerebral haemorrhage Dyskinesia Fear Gestational hypertension Hyperhidrosis Intranasal paraesthesia Nasal congestion Nasal dryness Neurosis Orthostatic hypotension Pallor Palpitations Tachycardia Vasoconstriction | Family A G protein-coupled receptor | Hypertension | This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium. | Alpha-1D adrenergic receptor : Dronedarone, Fenoldopam, Phenylephrine, Sertindole Alpha-1D adrenergic receptor agonist: Bromocriptine, Clonidine, Droxidopa, Midodrine, Norepinephrine, Oxymetazoline, Pergolide, Xylometazoline Alpha-1D adrenergic receptor antagonist: Alfuzosin, Amitriptyline, Carvedilol, Dapiprazole, Doxazosin, Doxepin, Epinephrine, Imipramine, Methotrimeprazine, Nicardipine, Nortriptyline, Phenoxybenzamine, Prazosin, Promazine, Propiomazine, Quetiapine, Silodosin, Tamsulosin, Terazosin Alpha-1D adrenergic receptor binder: Cabergoline, Methoxamine Alpha-1D adrenergic receptor partial agonist: Ergotamine | 16.04 | ||
| dfaADA2A | Alpha-2A adrenergic receptor | 5 | 799 | 85.06 | 84.50 | ND | 0.62 | 0.72 | 0.7 | Nature11159 | Mammalian | Bradycardia Cerebral haemorrhage Depressed level of consciousness Dyskinesia Ejaculation disorder Fear Gangrene Gestational hypertension Hallucination Intranasal paraesthesia Nasal congestion Nasal discomfort Nasal dryness Nervous system disorder Neurosis Orthostatic hypotension Pallor Palpitations Priapism Respiration abnormal Sneezing Somnolence Urinary incontinence Vasoconstriction | Family A G protein-coupled receptor | Heart failure
Hypertension Ischemic heart disease | Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol. {ECO:0000269|PubMed:23105096}. | Alpha-2A adrenergic receptor : Chlorpromazine, Dronedarone, Flupirtine, Lurasidone, Methyldopa Alpha-2A adrenergic receptor agonist: Apomorphine, Apraclonidine, Benzphetamine, Bethanidine, Brimonidine, Bromocriptine, Clonidine, Dexmedetomidine, Dihydroergotamine, Dipivefrin, Droxidopa, Ephedra, Epinephrine, Guanabenz, Guanfacine, Lofexidine, Methamphetamine, Naphazoline, Norepinephrine, Oxymetazoline, Pergolide, Phenylpropanolamine, Pseudoephedrine, Ropinirole, Tizanidine, Xylometazoline Alpha-2A adrenergic receptor antagonist: Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Cabergoline, Carvedilol, Clozapine, Doxepin, Ergoloid mesylate, Fenoldopam, Maprotiline, Methotrimeprazine, Mianserin, Mirtazapine, Nefazodone, Nortriptyline, Olanzapine, Paliperidone, Phenoxybenzamine, Phentolamine, Propericiazine, Quetiapine, Risperidone, Tolazoline, Trazodone, Yohimbine, Ziprasidone, Zuclopenthixol Alpha-2A adrenergic receptor binder: Desipramine, Loxapine, Prazosin Alpha-2A adrenergic receptor desensitize the target: Trimipramine Alpha-2A adrenergic receptor other/unknown: Lisuride Alpha-2A adrenergic receptor partial agonist: Ergotamine, Pramipexole Alpha-2A adrenergic receptor unknown: Epinastine | 16.04 | |
| dfaADA2B | Alpha-2B adrenergic receptor | 7 | 403 | 80.88 | 82.34 | ND | 0.76 | 0.67 | 0.5 | Nature11159 | Mammalian | Bradycardia Cerebral haemorrhage Depressed level of consciousness Dyskinesia Fear Gestational hypertension Hallucination Intranasal paraesthesia Nasal congestion Nasal dryness Neurosis Orthostatic hypotension Pallor Respiration abnormal Sneezing Urinary incontinence Vasoconstriction | Family A G protein-coupled receptor | Epilepsy, familial adult myoclonic, 2 (FAME2) [MIM:607876]: A form of cortical myoclonic tremor with epilepsy, a syndrome characterized by cortical myoclonus and variable occurrence of epileptic seizures. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom; both complex partial as well as generalized tonic clonic seizures are described. Some patients exhibit mild cognitive impairment. {ECO:0000269|PubMed:24114805}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine > norepinephrine > epinephrine = oxymetazoline > dopamine > p-tyramine = phenylephrine > serotonin > p-synephrine / p-octopamine. For antagonists, the rank order is yohimbine > chlorpromazine > phentolamine > mianserine > spiperone > prazosin > alprenolol > propanolol > pindolol. {ECO:0000269|PubMed:23105096}. | Alpha-2B adrenergic receptor : Dronedarone Alpha-2B adrenergic receptor agonist: Apomorphine, Apraclonidine, Brimonidine, Bromocriptine, Clonidine, Droxidopa, Ephedra, Epinephrine, Ergotamine, Etomidate, Methamphetamine, Norepinephrine, Pergolide, Ropinirole, Tizanidine, Xylometazoline Alpha-2B adrenergic receptor antagonist: Aripiprazole, Asenapine, Cabergoline, Carvedilol, Clozapine, Doxepin, Fenoldopam, Methotrimeprazine, Mianserin, Olanzapine, Paliperidone, Phenoxybenzamine, Quetiapine, Risperidone, Rotigotine, Yohimbine, Ziprasidone Alpha-2B adrenergic receptor binder: Guanabenz, Guanfacine, Loxapine, Oxymetazoline, Prazosin, Tolazoline Alpha-2B adrenergic receptor other/unknown: Lisuride, Trimipramine Alpha-2B adrenergic receptor partial agonist: Alpha-2B adrenergic receptor unknown: Pramipexole | 16.04 | |
| dfaADA2C | Alpha-2C adrenergic receptor | 7 | 460 | 83.34 | 84.22 | ND | 0.68 | 0.72 | 0.7 | Nature11159 | Mammalian | Bradycardia Cerebral haemorrhage Depressed level of consciousness Dyskinesia Fear Gestational hypertension Hallucination Intranasal paraesthesia Nasal congestion Nasal dryness Neurosis Orthostatic hypotension Pallor Priapism Respiration abnormal Sneezing Somnolence Urinary incontinence Vasoconstriction | Family A G protein-coupled receptor | Neuropsychiatric disorders
Raynaud's syndrome | Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. | Alpha-2C adrenergic receptor : Dronedarone Alpha-2C adrenergic receptor agonist: Apomorphine, Brimonidine, Bromocriptine, Clonidine, Droxidopa, Ephedra, Epinephrine, Methamphetamine, Norepinephrine, Oxymetazoline, Paliperidone, Pergolide, Risperidone, Ropinirole, Tizanidine, Xylometazoline Alpha-2C adrenergic receptor antagonist: Aripiprazole, Asenapine, Brexpiprazole, Cabergoline, Carvedilol, Clozapine, Doxepin, Fenoldopam, Iloperidone, Lurasidone, Methotrimeprazine, Mianserin, Olanzapine, Phenoxybenzamine, Quetiapine, Yohimbine, Ziprasidone Alpha-2C adrenergic receptor binder: Loxapine, Mirtazapine, Tolazoline Alpha-2C adrenergic receptor other/unknown: Lisuride Alpha-2C adrenergic receptor unknown: Pramipexole | 16.04 | |
| dfaADCK3 | Atypical kinase ADCK3, mitochondrial {ECO:0000305} | 4 | 67 | 99.91 | 97.61 | ND | 0.62 | 0.66 | 0.2 | Mammalian | Widely expressed, with highest levels in adrenal gland, heart, pancreas, nasal mucosa, stomach, uterus and skeletal muscle. {ECO:0000269|PubMed:24270420}. | Enzyme | Coenzyme Q10 deficiency, primary, 4 (COQ10D4) [MIM:612016]: An autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Patient manifest gait ataxia and cerebellar atrophy with slow progression. Additional features include brisk tendon reflexes and Hoffmann sign, variable psychomotor retardation and variable seizures. {ECO:0000269|PubMed:18319072, ECO:0000269|PubMed:18319074, ECO:0000269|PubMed:20580948, ECO:0000269|PubMed:22036850, ECO:0000269|PubMed:24048965, ECO:0000269|PubMed:24218524}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration (PubMed:25498144). Its substrate specificity is unclear: either acts as protein kinase that phosphorylates other proteins in the CoQ complex to stabilize their interactions or acts as a small molecule kinase that phosphorylates a prenyl lipid in the ubiquinone biosynthesis pathway (PubMed:25498144). Shows an unusual selectivity for binding ADP over ATP (PubMed:25498144). {ECO:0000269|PubMed:25498144, ECO:0000305|PubMed:21296186, ECO:0000305|PubMed:25540914}. | 16.04 | |||
| dfaADCK4 | AarF domain-containing protein kinase 4 | 4 | 66 | 80.99 | 85.26 | ND | 0.84 | 0.90 | 0.2 | Mammalian | Widely expressed, including renal podocytes. {ECO:0000269|PubMed:24270420}. | Kinase | Nephrotic syndrome 9 (NPHS9) [MIM:615573]: A form of nephrotic syndrome, a renal disease clinically characterized by progressive renal failure, severe proteinuria, hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show focal segmental glomerulosclerosis. {ECO:0000269|PubMed:24270420}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May play a role in CoQ10 (COQ10A and/or COQ10B) biosynthesis, which is required for podocyte migration. {ECO:0000269|PubMed:24270420}. | 16.04 | |||
| dfaADCY1 | Adenylate cyclase type 1 | 1 | 48 | 99.96 | 99.92 | ND | 0.01 | 0.48 | 0.2 | Mammalian | Detected in zona glomerulosa and zona fasciculata in the adrenal gland (at protein level) (PubMed:11549699). Brain, retina and adrenal medulla. {ECO:0000269|PubMed:11549699, ECO:0000269|PubMed:8314585}. | Enzyme | Deafness, autosomal recessive, 44 (DFNB44) [MIM:610154]: A form of non-syndromic deafness characterized by prelingual profound hearing loss affecting all frequencies. {ECO:0000269|PubMed:24482543}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling. Mediates responses to increased cellular Ca(2+)/calmodulin levels (By similarity). May be involved in regulatory processes in the central nervous system. May play a role in memory and learning. Plays a role in the regulation of the circadian rhythm of daytime contrast sensitivity probably by modulating the rhythmic synthesis of cyclic AMP in the retina (By similarity). {ECO:0000250|UniProtKB:O88444, ECO:0000250|UniProtKB:P19754}. | Adenylate cyclase type 1 product of: Adenosine monophosphate | 16.04 | ||
| dfaADCY5 | Adenylate cyclase type 5 | 4 | 55 | 97.32 | 99.21 | ND | 0.92 | 0.88 | 0.3 | Mammalian | Detected in pancreas islets (at protein level). Detected in pancreas islets. {ECO:0000269|PubMed:24740569}. | Enzyme | Dyskinesia, familial, with facial myokymia (FDFM) [MIM:606703]: A disorder characterized by predominantly perioral and periorbital myokymia, and face, neck and upper limb dystonic/choreic movements. Initially paroxysmal and worsened by stress, the dyskinetic episodes become nearly constant by the end of the third decade of life, but in some individuals, they may diminish in frequency and severity at older ages. {ECO:0000269|PubMed:22782511, ECO:0000269|PubMed:24700542}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:15385642, PubMed:26206488, PubMed:24700542). Mediates signaling downstream of ADRB1 (PubMed:24700542). Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (PubMed:24740569). {ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:24700542, ECO:0000269|PubMed:24740569, ECO:0000269|PubMed:26206488}. | 16.04 | |||
| dfaADK | Adenosine kinase | 3 | 436 | 96.89 | 95.55 | ND | 0.76 | 0.68 | 0.6 | Mammalian | Widely expressed. Highest level in placenta, liver, muscle and kidney. | Enzyme | Hypermethioninemia due to adenosine kinase deficiency (HMAKD) [MIM:614300]: A metabolic disorder characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S- adenosylmethionine and S-adenosylhomocysteine. Homocysteine levels are typically normal. {ECO:0000269|PubMed:21963049}. Note=The disease is caused by mutations affecting the gene represented in this entry. | ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives. Serves as a potential regulator of concentrations of extracellular adenosine and intracellular adenine nucleotides. | Adenosine kinase activator: Ribavirin Adenosine kinase product of: Adenosine monophosphate Adenosine kinase substrate: Abacavir, Adenosine, Adenosine triphosphate, Ribavirin | 15.11 | ||
| dfaADRB1 | Beta-1 adrenergic receptor | 4 | 1205 | 93.69 | 94.41 | ND | 0.68 | 0.38 | 0.6 | Nature11159 | Mammalian | Angina pectoris Anxiety Arrhythmia Asthenia Atrioventricular block Bradycardia Bronchospasm Cardiac failure Cardiac failure congestive Deafness transitory Dry eye Fear Hallucination Lung disorder Metabolic disorder Neurotoxicity Palpitations Peripheral coldness Psychotic disorder Raynaud's phenomenon Sleep disorder | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Asthma Cardiac arrhythmias Cardiovascular disease, unspecified Coronary heart disease Dilated cardiomyopathy Glaucoma Hypertension | Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. Mediates Ras activation through G(s)-alpha- and cAMP-mediated signaling. {ECO:0000269|PubMed:12391161}. | Beta-1 adrenergic receptor : Dronedarone, Olanzapine Beta-1 adrenergic receptor agonist: Amphetamine, Arbutamine, Clenbuterol, Dobutamine, Droxidopa, Ephedra, Epinephrine, Fenoterol, Isoetarine, Isoprenaline, Mephentermine, Norepinephrine, Phenylpropanolamine, Pirbuterol, Pseudoephedrine, Salbutamol Beta-1 adrenergic receptor antagonist: Alprenolol, Amiodarone, Asenapine, Atenolol, Betaxolol, Bethanidine, Bevantolol, Bisoprolol, Bupranolol, Carvedilol, Celiprolol, Esmolol, Labetalol, Levobunolol, Metipranolol, Metoprolol, Nadolol, Nebivolol, Nortriptyline, Oxprenolol, Penbutolol, Practolol, Propranolol, Sotalol, Timolol Beta-1 adrenergic receptor binder: Amitriptyline, Cabergoline, Loxapine, Mirtazapine, Trimipramine Beta-1 adrenergic receptor ligand: Vortioxetine Beta-1 adrenergic receptor other: Desipramine Beta-1 adrenergic receptor partial agonist: Acebutolol, Bopindolol, Carteolol, Pindolol | 16.04 | |
| dfaADRB2 | Beta-2 adrenergic receptor | 3 | 1866 | 89.89 | 88.87 | ND | 0.61 | 0.66 | 0.8 | Nature11159 | Mammalian | Angina pectoris Anxiety Arrhythmia Atrioventricular block Bradycardia Bronchospasm Cardiac arrest Cardiac failure Cardiac failure congestive Dry eye Fear Myocardial infarction Neurotoxicity Palpitations Peripheral coldness Raynaud's phenomenon Sleep disorder Tachycardia Tension Tremor Vasodilatation Ventricular arrhythmia | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Asthma Cardiac arrhythmias Chronic obstructive pulmonary disease, unspecified Depression Glaucoma Hypertension Inflammation Multiple sclerosis Obstructive airway disease Respiratory distress syndrome Skeletal muscle wasting Skeletal muscle weakness | Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine. | Beta-2 adrenergic receptor agonist: Amphetamine, Arbutamine, Arformoterol, Bambuterol, Clenbuterol, Dipivefrin, Dobutamine, Droxidopa, Epinephrine, Fenoterol, Formoterol, Indacaterol, Isoetarine, Isoprenaline, Mephentermine, Norepinephrine, Olodaterol, Orciprenaline, Phenylpropanolamine, Pirbuterol, Procaterol, Ritodrine, Salbutamol, Salmeterol, Terbutaline Beta-2 adrenergic receptor antagonist: Alprenolol, Asenapine, Betaxolol, Bethanidine, Bevantolol, Bisoprolol, Bupranolol, Carteolol, Carvedilol, Desipramine, Labetalol, Levobunolol, Metipranolol, Metoprolol, Nadolol, Nebivolol, Nortriptyline, Oxprenolol, Propranolol, Sotalol, Timolol Beta-2 adrenergic receptor antagonist;partial agonist: Penbutolol Beta-2 adrenergic receptor binder: Amitriptyline, Cabergoline, Mirtazapine, Trimipramine Beta-2 adrenergic receptor partial agonist: Acebutolol, Bopindolol, Pindolol, Pseudoephedrine Beta-2 adrenergic receptor unknown: Atenolol, Olanzapine, Phenoxybenzamine | 15.11 | |
| dfaADRB3 | Beta-3 adrenergic receptor | 1 | 1058 | 99.24 | 98.91 | ND | 0.58 | 0.60 | 0.7 | Nature11159 | Mammalian | Expressed mainly in adipose tissues. | Angina pectoris Arrhythmia Atrioventricular block Bradycardia Bronchospasm Cardiac failure Cardiac failure congestive Dry eye Hallucination Palpitations Peripheral coldness Psychotic disorder Raynaud's phenomenon Sleep disorder | Family A G protein-coupled receptor | Cardiac arrhythmias
Erectile dysfunction Gain weight in patients with morbid obesity Hypertension Hypertonicity of bladder Noninsulin-dependent diabetes mellitus Obesity Overactive bladder disorder | Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. Beta-3 is involved in the regulation of lipolysis and thermogenesis. | Beta-3 adrenergic receptor : Bopindolol Beta-3 adrenergic receptor agonist: Arbutamine, Clenbuterol, Droxidopa, Ephedra, Epinephrine, Fenoterol, Isoprenaline, Mirabegron, Norepinephrine Beta-3 adrenergic receptor antagonist: Bupranolol, Propranolol | 16.04 |
| dfaAGTR1 | Type-1 angiotensin II receptor | 2 | 1515 | 97.73 | 96.67 | ND | 0.73 | 0.62 | 0.7 | Nature11159 | Mammalian | Liver, lung, adrenal and adrenocortical adenomas. | Dizziness | Family A G protein-coupled receptor | Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. | Type-1 angiotensin II receptor antagonist: Azilsartan medoxomil, Candesartan, Eprosartan, Forasartan, Irbesartan, Losartan, Olmesartan, Saprisartan, Tasosartan, Telmisartan, Valsartan | 16.04 |
| dfaAGTR2 | Type-2 angiotensin II receptor | 4 | 493 | 95.78 | 98.63 | ND | 0.57 | 0.67 | 0.8 | Mammalian | In adult, highly expressed in myometrium with lower levels in adrenal gland and fallopian tube. Expressed in the cerebellum. Very highly expressed in fetal kidney and intestine. {ECO:0000269|PubMed:12089445}. | Family A G protein-coupled receptor | Hypertension | Receptor for angiotensin II. Cooperates with MTUS1 to inhibit ERK2 activation and cell proliferation. {ECO:0000269|PubMed:15123706}. | Type-2 angiotensin II receptor antagonist: Tasosartan | 16.04 | ||
| dfaAGTRA | Type-1A angiotensin II receptor | 1 | 130 | 99.02 | 99.70 | ND | 0.84 | 0.73 | 0.6 | Mammalian | Family A G protein-coupled receptor | Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. | 16.04 | |||||
| dfaAGTRB | Type-1B angiotensin II receptor | 1 | 315 | 99.42 | 99.20 | ND | 0.44 | 0.57 | 0.7 | Mammalian | Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. | 16.04 | ||||||
| dfaAK1A1 | Alcohol dehydrogenase [NADP(+)] | 6 | 86 | 97.86 | 99.66 | ND | 0.79 | 0.06 | 0.3 | Mammalian | Widely expressed. Highly expressed in kidney, salivary gland and liver. Detected in trachea, stomach, brain, lung, prostate, placenta, mammary gland, small intestine and lung. {ECO:0000269|PubMed:10510318, ECO:0000269|PubMed:11306097}. | Enzyme | Methanol Poisoning | Catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols. Catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol. Has broad substrate specificity. In vitro substrates include succinic semialdehyde, 4- nitrobenzaldehyde, 1,2-naphthoquinone, methylglyoxal, and D- glucuronic acid. Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs, including the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN). {ECO:0000269|PubMed:10510318, ECO:0000269|PubMed:11306097, ECO:0000269|PubMed:18276838}. | Alcohol dehydrogenase [NADP(+)] substrate: Doxorubicin Alcohol dehydrogenase [NADP(+)] unknown: Ethanol | 15.11 | ||
| dfaAK1BA | Aldo-keto reductase family 1 member B10 | 3 | 69 | 94.55 | 81.53 | ND | 0.79 | 0.09 | 0.5 | Mammalian | Found in many tissues. Highly expressed in small intestine, colon and adrenal gland. | Enzyme | Acts as all-trans-retinaldehyde reductase. Can efficiently reduce aliphatic and aromatic aldehydes, and is less active on hexoses (in vitro). May be responsible for detoxification of reactive aldehydes in the digested food before the nutrients are passed on to other organs. {ECO:0000269|PubMed:18087047}. | 15.11 | ||||
| dfaAK1C1 | Aldo-keto reductase family 1 member C1 | 6 | 162 | 98.02 | 97.33 | ND | 0.87 | 0.84 | 0.4 | Mammalian | Expressed in all tissues tested including liver, prostate, testis, adrenal gland, brain, uterus, mammary gland and keratinocytes. Highest levels found in liver, mammary gland and brain. {ECO:0000269|PubMed:11013348}. | Enzyme | Converts progesterone to its inactive form, 20-alpha- dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine, may have a role in the transport of bile. May have a role in monitoring the intrahepatic bile acid concentration. Has a low bile-binding ability. May play a role in myelin formation. {ECO:0000269|PubMed:11013348, ECO:0000269|PubMed:8573067}. | Aldo-keto reductase family 1 member C1 inhibitor: Acetylsalicylic acid, Salicylic acid | 15.11 | |||
| dfaAK1C2 | Aldo-keto reductase family 1 member C2 | 1 | 270 | 98.87 | 98.38 | ND | 0.84 | 0.71 | 0.3 | Mammalian | Expressed in fetal testes. Expressed in fetal and adult adrenal glands. {ECO:0000269|PubMed:21802064}. | Enzyme | 46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. {ECO:0000269|PubMed:21802064}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha- DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability. {ECO:0000269|PubMed:15929998, ECO:0000269|PubMed:17034817, ECO:0000269|PubMed:17442338, ECO:0000269|PubMed:8573067}. | Aldo-keto reductase family 1 member C2 inducer: Ursodeoxycholic acid | 15.11 | ||
| dfaAK1C3 | Aldo-keto reductase family 1 member C3 | 6 | 359 | 90.17 | 80.75 | ND | 0.57 | 0.66 | 0.5 | Mammalian | Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. The dominant HSD in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate. {ECO:0000269|PubMed:10557352, ECO:0000269|PubMed:10622721, ECO:0000269|PubMed:11165022, ECO:0000269|PubMed:7650035, ECO:0000269|PubMed:9415401, ECO:0000269|PubMed:9927279}. | Enzyme | Cancer, unspecific
Head and neck cancer | Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta- PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone. | Aldo-keto reductase family 1 member C3 substrate: Doxorubicin Aldo-keto reductase family 1 member C3 unknown: Bimatoprost | 15.11 | ||
| dfaAKT1 | RAC-alpha serine/threonine-protein kinase | 2 | 1451 | 93.89 | 89.19 | ND | 0.65 | 0.64 | 0.8 | Mammalian | Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. {ECO:0000269|PubMed:1718748, ECO:0000269|PubMed:17932490, ECO:0000269|PubMed:20333297}. | Kinase | Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:17611497}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The gene represented in this entry may be involved in disease pathogenesis. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Proteus syndrome (PROTEUSS) [MIM:176920]: A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes. {ECO:0000269|PubMed:21793738}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cowden syndrome 6 (CWS6) [MIM:615109]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. Note=The disease is caused by mutations affecting the gene represented in this entry. | AKT1 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)- response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr- 117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro- apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53. AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation. | RAC-alpha serine/threonine-protein kinase inducer: Arsenic trioxide RAC-alpha serine/threonine-protein kinase unknown: Adenosine triphosphate | 15.11 | ||
| dfaAKT2 | RAC-beta serine/threonine-protein kinase | 4 | 546 | 93.79 | 91.68 | ND | 0.64 | 0.74 | 0.6 | Mammalian | Expressed in all cell types so far analyzed. | Kinase | Note=Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, plays also a pivotal role in the biology of glioblastoma. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15166380, ECO:0000269|PubMed:19164855}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH) [MIM:240900]: A disorder characterized by hypoglycemia, low insulin levels, low serum levels of ketone bodies and branched-chain amino acids, left-sided hemihypertrophy, neonatal macrosomia, reduced consciousness and hypoglycemic seizures. {ECO:0000269|PubMed:21979934}. Note=The disease is caused by mutations affecting the gene represented in this entry. | AKT2 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)- response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'. | 15.11 | |||
| dfaAKT3 | RAC-gamma serine/threonine-protein kinase | 1 | 354 | 89.77 | 90.40 | ND | 0.77 | 0.79 | 0.5 | Mammalian | In adult tissues, it is highly expressed in brain, lung and kidney, but weakly in heart, testis and liver. In fetal tissues, it is highly expressed in heart, liver and brain and not at all in kidney. | Kinase | Note=AKT3 is a key modulator of several tumors like melanoma, glioma and ovarian cancer. Active AKT3 increases progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Promotes melanoma tumorigenesis by decreasing apoptosis. Plays a key role in the genesis of ovarian cancers through modulation of G2/M phase transition. With AKT2, plays a pivotal role in the biology of glioblastoma. Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MPPH2) [MIM:615937]: A syndrome characterized by megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome. {ECO:0000269|PubMed:22500628, ECO:0000269|PubMed:22729223, ECO:0000269|PubMed:22729224, ECO:0000269|PubMed:23745724}. Note=The disease is caused by mutations affecting the gene represented in this entry. | AKT3 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase- dependent apoptosis. {ECO:0000269|PubMed:18524868, ECO:0000269|PubMed:21191416}. | 16.04 | |||
| dfaAL5AP | Arachidonate 5-lipoxygenase-activating protein | 1 | 225 | 99.75 | 97.74 | ND | 0.67 | 0.58 | 0.7 | Mammalian | Other cytosolic protein | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Genetic variations in ALOX5AP may be associated with susceptibility to myocardial infarction. Involvement in myocardial infarction is however unclear: according to some authors (PubMed:14770184), a 4-SNP haplotype in ALOX5AP confers risk of myocardial infarction, while according to other (PubMed:17304054) ALOX5AP is not implicated in this condition. {ECO:0000269|PubMed:14770184, ECO:0000269|PubMed:17304054}. | Required for leukotriene biosynthesis by ALOX5 (5- lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, and could play an essential role in the transfer of arachidonic acid to ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of leukotrienes. {ECO:0000269|PubMed:2300173, ECO:0000269|PubMed:8440384}. | 16.04 | ||||
| dfaALBU | Serum albumin | 10 | 194 | 86.80 | 92.85 | ND | 0.30 | 0.71 | 0.4 | Mammalian | Plasma. | Secreted protein | Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc. | 15.11 | ||||
| dfaALDH2 | Aldehyde dehydrogenase, mitochondrial | 3 | 60 | 94.19 | 93.97 | ND | 0.03 | 0.62 | 0.7 | Mammalian | Oxidoreductase | Alcoholism | Aldehyde dehydrogenase, mitochondrial inhibitor: Disulfiram, Nitric Oxide Aldehyde dehydrogenase, mitochondrial substrate: Amyl Nitrite, Benzyl alcohol, Nitroglycerin Aldehyde dehydrogenase, mitochondrial unknown: Guanidine | 15.11 | ||||
| dfaALDOA | Fructose-bisphosphate aldolase A | 7 | 57 | 97.18 | 88.57 | ND | 0.05 | 0.82 | 0.4 | Mammalian | Enzyme | Glycogen storage disease 12 (GSD12) [MIM:611881]: A metabolic disorder associated with increased hepatic glycogen and hemolytic anemia. It may lead to myopathy with exercise intolerance and rhabdomyolysis. {ECO:0000269|PubMed:14615364, ECO:0000269|PubMed:14766013, ECO:0000269|PubMed:2825199, ECO:0000269|PubMed:8598869}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a key role in glycolysis and gluconeogenesis. In addition, may also function as scaffolding protein (By similarity). {ECO:0000250}. | 16.04 | ||||
| dfaALDR | Aldose reductase | 7 | 1393 | 96.55 | 92.08 | ND | 0.71 | 0.70 | 0.6 | Mammalian | Highly expressed in embryonic epithelial cells (EUE) in response to osmotic stress. {ECO:0000269|PubMed:8435445}. | Gastrointestinal disorder | Enzyme | Analgesics
Diabetic complications Diabetic neuropathy Diabetic retinopathy Neuropathic pain Noninsulin-dependent diabetes mellitus | Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies. | Aldose reductase inhibitor: Sulindac | 15.11 | |
| dfaALK | ALK tyrosine kinase receptor | 5 | 751 | 87.91 | 88.01 | ND | 0.78 | 0.77 | 0.6 | Mammalian | Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells. {ECO:0000269|PubMed:9174053}. | Kinase | Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. {ECO:0000269|PubMed:18724359, ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth. | Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK. {ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:11387242, ECO:0000269|PubMed:11809760, ECO:0000269|PubMed:12107166, ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:15908427, ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988}. | ALK tyrosine kinase receptor antagonist: Ceritinib ALK tyrosine kinase receptor inhibitor: Crizotinib ALK tyrosine kinase receptor unknown: Adenosine triphosphate | 15.11 | ||
| dfaALKB3 | Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 {ECO:0000305} | 1 | 41 | 99.99 | 99.91 | ND | 0.48 | 0.42 | 0.2 | Mammalian | Ubiquitous. Detected in heart, pancreas, skeletal muscle, thymus, testis, ovary, spleen, prostate, small intestine, peripheral blood leukocytes, urinary bladder and colon. {ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:16174769, ECO:0000269|PubMed:17979886}. | Enzyme | Dioxygenase that mediates demethylation of DNA and RNA containing 1-methyladenosine (m1A) (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410). Repairs alkylated DNA containing 1- methyladenosine (m1A) and 3-methylcytosine (m3C) by oxidative demethylation (PubMed:12486230, PubMed:12594517, PubMed:16174769). Has a strong preference for single-stranded DNA (PubMed:12486230, PubMed:12594517, PubMed:16174769). Able to process alkylated m3C within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKHB3 (PubMed:22055184). Also acts on RNA (PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410, PubMed:16858410). Demethylates N(1)- methyladenosine (m1A) RNA, an epigenetic internal modification of messenger RNAs (mRNAs) highly enriched within 5'-untranslated regions (UTRs) and in the vicinity of start codons (PubMed:26863196, PubMed:26863410). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:22055184, PubMed:16858410). {ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:12594517, ECO:0000269|PubMed:16174769, ECO:0000269|PubMed:16858410, ECO:0000269|PubMed:22055184, ECO:0000269|PubMed:26863196, ECO:0000269|PubMed:26863410}. | 16.04 | ||||
| dfaAMPB | Aminopeptidase B | 5 | 44 | 95.77 | 99.01 | ND | 0.76 | 0.63 | 0.4 | Mammalian | Protease | Exopeptidase which selectively removes arginine and/or lysine residues from the N-terminus of several peptide substrates including Arg(0)-Leu-enkephalin, Arg(0)-Met-enkephalin and Arg(- 1)-Lys(0)-somatostatin-14. Can hydrolyze leukotriene A4 (LTA-4) into leukotriene B4 (LTB-4) (By similarity). {ECO:0000250}. | 16.04 | |||||
| dfaAMPE | Glutamyl aminopeptidase | 1 | 48 | 89.84 | 93.84 | ND | 0.37 | 0.63 | 0.7 | Mammalian | Expressed by epithelial cells of the proximal tubule cells and the glomerulus of the nephron. Also found in a variety of other tissues. | Protease | Hypertension | Appears to have a role in the catabolic pathway of the renin-angiotensin system. Probably plays a role in regulating growth and differentiation of early B-lineage cells. | 15.11 | |||
| dfaAMPL | Cytosol aminopeptidase | 3 | 62 | 99.10 | 97.89 | ND | 0.32 | 0.56 | 1.3 | Mammalian | Protease | Presumably involved in the processing and regular turnover of intracellular proteins. Catalyzes the removal of unsubstituted N-terminal amino acids from various peptides. | 16.04 | |||||
| dfaAMPN | Aminopeptidase N | 5 | 692 | 95.93 | 95.51 | ND | 0.75 | 0.77 | 0.5 | Mammalian | Expressed in epithelial cells of the kidney, intestine, and respiratory tract; granulocytes, monocytes, fibroblasts, endothelial cells, cerebral pericytes at the blood- brain barrier, synaptic membranes of cells in the CNS. Also expressed in endometrial stromal cells, but not in the endometrial glandular cells. Found in the vasculature of tissues that undergo angiogenesis and in malignant gliomas and lymph node metastases from multiple tumor types but not in blood vessels of normal tissues. A soluble form has been found in plasma. It is found to be elevated in plasma and effusions of cancer patients. | Protease | Coronaviruses infections
Severe acute respiratory syndrome Tumors | Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. May play a critical role in the pathogenesis of cholesterol gallstone disease. May be involved in the metabolism of regulatory peptides of diverse cell types, responsible for the processing of peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines. Found to cleave antigen peptides bound to major histocompatibility complex class II molecules of presenting cells and to degrade neurotransmitters at synaptic junctions. Is also implicated as a regulator of IL-8 bioavailability in the endometrium, and therefore may contribute to the regulation of angiogenesis. Is used as a marker for acute myeloid leukemia and plays a role in tumor invasion. In case of human coronavirus 229E (HCoV-229E) infection, serves as receptor for HCoV-229E spike glycoprotein. Mediates as well human cytomegalovirus (HCMV) infection. {ECO:0000269|PubMed:10605003, ECO:0000269|PubMed:10676659, ECO:0000269|PubMed:11384645, ECO:0000269|PubMed:12473585, ECO:0000269|PubMed:9056417}. (Microbial infection) Acts as a receptor for human coronavirus 229E/HCoV-229E. {ECO:0000269|PubMed:12551991, ECO:0000269|PubMed:1350662}. | Aminopeptidase N inhibitor: Icatibant Aminopeptidase N other: Ezetimibe | 15.11 | ||
| dfaAMYP | Pancreatic alpha-amylase | 3 | 51 | 100.00 | 99.67 | ND | 0.94 | 0.90 | 0.4 | Mammalian | Hydrolase | Hypoglycemia
Pancreatic disease | Pancreatic alpha-amylase inhibitor: Acarbose Pancreatic alpha-amylase unknown: Miglitol | 15.11 | ||||
| dfaANDR | Androgen receptor | 4 | 1678 | 89.24 | 85.30 | ND | 0.66 | 0.66 | 0.6 | Nature11159 VirtualToxLab | Mammalian | Isoform 2 is mainly expressed in heart and skeletal muscle. {ECO:0000269|PubMed:15634333}. | Acne Amenorrhoea Azoospermia Bone disorder Breast pain Cushingoid Depression Electrolyte imbalance Endocrine disorder Epiphyses premature fusion Gynaecomastia Hepatic function abnormal Hirsutism Hypercalcaemia Infertility Jaundice cholestatic Libido decreased Menstrual disorder Metrorrhagia Oedema Osteoporosis Priapism Virilism Weight increased | Nuclear receptor | Androgen insensitivity syndrome (AIS) [MIM:300068]: An X- linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10221770, ECO:0000269|PubMed:10404311, ECO:0000269|PubMed:10458483, ECO:0000269|PubMed:10571951, ECO:0000269|PubMed:10590024, ECO:0000269|PubMed:10690872, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:11744994, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1426313, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:1464650, ECO:0000269|PubMed:1480178, ECO:0000269|PubMed:1487249, ECO:0000269|PubMed:1569163, ECO:0000269|PubMed:1609793, ECO:0000269|PubMed:1775137, ECO:0000269|PubMed:1999491, ECO:0000269|PubMed:2082179, ECO:0000269|PubMed:2594783, ECO:0000269|PubMed:7537149, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7633398, ECO:0000269|PubMed:7641413, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7962294, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:7981689, ECO:0000269|PubMed:7993455, ECO:0000269|PubMed:8040309, ECO:0000269|PubMed:8096390, ECO:0000269|PubMed:8103398, ECO:0000269|PubMed:8162033, ECO:0000269|PubMed:8224266, ECO:0000269|PubMed:8281140, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8413310, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8626869, ECO:0000269|PubMed:8647313, ECO:0000269|PubMed:8683794, ECO:0000269|PubMed:8723113, ECO:0000269|PubMed:8768864, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8830623, ECO:0000269|PubMed:8918984, ECO:0000269|PubMed:8990010, ECO:0000269|PubMed:9001799, ECO:0000269|PubMed:9007482, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9106550, ECO:0000269|PubMed:9160185, ECO:0000269|PubMed:9252933, ECO:0000269|PubMed:9255042, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9328206, ECO:0000269|PubMed:9544375, ECO:0000269|PubMed:9554754, ECO:0000269|PubMed:9610419, ECO:0000269|PubMed:9627582, ECO:0000269|PubMed:9698822, ECO:0000269|PubMed:9788719, ECO:0000269|PubMed:9851768, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.109, ECO:0000269|Ref.175}. Note=The disease is caused by mutations affecting the gene represented in this entry. Spinal and bulbar muscular atrophy X-linked 1 (SMAX1) [MIM:313200]: An X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. {ECO:0000269|PubMed:15851746}. Note=The disease is caused by mutations affecting the gene represented in this entry. Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. Note=Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. Androgen insensitivity, partial (PAIS) [MIM:312300]: A disorder that is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10470409, ECO:0000269|PubMed:10502786, ECO:0000269|PubMed:10543676, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:1303262, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1424203, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:2010552, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7649358, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7909256, ECO:0000269|PubMed:7910529, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:8033918, ECO:0000269|PubMed:8097257, ECO:0000269|PubMed:8126121, ECO:0000269|PubMed:8205256, ECO:0000269|PubMed:8281139, ECO:0000269|PubMed:8325932, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8550758, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8823308, ECO:0000269|PubMed:8824883, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9196614, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9329414, ECO:0000269|PubMed:9543136, ECO:0000269|PubMed:9607727, ECO:0000269|PubMed:9768671, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.117}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. {ECO:0000269|PubMed:14664718, ECO:0000269|PubMed:15563469, ECO:0000269|PubMed:17591767, ECO:0000269|PubMed:17911242, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:19345326, ECO:0000269|PubMed:20980437}. | Androgen receptor agonist: Danazol, Drostanolone, Fludrocortisone, Fluoxymesterone, Levonorgestrel, Methyltestosterone, Nandrolone decanoate, Nandrolone phenpropionate, Oxandrolone, Testosterone, Testosterone Propionate Androgen receptor antagonist: Bicalutamide, Cyproterone acetate, Drospirenone, Flutamide, Nilutamide, Spironolactone Androgen receptor binder: Ketoconazole Androgen receptor inhibitor: Enzalutamide | 15.11 |
| dfaANKK1 | Ankyrin repeat and protein kinase domain-containing protein 1 | 3 | 64 | 84.78 | 93.34 | ND | 0.48 | 0.98 | 0.4 | Mammalian | Highly expressed in brain and weakly expressed in placenta and spinal cord. {ECO:0000269|PubMed:14741327, ECO:0000269|PubMed:15146457}. | Kinase | 16.04 | |||||
| dfaANM1 | Protein arginine N-methyltransferase 1 | 5 | 56 | 99.23 | 93.26 | ND | 0.26 | 0.73 | 0.4 | Mammalian | Widely expressed. {ECO:0000269|PubMed:11097842}. | Writer | Arginine methyltransferase that methylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues present in proteins such as ESR1, histone H2, H3 and H4, PIAS1, HNRNPA1, HNRNPD, NFATC2IP, SUPT5H, TAF15 and EWS. Constitutes the main enzyme that mediates monomethylation and asymmetric dimethylation of histone H4 'Arg-4' (H4R3me1 and H4R3me2a, respectively), a specific tag for epigenetic transcriptional activation. Together with dimethylated PIAS1, represses STAT1 transcriptional activity, in the late phase of interferon gamma (IFN-gamma) signaling. May be involved in the regulation of TAF15 transcriptional activity, act as an activator of estrogen receptor (ER)-mediated transactivation, play a key role in neurite outgrowth and act as a negative regulator of megakaryocytic differentiation, by modulating p38 MAPK pathway. Methylates FOXO1 and retains it in the nucleus increasing its transcriptional activity. Methylates CHTOP and this methylation is critical for its 5-hydroxymethylcytosine (5hmC)-binding activity (PubMed:25284789). Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner (PubMed:25284789). {ECO:0000269|PubMed:11387442, ECO:0000269|PubMed:11448779, ECO:0000269|PubMed:12718890, ECO:0000269|PubMed:18320585, ECO:0000269|PubMed:18657504, ECO:0000269|PubMed:18773938, ECO:0000269|PubMed:19124016, ECO:0000269|PubMed:19136629, ECO:0000269|PubMed:19405910, ECO:0000269|PubMed:20442406, ECO:0000269|PubMed:25284789}. | 16.04 | ||||
| dfaANM3 | Protein arginine N-methyltransferase 3 | 1 | 48 | 99.89 | 100.00 | ND | 0.48 | 0.82 | 0.4 | Mammalian | Writer | Methylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in some proteins. | 15.11 | |||||
| dfaAOC1 | Amiloride-sensitive amine oxidase [copper-containing] | 5 | 40 | 99.03 | 88.13 | ND | 0.62 | 0.67 | 0.4 | Mammalian | Placenta and kidney. | Enzyme | Catalyzes the degradation of compounds such as putrescine, histamine, spermine, and spermidine, substances involved in allergic and immune responses, cell proliferation, tissue differentiation, tumor formation, and possibly apoptosis. Placental DAO is thought to play a role in the regulation of the female reproductive function. | Amiloride-sensitive amine oxidase [copper-containing] inhibitor: Amiloride | 15.11 | |||
| dfaAOC3 | Membrane primary amine oxidase | 4 | 146 | 92.02 | 86.74 | ND | 0.56 | 0.64 | 0.7 | Mammalian | Strongly expressed on the high endothelial venules of peripheral lymph nodes and on hepatic endothelia. Also highly expressed in appendix, lung and small intestine. Expressed also in adipose tissue, in bone marrow, colon, heart, kidney, ovary, pancreas, placenta, prostate, skeletal muscle, spleen and testis. Isoform 2 seems to be the predominant transcript in fetal kidneys, fetal cartilage and fetal tonsils. The highest relative expression of isoform 2 occurs in skeletal muscle, heart, pancreas, kidney, and lung. {ECO:0000269|PubMed:17400359, ECO:0000269|PubMed:23349812, ECO:0000269|PubMed:9653080}. | Enzyme | Inflammation | Cell adhesion protein that participates in lymphocyte extravasation and recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin-independent fashion. Has semicarbazide-sensitive (SSAO) monoamine oxidase activity. May play a role in adipogenesis. {ECO:0000269|PubMed:17400359, ECO:0000269|PubMed:19588076, ECO:0000269|PubMed:23349812, ECO:0000269|PubMed:9653080}. | Membrane primary amine oxidase inhibitor: Hydralazine, Phenelzine | 16.04 | ||
| dfaAOFB | Amine oxidase [flavin-containing] B | 2 | 1951 | 94.68 | 82.97 | ND | 0.48 | 0.66 | 0.8 | Mammalian | Mania Psychotic disorder | Oxidoreductase | Major depressive disorder
Neurological diseases Parkinson's disease | Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine. | Amine oxidase [flavin-containing] B antagonist: Phenelzine, Phentermine Amine oxidase [flavin-containing] B inhibitor: Amantadine, Furazolidone, Isocarboxazid, Linezolid, Methamphetamine, Nandrolone decanoate, Nicotine, Pargyline, Phentermine, Rasagiline, Selegiline, Tranylcypromine, Zonisamide Amine oxidase [flavin-containing] B substrate: Dopamine, Phenelzine, Sertraline Amine oxidase [flavin-containing] B unknown: Amphetamine, Flavin adenine dinucleotide, Moclobemide, Procaine | 15.11 | ||
| dfaAPEX1 | DNA-(apurinic or apyrimidinic site) lyase | 4 | 446 | 84.72 | 83.62 | ND | 0.59 | 0.69 | 0.4 | Mammalian | Enzyme | Ovarian cancer
Tumors | Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 in DNA repair and redox regulation of transcriptional factors. Functions as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Does also incise at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Has a 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses a DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate) blocking the 3' side of DNA strand breaks. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Acts as a loading factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'- phosphate (dRp) excision activity of POLB. Plays a role in the protection from granzymes-mediated cellular repair leading to cell death. Also involved in the DNA cleavage step of class switch recombination (CSR). On the other hand, APEX1 also exerts reversible nuclear redox activity to regulate DNA binding affinity and transcriptional activity of transcriptional factors by controlling the redox status of their DNA-binding domain, such as the FOS/JUN AP-1 complex after exposure to IR. Involved in calcium-dependent down-regulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of transcriptional repression. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Acts also as an endoribonuclease involved in the control of single-stranded RNA metabolism. Plays a role in regulating MYC mRNA turnover by preferentially cleaving in between UA and CA dinucleotides of the MYC coding region determinant (CRD). In association with NMD1, plays a role in the rRNA quality control process during cell cycle progression. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA. Binds DNA and RNA. {ECO:0000269|PubMed:10023679, ECO:0000269|PubMed:11118054, ECO:0000269|PubMed:11452037, ECO:0000269|PubMed:11809897, ECO:0000269|PubMed:11832948, ECO:0000269|PubMed:12524539, ECO:0000269|PubMed:16617147, ECO:0000269|PubMed:1719477, ECO:0000269|PubMed:18179823, ECO:0000269|PubMed:18439621, ECO:0000269|PubMed:18579163, ECO:0000269|PubMed:18809583, ECO:0000269|PubMed:19188445, ECO:0000269|PubMed:19401441, ECO:0000269|PubMed:19934257, ECO:0000269|PubMed:20699270, ECO:0000269|PubMed:21496894, ECO:0000269|PubMed:21762700, ECO:0000269|PubMed:8355688, ECO:0000269|PubMed:8621488, ECO:0000269|PubMed:8932375, ECO:0000269|PubMed:9108029, ECO:0000269|PubMed:9207062, ECO:0000269|PubMed:9560228, ECO:0000269|PubMed:9804799}. | DNA-(apurinic or apyrimidinic site) lyase inhibitor: Lucanthone | 16.04 | |||
| dfaARBK1 | Beta-adrenergic receptor kinase 1 | 4 | 81 | 85.89 | 88.53 | ND | 0.62 | 0.77 | 0.4 | Mammalian | Expressed in peripheral blood leukocytes. {ECO:0000269|PubMed:10085131}. | Kinase | Congestive heart failure
Heart failure Hypertension Ventricular dysfunction | Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner. {ECO:0000269|PubMed:19306925}. | 16.04 | |||
| dfaARGI1 | Arginase-1 | 1 | 54 | 99.90 | 99.90 | ND | 0.76 | 0.43 | 0.2 | Mammalian | Enzyme | Argininemia (ARGIN) [MIM:207800]: A rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia and progressive spastic quadriplegia. {ECO:0000269|PubMed:1463019, ECO:0000269|PubMed:22959135, ECO:0000269|PubMed:23859858, ECO:0000269|PubMed:7649538}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Arginase-1 unknown: L-Ornithine | 15.11 | ||||
| dfaARGI2 | Arginase-2, mitochondrial | 1 | 41 | 99.93 | 99.96 | ND | 0.51 | 0.48 | 0.5 | Mammalian | Expressed most strongly in kidney and prostate, much less strongly in the brain, skeletal muscle, placenta, lung, mammary gland, macrophage, uterus, testis and gut, but apparently not in the liver, heart and pancreas. | Enzyme | Erectile dysfunction
Sexual arousal disorders | May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis. Extrahepatic arginase functions to regulate L-arginine bioavailability to NO synthase. Since NO synthase is found in the penile corpus cavernosum smooth muscle, the clitoral corpus cavernosum and the vagina, arginase II plays a role in both male and female sexual arousal. It is therefore a potential target for the treatment of male and female sexual arousal disorders. {ECO:0000269|PubMed:12859189}. | Arginase-2, mitochondrial : L-Arginine, L-Ornithine | 16.04 | ||
| dfaARY2 | Arylamine N-acetyltransferase 2 | 2 | 59 | 99.64 | 97.03 | ND | 0.36 | 0.52 | 0.3 | Mammalian | Enzyme | Participates in the detoxification of a plethora of hydrazine and arylamine drugs. Catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivate several known carcinogens. | Arylamine N-acetyltransferase 2 inhibitor: Acetaminophen Arylamine N-acetyltransferase 2 substrate: Clonazepam, Dapsone, Ezogabine, Isoniazid, Sulfamethoxazole | 16.04 | ||||
| dfaASIC3 | Acid-sensing ion channel 3 | 2 | 45 | 90.27 | 82.31 | ND | 0.71 | 0.71 | 0.4 | Mammalian | Expressed by sensory neurons. Strongly expressed in brain, spinal chord, lung, lymph nodes, kidney, pituitary, heart and testis. {ECO:0000269|PubMed:9571199, ECO:0000269|PubMed:9886053}. | Ligand-gated ion channel | Analgesics
Pain, unspecific | Cation channel with high affinity for sodium, which is gated by extracellular protons and inhibited by the diuretic amiloride. Generates a biphasic current with a fast inactivating and a slow sustained phase. In sensory neurons is proposed to mediate the pain induced by acidosis that occurs in ischemic, damaged or inflamed tissue. May be involved in hyperalgesia. May play a role in mechanoreception. Heteromeric channel assembly seems to modulate channel properties. {ECO:0000269|PubMed:9744806, ECO:0000269|PubMed:9886053}. | 16.04 | |||
| dfaAT1A1 | Sodium/potassium-transporting ATPase subunit alpha-1 | 1 | 44 | 99.80 | 99.97 | ND | 0.55 | 0.98 | 0.7 | Mammalian | This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients. | 15.11 | ||||||
| dfaATR | Serine/threonine-protein kinase ATR | 2 | 88 | 96.46 | 94.12 | ND | 0.65 | 0.74 | 0.7 | Mammalian | Ubiquitous, with highest expression in testis. Isoform 2 is found in pancreas, placenta and liver but not in heart, testis and ovary. {ECO:0000269|PubMed:11470508, ECO:0000269|PubMed:8610130, ECO:0000269|PubMed:8843195}. | Kinase | Seckel syndrome 1 (SCKL1) [MIM:210600]: A rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation. {ECO:0000269|PubMed:12640452}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cutaneous telangiectasia and cancer syndrome, familial (FCTCS) [MIM:614564]: A disease characterized by cutaneous telangiectases in infancy with patchy alopecia over areas of affected skin, thinning of the lateral eyebrows, and mild dental and nail anomalies. Affected individuals are at increased risk of developing oropharyngeal cancer, and other malignancies have been reported as well. {ECO:0000269|PubMed:22341969}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. {ECO:0000269|PubMed:10597277, ECO:0000269|PubMed:10608806, ECO:0000269|PubMed:10859164, ECO:0000269|PubMed:11114888, ECO:0000269|PubMed:11418864, ECO:0000269|PubMed:11673449, ECO:0000269|PubMed:11721054, ECO:0000269|PubMed:11865061, ECO:0000269|PubMed:12526805, ECO:0000269|PubMed:12791985, ECO:0000269|PubMed:12814551, ECO:0000269|PubMed:14657349, ECO:0000269|PubMed:14729973, ECO:0000269|PubMed:14742437, ECO:0000269|PubMed:15210935, ECO:0000269|PubMed:15314022, ECO:0000269|PubMed:15496423, ECO:0000269|PubMed:16260606, ECO:0000269|PubMed:21144835, ECO:0000269|PubMed:9427750, ECO:0000269|PubMed:9636169, ECO:0000269|PubMed:9925639}. | 16.04 | |||
| dfaATS4 | A disintegrin and metalloproteinase with thrombospondin motifs 4 | 4 | 196 | 93.62 | 95.68 | ND | 0.67 | 0.79 | 0.8 | Mammalian | Expressed in brain, lung and heart. Expressed at very low level in placenta and skeletal muscles. Isoform 2 is detected in osteoarthritic synovium. {ECO:0000269|PubMed:23897278}. | Protease | Osteoarthritis | Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. Could also be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease. Cleaves aggrecan at the '392-Glu-|-Ala-393' site. | A disintegrin and metalloproteinase with thrombospondin motifs 4 inhibitor: Tinzaparin | 15.11 | ||
| dfaATS5 | A disintegrin and metalloproteinase with thrombospondin motifs 5 | 6 | 378 | 93.25 | 85.81 | ND | 0.58 | 0.69 | 0.5 | Mammalian | Expressed at low level in placenta primarily but also detected in heart and brain, cervix, uterus, bladder, esophagus, rib cartilage, chondroblastoma, fibrous tissue and a joint capsule from an arthritic patient. | Protease | Osteoarthritis | Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. May play a role in proteolytic processing mostly during the peri-implantation period. | 15.11 | |||
| dfaAURKA | Aurora kinase A | 6 | 1914 | 93.96 | 93.35 | ND | 0.72 | 0.75 | 0.6 | Mammalian | Highly expressed in testis and weakly in skeletal muscle, thymus and spleen. Also highly expressed in colon, ovarian, prostate, neuroblastoma, breast and cervical cancer cell lines. | Kinase | Colorectal Cancer
Lymphoma, Unspecified Solid tumors | Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis. {ECO:0000269|PubMed:11039908, ECO:0000269|PubMed:11551964, ECO:0000269|PubMed:12390251, ECO:0000269|PubMed:13678582, ECO:0000269|PubMed:14523000, ECO:0000269|PubMed:14702041, ECO:0000269|PubMed:14990569, ECO:0000269|PubMed:15128871, ECO:0000269|PubMed:15147269, ECO:0000269|PubMed:15987997, ECO:0000269|PubMed:17125279, ECO:0000269|PubMed:17360485, ECO:0000269|PubMed:17604723, ECO:0000269|PubMed:18056443, ECO:0000269|PubMed:18615013, ECO:0000269|PubMed:19351716, ECO:0000269|PubMed:19357306, ECO:0000269|PubMed:19668197, ECO:0000269|PubMed:19812038, ECO:0000269|PubMed:20643351, ECO:0000269|PubMed:9606188}. | 15.11 | |||
| dfaAURKB | Aurora kinase B | 4 | 1476 | 91.37 | 88.42 | ND | 0.54 | 0.69 | 1.0 | Mammalian | High level expression seen in the thymus. It is also expressed in the spleen, lung, testis, colon, placenta and fetal liver. Expressed during S and G2/M phase and expression is up-regulated in cancer cells during M phase. {ECO:0000269|PubMed:9809983, ECO:0000269|PubMed:9858806}. | Kinase | Note=Disruptive regulation of expression is a possible mechanism of the perturbation of chromosomal integrity in cancer cells through its dominant-negative effect on cytokinesis. | Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis. Required for central/midzone spindle assembly and cleavage furrow formation. Key component of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage: phosphorylates CHMP4C, leading to retain abscission- competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis (PubMed:22422861, PubMed:24814515). AURKB phosphorylates the CPC complex subunits BIRC5/survivin, CDCA8/borealin and INCENP. Phosphorylation of INCENP leads to increased AURKB activity. Other known AURKB substrates involved in centromeric functions and mitosis are CENPA, DES/desmin, GPAF, KIF2C, NSUN2, RACGAP1, SEPT1, VIM/vimentin, GSG2/Haspin, and histone H3. A positive feedback loop involving GSG2 and AURKB contributes to localization of CPC to centromeres. Phosphorylation of VIM controls vimentin filament segregation in cytokinetic process, whereas histone H3 is phosphorylated at 'Ser-10' and 'Ser-28' during mitosis (H3S10ph and H3S28ph, respectively). A positive feedback between GSG2 and AURKB contributes to CPC localization. AURKB is also required for kinetochore localization of BUB1 and SGOL1. Phosphorylation of p53/TP53 negatively regulates its transcriptional activity. Key regulator of active promoters in resting B- and T-lymphocytes: acts by mediating phosphorylation of H3S28ph at active promoters in resting B-cells, inhibiting RNF2/RING1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes. {ECO:0000269|PubMed:11516652, ECO:0000269|PubMed:11756469, ECO:0000269|PubMed:11784863, ECO:0000269|PubMed:11856369, ECO:0000269|PubMed:12458200, ECO:0000269|PubMed:12686604, ECO:0000269|PubMed:12689593, ECO:0000269|PubMed:12925766, ECO:0000269|PubMed:14602875, ECO:0000269|PubMed:14610074, ECO:0000269|PubMed:14722118, ECO:0000269|PubMed:15020684, ECO:0000269|PubMed:15249581, ECO:0000269|PubMed:16103226, ECO:0000269|PubMed:17617734, ECO:0000269|PubMed:20959462, ECO:0000269|PubMed:21658950, ECO:0000269|PubMed:22422861, ECO:0000269|PubMed:24814515}. | 16.04 | |||
| dfaAURKC | Aurora kinase C | 6 | 104 | 94.61 | 89.93 | ND | 0.81 | 0.91 | 0.6 | Mammalian | Isoform 1 and isoform 2 are expressed in testis. Elevated expression levels were seen only in a subset of cancer cell lines such as Hep-G2, Huh-7 and HeLa. Expression is maximum at M phase. {ECO:0000269|PubMed:15670791}. | Kinase | Spermatogenic failure 5 (SPGF5) [MIM:243060]: An infertility disorder caused by spermatogenesis defects. Semen from affected men show close to 100% morphologically abnormal multiflagellar spermatozoa with low motility, oversized irregular heads, and abnormal midpiece and acrosome. {ECO:0000269|PubMed:17435757, ECO:0000269|PubMed:21733974}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Plays also a role in meiosis and more particularly in spermatogenesis. Has redundant cellular functions with AURKB and can rescue an AURKB knockdown. Like AURKB, AURKC phosphorylates histone H3 at 'Ser-10' and 'Ser-28'. Phosphorylates TACC1, another protein involved in cell division, at 'Ser-228'. {ECO:0000269|PubMed:15316025, ECO:0000269|PubMed:15499654, ECO:0000269|PubMed:15670791, ECO:0000269|PubMed:15938719, ECO:0000269|PubMed:21493633, ECO:0000269|PubMed:21531210}. | 16.04 | |||
| dfaB2CL1 | Bcl-2-like protein 1 | 1 | 266 | 98.68 | 93.74 | ND | 0.74 | 0.83 | 0.8 | Mammalian | Bcl-X(S) is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, Bcl-X(L) is found in tissues containing long-lived postmitotic cells, such as adult brain. | Other ion channel | Anaplastic Large Cell Lymphomas
Colorectal cancer Mesothelioma | Potent inhibitor of cell death. Inhibits activation of caspases. Appears to regulate cell death by blocking the voltage- dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis. Isoform Bcl-X(L) also regulates presynaptic plasticity, including neurotransmitter release and recovery, number of axonal mitochondria as well as size and number of synaptic vesicle clusters. During synaptic stimulation, increases ATP availability from mitochondria through regulation of mitochondrial membrane ATP synthase F(1)F(0) activity and regulates endocytic vesicle retrieval in hippocampal neurons through association with DMN1L and stimulation of its GTPase activity in synaptic vesicles. May attenuate inflammation impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785). {ECO:0000269|PubMed:17418785}. Isoform Bcl-X(S) promotes apoptosis. | 15.11 | |||
| dfaB2LA1 | Bcl-2-related protein A1 | 2 | 127 | 85.26 | 90.51 | ND | 0.05 | 0.57 | 0.4 | Mammalian | Seems to be restricted to the hematopoietic compartment. Expressed in peripheral blood, spleen, and bone marrow, at moderate levels in lung, small intestine and testis, at a minimal levels in other tissues. Also found in vascular smooth muscle cells and hematopoietic malignancies. | Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity). Can inhibit apoptosis induced by serum starvation in the mammary epithelial cell line HC11 (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q07440}. | 16.04 | |||||
| dfaBACE1 | Beta-secretase 1 | 2 | 2669 | 98.06 | 94.95 | ND | 0.64 | 0.58 | 0.7 | Mammalian | Expressed at high levels in the brain and pancreas. In the brain, expression is highest in the substantia nigra, locus coruleus and medulla oblongata. {ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:11083922}. | Protease | Alzheimer's disease | Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. {ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:20354142}. | 15.11 | |||
| dfaBACE2 | Beta-secretase 2 | 1 | 417 | 98.05 | 97.68 | ND | 0.43 | 0.68 | 0.5 | Mammalian | Brain. Present in neurons within the hippocampus, frontal cortex and temporal cortex (at protein level). Expressed at low levels in most peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at low levels in the brain. Found in spinal cord, medulla oblongata, substantia nigra and locus coruleus. Expressed in the ductal epithelium of both normal and malignant prostate. {ECO:0000269|PubMed:10591213, ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:10683441, ECO:0000269|PubMed:10749877, ECO:0000269|PubMed:10838186, ECO:0000269|PubMed:10965118, ECO:0000269|PubMed:11083922}. | Protease | Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C- terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672. {ECO:0000269|PubMed:10591213, ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:11423558, ECO:0000269|PubMed:15857888, ECO:0000269|PubMed:16816112}. | 15.11 | ||||
| dfaBAD | Bcl2-associated agonist of cell death | 4 | 54 | 99.57 | 99.77 | ND | 0.81 | 0.70 | 0.4 | Mammalian | Expressed in a wide variety of tissues. | Other cytosolic protein | Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathways. {ECO:0000250}. | 16.04 | ||||
| dfaBCL2 | Apoptosis regulator Bcl-2 | 1 | 388 | 97.75 | 94.66 | ND | 0.79 | 0.88 | 0.6 | Mammalian | Expressed in a variety of tissues. | Other ion channel | Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. | Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785). {ECO:0000269|PubMed:17418785, ECO:0000269|PubMed:18570871}. | Apoptosis regulator Bcl-2 modulator: Ibuprofen | 15.11 | ||
| dfaBGAL | Beta-galactosidase | 1 | 65 | 98.87 | 98.23 | ND | 0.49 | 0.71 | 0.5 | Mammalian | Enzyme | GM1-gangliosidosis 1 (GM1G1) [MIM:230500]: An autosomal recessive lysosomal storage disease marked by the accumulation of GM1 gangliosides, glycoproteins and keratan sulfate primarily in neurons of the central nervous system. GM1-gangliosidosis type 1 is characterized by onset within the first three months of life, central nervous system degeneration, coarse facial features, hepatosplenomegaly, skeletal dysmorphology reminiscent of Hurler syndrome, and rapidly progressive psychomotor deterioration. Urinary oligosaccharide levels are high. It leads to death usually between the first and second year of life. {ECO:0000269|PubMed:10338095, ECO:0000269|PubMed:10737981, ECO:0000269|PubMed:10839995, ECO:0000269|PubMed:1487238, ECO:0000269|PubMed:15365997, ECO:0000269|PubMed:15714521, ECO:0000269|PubMed:15791924, ECO:0000269|PubMed:16538002, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:1928092, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:25936995, ECO:0000269|PubMed:8213816, ECO:0000269|Ref.24, ECO:0000269|Ref.27}. Note=The disease is caused by mutations affecting the gene represented in this entry. GM1-gangliosidosis 2 (GM1G2) [MIM:230600]: A gangliosidosis characterized by onset between ages 1 and 5. The main symptom is locomotor ataxia, ultimately leading to a state of decerebration with epileptic seizures. Patients do not display the skeletal changes associated with the infantile form, but they nonetheless excrete elevated amounts of beta-linked galactose- terminal oligosaccharides. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10737981, ECO:0000269|PubMed:12644936, ECO:0000269|PubMed:15714521, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:25936995, ECO:0000269|PubMed:8213816}. Note=The disease is caused by mutations affecting the gene represented in this entry. GM1-gangliosidosis 3 (GM1G3) [MIM:230650]: A gangliosidosis with a variable phenotype. Patients show mild skeletal abnormalities, dysarthria, gait disturbance, dystonia and visual impairment. Visceromegaly is absent. Intellectual deficit can initially be mild or absent but progresses over time. Inheritance is autosomal recessive. {ECO:0000269|PubMed:11511921, ECO:0000269|PubMed:15986423, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:25936995, ECO:0000269|PubMed:8198123, ECO:0000269|Ref.24, ECO:0000269|Ref.26}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mucopolysaccharidosis 4B (MPS4B) [MIM:253010]: A form of mucopolysaccharidosis type 4, an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate. Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal and there is no direct central nervous system involvement, although the skeletal changes may result in neurologic complications. There is variable severity, but patients with the severe phenotype usually do not survive past the second or third decade of life. {ECO:0000269|PubMed:11511921, ECO:0000269|PubMed:12393180, ECO:0000269|PubMed:16538002, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:1928092, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:7586649}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans. Isoform 2 has no beta-galactosidase catalytic activity, but plays functional roles in the formation of extracellular elastic fibers (elastogenesis) and in the development of connective tissue. Seems to be identical to the elastin-binding protein (EBP), a major component of the non-integrin cell surface receptor expressed on fibroblasts, smooth muscle cells, chondroblasts, leukocytes, and certain cancer cell types. In elastin producing cells, associates with tropoelastin intracellularly and functions as a recycling molecular chaperone which facilitates the secretions of tropoelastin and its assembly into elastic fibers. | 15.11 | ||||
| dfaBIRC2 | Baculoviral IAP repeat-containing protein 2 | 1 | 190 | 99.87 | 99.47 | ND | 0.55 | 0.71 | 0.7 | Mammalian | Present in many fetal and adult tissues. Mainly expressed in adult skeletal muscle, thymus, testis, ovary, and pancreas, low or absent in brain and peripheral blood leukocytes. | Enzyme | Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin- protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin- protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO, IKBKE and MXD1/MAD1. Can also function as an E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase- dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle. {ECO:0000269|PubMed:15665297, ECO:0000269|PubMed:18082613, ECO:0000269|PubMed:21145488, ECO:0000269|PubMed:21653699, ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:23453969}. | 15.11 | ||||
| dfaBKRB1 | B1 bradykinin receptor | 5 | 584 | 98.18 | 98.96 | ND | 0.53 | 0.72 | 0.7 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Diabetic nephropathy
Inflammatory diseases Ischemic vascular disease Prostate cancer | This is a receptor for bradykinin. Could be a factor in chronic pain and inflammation. | 16.04 | |||
| dfaBKRB2 | B2 bradykinin receptor | 3 | 344 | 97.57 | 97.99 | ND | 0.82 | 0.82 | 0.7 | Nature11159 | Mammalian | Ubiquitous. Widespread in normal smooth muscle tissue and neurons. {ECO:0000269|PubMed:7835885}. | Family A G protein-coupled receptor | Alzheimer's disease
Analgesics Arthritis Asthma Brain Cancer Cardiac hypertrophy Cardiovascular disease, unspecified Cerebral edema Chronic rhinitis Colitis Diabetic disorders Diabetic nephropathy Hepatorenal syndrome Hereditary Angioedema (HAE) Hypertension Liver Disease Lung cancer Myocardial infarction Pancreatitis Pediatric Restenosis Sepsis Tissue injury Traumatic brain injuries Visceral pain | Receptor for bradykinin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. | B2 bradykinin receptor antagonist: Icatibant | 16.04 | |
| dfaBLK | Tyrosine-protein kinase Blk | 5 | 260 | 91.42 | 92.56 | ND | 0.32 | 0.72 | 0.6 | Mammalian | Expressed in lymphatic organs, pancreatic islets, Leydig cells, striate ducts of salivary glands and hair follicles. {ECO:0000269|PubMed:19667185}. | Kinase | Maturity-onset diabetes of the young 11 (MODY11) [MIM:613375]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:19667185}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling. B-cell receptor (BCR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated coreceptors. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. Signaling through BLK plays an important role in transmitting signals through surface immunoglobulins and supports the pro-B to pre-B transition, as well as the signaling for growth arrest and apoptosis downstream of B-cell receptor. Specifically binds and phosphorylates CD79A at 'Tyr-188'and 'Tyr-199', as well as CD79B at 'Tyr-196' and 'Tyr- 207'. Phosphorylates also the immunoglobulin G receptors FCGR2A, FCGR2B and FCGR2C. With FYN and LYN, plays an essential role in pre-B-cell receptor (pre-BCR)-mediated NF-kappa-B activation. Contributes also to BTK activation by indirectly stimulating BTK intramolecular autophosphorylation. In pancreatic islets, acts as a modulator of beta-cells function through the up-regulation of PDX1 and NKX6-1 and consequent stimulation of insulin secretion in response to glucose. {ECO:0000269|PubMed:19667185, ECO:0000269|PubMed:8756631}. | 16.04 | |||
| dfaBLM | Bloom syndrome protein | 6 | 537 | 86.03 | 88.22 | ND | 0.22 | 0.35 | 0.3 | Mammalian | Enzyme | Bloom syndrome (BLM) [MIM:210900]: An autosomal recessive disorder. It is characterized by proportionate pre- and postnatal growth deficiency, sun-sensitive telangiectatic hypo- and hyperpigmented skin, predisposition to malignancy, and chromosomal instability. {ECO:0000269|PubMed:10862105, ECO:0000269|PubMed:7585968, ECO:0000269|PubMed:9285778}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Participates in DNA replication and repair. Exhibits a magnesium-dependent ATP-dependent DNA-helicase activity that unwinds single- and double-stranded DNA in a 3'-5' direction. Involved in 5'-end resection of DNA during double-strand break (DSB) repair: unwinds DNA and recruits DNA2 which mediates the cleavage of 5'-ssDNA. Negatively regulates sister chromatid exchange (SCE). {ECO:0000269|PubMed:12019152, ECO:0000269|PubMed:21325134, ECO:0000269|PubMed:23509288, ECO:0000269|PubMed:9388193}. | 16.04 | ||||
| dfaBMP1 | Bone morphogenetic protein 1 | 4 | 269 | 97.52 | 99.79 | ND | 0.77 | 0.71 | 0.4 | Mammalian | Ubiquitous. | Protease | Osteogenesis imperfecta 13 (OI13) [MIM:614856]: An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI13 is characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, severe bone deformity, and recurrent fractures affecting both upper and lower limbs. {ECO:0000269|PubMed:22052668, ECO:0000269|PubMed:22482805, ECO:0000269|PubMed:25402547}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cleaves the C-terminal propeptides of procollagen I, II and III. Induces cartilage and bone formation. May participate in dorsoventral patterning during early development by cleaving chordin (CHRD). Responsible for the proteolytic activation of lysyl oxidase LOX. | 16.04 | |||
| dfaBMP2K | BMP-2-inducible protein kinase | 2 | 65 | 80.81 | 87.06 | ND | 0.81 | 0.94 | 0.5 | Mammalian | Kinase | May be involved in osteoblast differentiation. | 16.04 | |||||
| dfaBMPR2 | Bone morphogenetic protein receptor type-2 | 3 | 71 | 99.66 | 95.38 | ND | 0.86 | 0.97 | 0.2 | Mammalian | Highly expressed in heart and liver. | Kinase | Pulmonary hypertension, primary, 1 (PPH1) [MIM:178600]: A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. {ECO:0000269|PubMed:10903931, ECO:0000269|PubMed:10973254, ECO:0000269|PubMed:11015450, ECO:0000269|PubMed:11115378, ECO:0000269|PubMed:12358323, ECO:0000269|PubMed:15965979, ECO:0000269|PubMed:25187962}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pulmonary venoocclusive disease 1, autosomal dominant (PVOD1) [MIM:265450]: A disease characterized by widespread fibrous obstruction and intimal thickening of septal veins and preseptal venules, a low diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and nodular ground-glass opacities, septal lines and lymph node enlargement showed by high-resolution computed tomography of the chest. It is frequently associated with pulmonary capillary dilatation and proliferation, and is a rare and devastating cause of pulmonary hypertension. {ECO:0000269|PubMed:12446270, ECO:0000269|PubMed:16429395}. Note=The disease is caused by mutations affecting the gene represented in this entry. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP-7, BMP-2 and, less efficiently, BMP-4. Binding is weak but enhanced by the presence of type I receptors for BMPs. | 15.11 | |||
| dfaBMR1A | Bone morphogenetic protein receptor type-1A | 4 | 74 | 99.97 | 96.92 | ND | 0.91 | 0.76 | 0.3 | Mammalian | Highly expressed in skeletal muscle. | Kinase | Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers. {ECO:0000269|PubMed:11536076, ECO:0000269|PubMed:12136244, ECO:0000269|PubMed:12417513, ECO:0000269|PubMed:12630959}. Note=The disease is caused by mutations affecting the gene represented in this entry. Polyposis syndrome, mixed hereditary 2 (HMPS2) [MIM:610069]: A disease is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome. {ECO:0000269|PubMed:11381269, ECO:0000269|PubMed:16525031}. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP2, BMP4, GDF5 and GDF6. Positively regulates chondrocyte differentiation through GDF5 interaction. Mediates induction of adipogenesis by GDF6. {ECO:0000250|UniProtKB:P36895}. | 16.04 | |||
| dfaBMR1B | Bone morphogenetic protein receptor type-1B | 5 | 70 | 90.49 | 93.25 | ND | 0.93 | 0.73 | 0.3 | Mammalian | Kinase | Acromesomelic chondrodysplasia, with genital anomalies (AMDGA) [MIM:609441]: A form of chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). {ECO:0000269|PubMed:15805157}. Note=The disease is caused by mutations affecting the gene represented in this entry. Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. {ECO:0000269|PubMed:14523231, ECO:0000269|PubMed:16957682}. Note=The disease is caused by mutations affecting the gene represented in this entry. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP7/OP-1 and GDF5. Positively regulates chondrocyte differentiation through GDF5 interaction (By similarity). {ECO:0000250|UniProtKB:P36898}. | 15.11 | ||||
| dfaBMX | Cytoplasmic tyrosine-protein kinase BMX | 7 | 84 | 99.46 | 98.79 | ND | 0.73 | 0.78 | 0.4 | Mammalian | Highly expressed in cells with great migratory potential, including endothelial cells and metastatic carcinoma cell lines. | Kinase | Non-receptor tyrosine kinase that plays central but diverse modulatory roles in various signaling processes involved in the regulation of actin reorganization, cell migration, cell proliferation and survival, cell adhesion, and apoptosis. Participates in signal transduction stimulated by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen receptors and integrins. Induces tyrosine phosphorylation of BCAR1 in response to integrin regulation. Activation of BMX by integrins is mediated by PTK2/FAK1, a key mediator of integrin signaling events leading to the regulation of actin cytoskeleton and cell motility. Plays a critical role in TNF-induced angiogenesis, and implicated in the signaling of TEK and FLT1 receptors, 2 important receptor families essential for angiogenesis. Required for the phosphorylation and activation of STAT3, a transcription factor involved in cell differentiation. Also involved in interleukin-6 (IL6) induced differentiation. Plays also a role in programming adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts. May be involved in regulation of endocytosis through its interaction with an endosomal protein RUFY1. May also play a role in the growth and differentiation of hematopoietic cells; as well as in signal transduction in endocardial and arterial endothelial cells. {ECO:0000269|PubMed:10688651, ECO:0000269|PubMed:11331870, ECO:0000269|PubMed:12370298, ECO:0000269|PubMed:12832404, ECO:0000269|PubMed:15788485, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:9520419}. | 15.11 | ||||
| dfaBRAF | Serine/threonine-protein kinase B-raf | 2 | 610 | 96.77 | 96.59 | ND | 0.81 | 0.81 | 0.6 | Mammalian | Brain and testis. | Kinase | Note=Defects in BRAF are found in a wide range of cancers. {ECO:0000269|PubMed:18974108}. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:12198537, ECO:0000269|PubMed:23263490, ECO:0000269|PubMed:24455489}. Note=The disease may be caused by mutations affecting the gene represented in this entry. Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:12460919}. Note=The gene represented in this entry is involved in disease pathogenesis. Familial non-Hodgkin lymphoma (NHL) [MIM:605027]: Cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss. {ECO:0000269|PubMed:14612909}. Note=The gene represented in this entry is involved in disease pathogenesis. Cardiofaciocutaneous syndrome 1 (CFC1) [MIM:115150]: A multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:16474404, ECO:0000269|PubMed:18042262, ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry. Noonan syndrome 7 (NS7) [MIM:613706]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry. LEOPARD syndrome 3 (LPRD3) [MIM:613707]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation. {ECO:0000269|PubMed:18974108}. | Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, and thereby contributes to the MAP kinase signal transduction pathway. {ECO:0000269|PubMed:21441910}. | Serine/threonine-protein kinase B-raf inhibitor: Sorafenib | 15.11 | ||
| dfaBRD2 | Bromodomain-containing protein 2 | 1 | 75 | 99.69 | 96.56 | ND | 0.34 | 0.43 | 0.3 | Mammalian | Reader | May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly. {ECO:0000250, ECO:0000269|PubMed:18406326}. | 15.11 | |||||
| dfaBRD3 | Bromodomain-containing protein 3 | 4 | 69 | 96.04 | 97.67 | ND | 0.44 | 0.50 | 0.4 | Mammalian | Ubiquitous. | Reader | Note=A chromosomal aberration involving BRD3 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with NUT which produces a BRD3-NUT fusion protein. | Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors. Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets (By similarity). Regulates transcription of the CCND1 gene. {ECO:0000250, ECO:0000269|PubMed:18406326}. | 16.04 | |||
| dfaBRD4 | Bromodomain-containing protein 4 | 5 | 212 | 95.49 | 97.09 | ND | 0.57 | 0.53 | 0.4 | Mammalian | Ubiquitously expressed. {ECO:0000269|PubMed:12543779}. | Reader | Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. {ECO:0000269|PubMed:11733348, ECO:0000269|PubMed:12543779}. | Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P- TEFb complex and recruiting it to promoters: BRD4 is required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P- TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo (PubMed:22509028). In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters. {ECO:0000269|PubMed:22509028}. Isoform B: Acts as a chromatin insulator in the DNA damage response pathway. Inhibits DNA damage response signaling by recruiting the condensin-2 complex to acetylated histones, leading to chromatin structure remodeling, insulating the region from DNA damage response by limiting spreading of histone H2AFX/H2A.x phosphorylation. | 15.11 | |||
| dfaBRS3 | Bombesin receptor subtype-3 | 4 | 225 | 95.23 | 92.31 | ND | 0.73 | 0.49 | 0.6 | Mammalian | In germ cells in testis. Lung carcinoma cells. | Family A G protein-coupled receptor | Cancer, unspecific
Obesity | Role in sperm cell division, maturation, or function. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. | 16.04 | |||
| dfaBRSK1 | Serine/threonine-protein kinase BRSK1 | 5 | 232 | 90.31 | 89.78 | ND | 0.58 | 0.48 | 0.4 | Mammalian | Widely expressed, with highest levels in brain and testis. Protein levels remain constant throughout the cell cycle. {ECO:0000269|PubMed:15150265}. | Kinase | Serine/threonine-protein kinase that plays a key role in polarization of neurons and centrosome duplication. Phosphorylates CDC25B, CDC25C, MAPT/TAU, RIMS1, TUBG1, TUBG2 and WEE1. Following phosphorylation and activation by STK11/LKB1, acts as a key regulator of polarization of cortical neurons, probably by mediating phosphorylation of microtubule-associated proteins such as MAPT/TAU at 'Thr-529' and 'Ser-579'. Also regulates neuron polarization by mediating phosphorylation of WEE1 at 'Ser-642' in post-mitotic neurons, leading to down-regulate WEE1 activity in polarized neurons. In neurons, localizes to synaptic vesicles and plays a role in neurotransmitter release, possibly by phosphorylating RIMS1. Also acts as a positive regulator of centrosome duplication by mediating phosphorylation of gamma- tubulin (TUBG1 and TUBG2) at 'Ser-131', leading to translocation of gamma-tubulin and its associated proteins to the centrosome. Involved in the UV-induced DNA damage checkpoint response, probably by inhibiting CDK1 activity through phosphorylation and activation of WEE1, and inhibition of CDC25B and CDC25C. {ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15150265, ECO:0000269|PubMed:20026642, ECO:0000269|PubMed:21985311}. | 16.04 | ||||
| dfaBRSK2 | Serine/threonine-protein kinase BRSK2 | 3 | 68 | 99.96 | 96.61 | ND | 0.75 | 0.87 | 0.4 | Mammalian | Detected in pancreas islets (at protein level). {ECO:0000269|PubMed:22798068}. | Kinase | Serine/threonine-protein kinase that plays a key role in polarization of neurons and axonogenesis, cell cycle progress and insulin secretion. Phosphorylates CDK16, CDC25C, MAPT/TAU, PAK1 and WEE1. Following phosphorylation and activation by STK11/LKB1, acts as a key regulator of polarization of cortical neurons, probably by mediating phosphorylation of microtubule-associated proteins such as MAPT/TAU at 'Thr-529' and 'Ser-579'. Also regulates neuron polarization by mediating phosphorylation of WEE1 at 'Ser-642' in postmitotic neurons, leading to down-regulate WEE1 activity in polarized neurons. Plays a role in the regulation of the mitotic cell cycle progress and the onset of mitosis. Plays a role in the regulation of insulin secretion in response to elevated glucose levels, probably via phosphorylation of CDK16 and PAK1. While BRSK2 phosphorylated at Thr-174 can inhibit insulin secretion (PubMed:22798068), BRSK2 phosphorylated at Thr-260 can promote insulin secretion (PubMed:22669945). Regulates reorganization of the actin cytoskeleton. May play a role in the apoptotic response triggered by endoplasmatic reticulum (ER) stress. {ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:20026642, ECO:0000269|PubMed:21985311, ECO:0000269|PubMed:22669945, ECO:0000269|PubMed:22798068, ECO:0000269|PubMed:23029325}. | 16.04 | ||||
| dfaBTK | Tyrosine-protein kinase BTK | 7 | 341 | 91.02 | 93.22 | ND | 0.63 | 0.72 | 0.7 | Mammalian | Predominantly expressed in B-lymphocytes. | Kinase | X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin. {ECO:0000269|PubMed:10220140, ECO:0000269|PubMed:10612838, ECO:0000269|PubMed:10678660, ECO:0000269|PubMed:7627183, ECO:0000269|PubMed:7633420, ECO:0000269|PubMed:7633429, ECO:0000269|PubMed:7711734, ECO:0000269|PubMed:7809124, ECO:0000269|PubMed:7849006, ECO:0000269|PubMed:7849697, ECO:0000269|PubMed:7849721, ECO:0000269|PubMed:7880320, ECO:0000269|PubMed:7897635, ECO:0000269|PubMed:8013627, ECO:0000269|PubMed:8162018, ECO:0000269|PubMed:8162056, ECO:0000269|PubMed:8634718, ECO:0000269|PubMed:8695804, ECO:0000269|PubMed:8723128, ECO:0000269|PubMed:8834236, ECO:0000269|PubMed:9260159, ECO:0000269|PubMed:9280283, ECO:0000269|PubMed:9445504, ECO:0000269|PubMed:9545398}. Note=The disease is caused by mutations affecting the gene represented in this entry. X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). Note=The disease may be caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. {ECO:0000269|PubMed:11606584, ECO:0000269|PubMed:16415872, ECO:0000269|PubMed:16517732, ECO:0000269|PubMed:16738337, ECO:0000269|PubMed:17932028, ECO:0000269|PubMed:9012831}. | Tyrosine-protein kinase BTK inhibitor: Ibrutinib | 15.11 | ||
| dfaC11B1 | Cytochrome P450 11B1, mitochondrial | 5 | 447 | 94.17 | 95.19 | ND | 0.64 | 0.66 | 0.5 | Mammalian | Cytochrome P450 | Adrenal hyperplasia 4 (AH4) [MIM:202010]: A form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late- onset (NC or LOAH)and 'cryptic' (asymptomatic). {ECO:0000269|PubMed:16046588, ECO:0000269|PubMed:20089618, ECO:0000269|PubMed:2022736, ECO:0000269|PubMed:20331679, ECO:0000269|PubMed:20947076, ECO:0000269|PubMed:23940125, ECO:0000269|PubMed:24022297, ECO:0000269|PubMed:24536089, ECO:0000269|PubMed:24987415, ECO:0000269|PubMed:26053152, ECO:0000269|PubMed:26476331, ECO:0000269|PubMed:9302260}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperaldosteronism 1 (FH1) [MIM:103900]: A disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol. There is significant phenotypic heterogeneity, and some individuals never develop hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2. | Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochrome P450 XIB. | Cytochrome P450 11B1, mitochondrial inducer: Mitotane Cytochrome P450 11B1, mitochondrial inhibitor: Cimetidine, Clotrimazole, Etomidate, Fluconazole, Ketoconazole, Metoclopramide, Metyrapone, Miconazole, Phenytoin, Spironolactone Cytochrome P450 11B1, mitochondrial substrate: Hydrocortisone | 16.04 | |||
| dfaC11B2 | Cytochrome P450 11B2, mitochondrial | 3 | 456 | 97.36 | 91.22 | ND | 0.63 | 0.64 | 0.6 | Mammalian | Cytochrome P450 | Corticosterone methyloxidase 1 deficiency (CMO-1 deficiency) [MIM:203400]: Autosomal recessive disorder of aldosterone biosynthesis. There are two biochemically different forms of selective aldosterone deficiency be termed corticosterone methyloxidase (CMO) deficiency type 1 and type 2. In CMO-1 deficiency, aldosterone is undetectable in plasma, while its immediate precursor, 18-hydroxycorticosterone, is low or normal. {ECO:0000269|PubMed:11238478, ECO:0000269|PubMed:9177280}. Note=The disease is caused by mutations affecting the gene represented in this entry. Corticosterone methyloxidase 2 deficiency (CMO-2 deficiency) [MIM:610600]: Autosomal recessive disorder of aldosterone biosynthesis. In CMO-2 deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18- hydroxycorticosterone. Consequently, patients have a greatly increased ratio of 18-hydroxycorticosterone to aldosterone and a low ratio of corticosterone to 18-hydroxycorticosterone in serum. {ECO:0000269|PubMed:12788848, ECO:0000269|PubMed:1346492, ECO:0000269|PubMed:1594605, ECO:0000269|PubMed:9625333, ECO:0000269|PubMed:9814506}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperaldosteronism 1 (FH1) [MIM:103900]: A disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol. There is significant phenotypic heterogeneity, and some individuals never develop hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2. | Preferentially catalyzes the conversion of 11- deoxycorticosterone to aldosterone via corticosterone and 18- hydroxycorticosterone. {ECO:0000269|PubMed:23322723}. | Cytochrome P450 11B2, mitochondrial antagonist: Spironolactone Cytochrome P450 11B2, mitochondrial inducer: Metoclopramide Cytochrome P450 11B2, mitochondrial inhibitor: Eplerenone, Etomidate, Metyrapone Cytochrome P450 11B2, mitochondrial substrate: Hydrocortisone | 16.04 | |||
| dfaC1R | Complement C1r subcomponent | 1 | 77 | 99.74 | 99.76 | ND | 0.39 | 0.40 | 0.3 | Mammalian | Protease | C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system. | Complement C1r subcomponent : Abciximab, Adalimumab, Alefacept, Alemtuzumab, Basiliximab, Bevacizumab, Cetuximab, Daclizumab, Efalizumab, Etanercept, Gemtuzumab ozogamicin, Ibritumomab, Muromonab, Natalizumab, Palivizumab, Rituximab, Tositumomab, Trastuzumab | 16.04 | ||||
| dfaC1S | Complement C1s subcomponent | 1 | 83 | 99.93 | 99.86 | ND | 0.57 | 0.70 | 0.4 | Mammalian | Protease | Complement component C1s deficiency (C1SD) [MIM:613783]: A rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis. {ECO:0000269|PubMed:11390518}. Note=The disease is caused by mutations affecting the gene represented in this entry. | C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4. | Complement C1s subcomponent : Abciximab, Adalimumab, Basiliximab, Cetuximab, Etanercept, Gemtuzumab ozogamicin, Ibritumomab, Muromonab, Rituximab, Trastuzumab | 16.04 | |||
| dfaC3AR | C3a anaphylatoxin chemotactic receptor | 2 | 56 | 99.55 | 91.13 | ND | 0.32 | 0.51 | 0.6 | Mammalian | Widely expressed in several differentiated hematopoietic cell lines, in the lung, spleen, ovary, placenta, small intestine, throughout the brain, heart, and endothelial cells. Mostly expressed in lymphoid tissues. | Family A G protein-coupled receptor | Receptor for the chemotactic and inflammatory peptide anaphylatoxin C3a. This receptor stimulates chemotaxis, granule enzyme release and superoxide anion production. | 16.04 | ||||
| dfaC5AR1 | C5a anaphylatoxin chemotactic receptor 1 | 5 | 188 | 97.07 | 97.27 | ND | 0.45 | 0.36 | 0.6 | Mammalian | Family A G protein-coupled receptor | Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:1847994, PubMed:8182049, PubMed:7622471, PubMed:9553099, PubMed:10636859, PubMed:15153520). The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events (PubMed:8182049, PubMed:7622471, PubMed:9553099). Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:10636859, PubMed:15153520). {ECO:0000269|PubMed:10636859, ECO:0000269|PubMed:15153520, ECO:0000269|PubMed:1847994, ECO:0000269|PubMed:7622471, ECO:0000269|PubMed:8182049, ECO:0000269|PubMed:9553099}. | 16.04 | |||||
| dfaCA2D1 | Voltage-dependent calcium channel subunit alpha-2/delta-1 | 5 | 177 | 97.91 | 98.26 | ND | 0.51 | 0.54 | 0.5 | Mammalian | Isoform 1 is expressed in skeletal muscle. Isoform 2 is expressed in the central nervous system. Isoform 2, isoform 4 and isoform 5 are expressed in neuroblastoma cells. Isoform 3, isoform 4 and isoform 5 are expressed in the aorta. {ECO:0000269|PubMed:1309651, ECO:0000269|PubMed:8107964}. | Calcium channel auxiliary subunit alpha2delta family | The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction coupling (By similarity). {ECO:0000250}. | Voltage-dependent calcium channel subunit alpha-2/delta-1 : Magnesium Sulfate Voltage-dependent calcium channel subunit alpha-2/delta-1 activator: Ibutilide Voltage-dependent calcium channel subunit alpha-2/delta-1 inhibitor: Amlodipine, Cyclandelate, Felodipine, Gabapentin, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Nisoldipine, Nitrendipine | 16.04 | |||
| dfaCAC1B | Voltage-dependent N-type calcium channel subunit alpha-1B | 7 | 264 | 96.44 | 97.55 | ND | 0.74 | 0.68 | 0.4 | Nature11159 | Mammalian | Isoform Alpha-1b-1 and isoform Alpha-1b-2 are expressed in the central nervous system, but not in skeletal muscle or aorta. | Flushing Oedema peripheral | Voltage-gated ion channel | Dystonia 23 (DYT23) [MIM:614860]: A form of dystonia, a disorder defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT23 is an autosomal dominant dystonia affecting the face, neck, limbs. Some DYT23 patients manifest generalized myoclonus in addition to progressive action-induced multifocal dystonia. {ECO:0000269|PubMed:25296916}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1B gives rise to N-type calcium currents. N-type calcium channels belong to the 'high-voltage activated' (HVA) group and are blocked by omega-conotoxin-GVIA (omega-CTx-GVIA) and by omega-agatoxin- IIIA (omega-Aga-IIIA). They are however insensitive to dihydropyridines (DHP), and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing alpha-1B subunit may play a role in directed migration of immature neurons. | Voltage-dependent N-type calcium channel subunit alpha-1B inhibitor: Amlodipine, Gabapentin, Levetiracetam, Verapamil | 16.04 |
| dfaCAC1C | Voltage-dependent L-type calcium channel subunit alpha-1C | 3 | 452 | 96.33 | 95.39 | ND | 0.80 | 0.78 | 0.6 | Nature11159 | Mammalian | Expressed in brain, heart, jejunum, ovary, pancreatic beta-cells and vascular smooth muscle. Overall expression is reduced in atherosclerotic vascular smooth muscle. {ECO:0000269|PubMed:12176756, ECO:0000269|PubMed:17071743, ECO:0000269|PubMed:8392192}. | Arrhythmia Flushing Gingival hyperplasia Oedema peripheral | Voltage-gated ion channel | Timothy syndrome (TS) [MIM:601005]: Disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism. {ECO:0000269|PubMed:15454078, ECO:0000269|PubMed:15863612, ECO:0000269|PubMed:24728418, ECO:0000269|PubMed:25260352, ECO:0000269|PubMed:25633834, ECO:0000269|PubMed:26253506}. Note=The disease is caused by mutations affecting the gene represented in this entry. Brugada syndrome 3 (BRGDA3) [MIM:611875]: A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:17224476}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds. Binding of calmodulin or CABP1 at the same regulatory sites results in an opposit effects on the channel function. {ECO:0000269|PubMed:12176756, ECO:0000269|PubMed:17071743, ECO:0000269|PubMed:7737988, ECO:0000269|PubMed:8392192, ECO:0000269|PubMed:9013606, ECO:0000269|PubMed:9607315}. | Voltage-dependent L-type calcium channel subunit alpha-1C : Clevidipine, Dronedarone, Ethanol, Magnesium Sulfate Voltage-dependent L-type calcium channel subunit alpha-1C activator: Ibutilide Voltage-dependent L-type calcium channel subunit alpha-1C inhibitor: Amlodipine, Cinnarizine, Drotaverine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil | 16.04 |
| dfaCAC1D | Voltage-dependent L-type calcium channel subunit alpha-1D | 2 | 239 | 95.61 | 94.57 | ND | 0.62 | 0.72 | 0.7 | Mammalian | Expressed in pancreatic islets and in brain, where it has been seen in cerebral cortex, hippocampus, basal ganglia, habenula and thalamus. Expressed in the small cell lung carcinoma cell line SCC-9. No expression in skeletal muscle. {ECO:0000269|PubMed:1335101}. | Arrhythmia Diplopia Flushing Oedema peripheral | Voltage-gated ion channel | Sinoatrial node dysfunction and deafness (SANDD) [MIM:614896]: A disease characterized by congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia. {ECO:0000269|PubMed:21131953}. Note=The disease is caused by mutations affecting the gene represented in this entry. Primary aldosteronism, seizures, and neurologic abnormalities (PASNA) [MIM:615474]: A disorder characterized by hypertension, hypokalemia, and high aldosterone levels with low plasma renin activity and an elevated aldosterone/renin ratio. Other features include generalized seizures, cerebral palsy, spasticity, intellectual disability, and developmental delay. {ECO:0000269|PubMed:23913001}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1D gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). {ECO:0000269|PubMed:18482979}. | Voltage-dependent L-type calcium channel subunit alpha-1D : Clevidipine, Dronedarone, Ethanol Voltage-dependent L-type calcium channel subunit alpha-1D inhibitor: Amlodipine, Cinnarizine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil | 16.04 | |
| dfaCAC1G | Voltage-dependent T-type calcium channel subunit alpha-1G | 4 | 222 | 93.31 | 97.74 | ND | 0.24 | 0.40 | 0.4 | Mammalian | Highly expressed in brain, in particular in the amygdala, subthalamic nuclei, cerebellum and thalamus. Moderate expression in heart; low expression in placenta, kidney and lung. Also expressed in colon and bone marrow and in tumoral cells to a lesser extent. Highly expressed in fetal brain, but also in peripheral fetal tissues as heart, kidney and lung, suggesting a developmentally regulated expression. | Voltage-gated ion channel | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. | Voltage-dependent T-type calcium channel subunit alpha-1G inhibitor: Cinnarizine, Ethosuximide, Flunarizine, Methsuximide, Trimethadione, Verapamil, Zonisamide | 16.04 | |||
| dfaCAC1S | Voltage-dependent L-type calcium channel subunit alpha-1S | 4 | 78 | 99.15 | 99.85 | ND | 0.33 | 0.34 | 0.4 | Mammalian | Skeletal muscle specific. | Voltage-gated ion channel | Periodic paralysis hypokalemic 1 (HOKPP1) [MIM:170400]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:17418573, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:7987325, ECO:0000269|PubMed:8004673}. Note=The disease is caused by mutations affecting the gene represented in this entry. Malignant hyperthermia 5 (MHS5) [MIM:601887]: Autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. {ECO:0000269|PubMed:9199552}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Thyrotoxic periodic paralysis 1 (TTPP1) [MIM:188580]: A sporadic muscular disorder characterized by episodic weakness and hypokalemia during a thyrotoxic state. It is clinically similar to hereditary hypokalemic periodic paralysis, except for the fact that hyperthyroidism is an absolute requirement for disease manifestation. The disease presents with recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Thyrotoxic periodic paralysis can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves disease. {ECO:0000269|PubMed:15001631}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle. | Voltage-dependent L-type calcium channel subunit alpha-1S : Clevidipine, Dronedarone, Ethanol, Magnesium Sulfate Voltage-dependent L-type calcium channel subunit alpha-1S inhibitor: Amlodipine, Cinnarizine, Felodipine, Isradipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil | 16.04 | ||
| dfaCAH1 | Carbonic anhydrase 1 | 3 | 2851 | 94.25 | 88.24 | ND | 0.64 | 0.64 | 0.6 | Mammalian | Aplastic anaemia Decreased appetite Electrolyte imbalance Glycosuria Gout Haemolysis Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Hyponatraemia Pancreatic disorder Pancreatitis Purine metabolism disorder Thrombocytopenia Xanthopsia | Lyase | Glaucoma
Hypertension Pancreatic cancer | Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea. {ECO:0000269|PubMed:10550681}. | Carbonic anhydrase 1 inhibitor: Methyclothiazide | 15.11 | ||
| dfaCAH12 | Carbonic anhydrase 12 | 1 | 1156 | 94.18 | 81.48 | ND | 0.71 | 0.58 | 0.6 | Mammalian | Highly expressed in colon, kidney, prostate, intestine and activated lymphocytes. Expressed at much higher levels in the renal cell cancers than in surrounding normal kidney tissue. Moderately expressed in pancreas, ovary and testis. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Photosensitivity reaction Purine metabolism disorder Thrombocytopenia | Lyase | Hyperchlorhidrosis, isolated (HCHLH) [MIM:143860]: A disorder characterized by excessive sweating and increased sweat chloride levels. Affected individuals suffer from episodes of hyponatremic dehydration and report increased amounts of visible salt precipitates in sweat. {ECO:0000269|PubMed:21035102}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Reversible hydration of carbon dioxide. | Carbonic anhydrase 12 inhibitor: Benzthiazide | 15.11 | |
| dfaCAH13 | Carbonic anhydrase 13 | 3 | 222 | 86.88 | 89.71 | ND | 0.74 | 0.72 | 0.7 | Mammalian | Expressed in thymus, small intestine, spleen, prostate, ovary, colon and testis. {ECO:0000269|PubMed:14600151}. | Electrolyte imbalance Haemorrhagic diathesis Hypokalaemia Paraesthesia | Lyase | Reversible hydration of carbon dioxide. | Carbonic anhydrase 13 inhibitor: Zonisamide | 15.11 | ||
| dfaCAH14 | Carbonic anhydrase 14 | 2 | 384 | 91.20 | 80.95 | ND | 0.65 | 0.63 | 0.6 | Mammalian | High expression in all parts of the central nervous system and lower expression in adult liver, heart, small intestine, colon, kidney, urinary bladder and skeletal muscle. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Photosensitivity reaction Purine metabolism disorder | Lyase | Renal failure | Reversible hydration of carbon dioxide. | Carbonic anhydrase 14 inhibitor: Acetazolamide | 15.11 | |
| dfaCAH15 | Carbonic anhydrase 15 | 2 | 77 | 83.96 | 85.83 | ND | 0.74 | 0.84 | 0.4 | Mammalian | Enzyme | Reversible hydration of carbon dioxide. {ECO:0000250}. | 16.04 | |||||
| dfaCAH2 | Carbonic anhydrase 2 | 1 | 3431 | 96.34 | 90.24 | ND | 0.66 | 0.44 | 0.6 | Mammalian | Aplastic anaemia Decreased appetite Electrolyte imbalance Glycosuria Gout Haemolysis Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatic disorder Pancreatitis Photosensitivity reaction Pulmonary oedema Purine metabolism disorder Purpura Thrombocytopenia Xanthopsia | Lyase | Osteopetrosis, autosomal recessive 3 (OPTB3) [MIM:259730]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation. {ECO:0000269|PubMed:15300855, ECO:0000269|PubMed:1542674, ECO:0000269|PubMed:1928091, ECO:0000269|PubMed:8834238, ECO:0000269|PubMed:9143915}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate exchange activity of SLC26A6. {ECO:0000250, ECO:0000269|PubMed:10550681, ECO:0000269|PubMed:11831900, ECO:0000269|PubMed:15990874}. | Carbonic anhydrase 2 inhibitor: Methyclothiazide | 15.11 | ||
| dfaCAH4 | Carbonic anhydrase 4 | 4 | 1187 | 93.53 | 93.12 | ND | 0.71 | 0.02 | 0.5 | Mammalian | Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels. {ECO:0000269|PubMed:15563508}. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatic disorder Pancreatitis Photosensitivity reaction Purine metabolism disorder Thirst Thrombocytopenia Xanthopsia | Lyase | Retinitis pigmentosa 17 (RP17) [MIM:600852]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:15563508, ECO:0000269|PubMed:17652713, ECO:0000269|PubMed:20450258}. Note=The disease is caused by mutations affecting the gene represented in this entry. Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype. | Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid. {ECO:0000269|PubMed:15563508}. | Carbonic anhydrase 4 inhibitor: Methyclothiazide | 15.11 | |
| dfaCAH7 | Carbonic anhydrase 7 | 1 | 364 | 92.05 | 82.36 | ND | 0.71 | 0.51 | 0.6 | Mammalian | Lyase | Reversible hydration of carbon dioxide. | Carbonic anhydrase 7 inhibitor: Methazolamide | 15.11 | ||||
| dfaCAH9 | Carbonic anhydrase 9 | 1 | 1519 | 93.20 | 81.88 | ND | 0.60 | 0.47 | 0.7 | Mammalian | Expressed primarily in carcinoma cells lines. Expression is restricted to very few normal tissues and the most abundant expression is found in the epithelial cells of gastric mucosa. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Purine metabolism disorder Thrombocytopenia | Lyase | Bladder cancer
Head and neck squamous cell carcinomas Pancreatic cancer Renal cell carcinoma | Reversible hydration of carbon dioxide. Participates in pH regulation. May be involved in the control of cell proliferation and transformation. Appears to be a novel specific biomarker for a cervical neoplasia. {ECO:0000269|PubMed:18703501}. | Carbonic anhydrase 9 inhibitor: Benzthiazide, Hydrochlorothiazide, Hydroflumethiazide, Zonisamide | 16.04 | |
| dfaCALRL | Calcitonin gene-related peptide type 1 receptor | 1 | 498 | 99.62 | 99.80 | ND | 0.74 | 0.78 | 0.8 | Mammalian | Predominantly expressed in the lung and heart. | Family B G protein-coupled receptor | Cluster Headaches
Diabetes mellitus Migraine Opioid dependence | Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. {ECO:0000250, ECO:0000269|PubMed:22102369}. | 15.11 | |||
| dfaCAN1 | Calpain-1 catalytic subunit | 4 | 539 | 96.43 | 96.89 | ND | 0.72 | 0.69 | 0.7 | Mammalian | Ubiquitous. | Protease | Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. | 15.11 | ||||
| dfaCAN2 | Calpain-2 catalytic subunit | 3 | 105 | 84.52 | 84.36 | ND | 0.84 | 0.70 | 0.5 | Mammalian | Ubiquitous. | Protease | Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Proteolytically cleaves MYOC at 'Arg-226' (PubMed:17650508). {ECO:0000269|PubMed:17650508}. | 16.04 | ||||
| dfaCARM1 | Histone-arginine methyltransferase CARM1 | 2 | 96 | 99.11 | 97.97 | ND | 0.72 | 0.76 | 0.6 | Mammalian | Overexpressed in prostate adenocarcinomas and high-grade prostatic intraepithelial neoplasia. {ECO:0000269|PubMed:15221992}. | Writer | Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg- 2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA- stabilizing properties and the half-life of their target mRNAs. {ECO:0000269|PubMed:16497732, ECO:0000269|PubMed:19405910}. | 15.11 | ||||
| dfaCASP1 | Caspase-1 | 1 | 649 | 96.86 | 94.65 | ND | 0.70 | 0.73 | 0.8 | Mammalian | Expressed in larger amounts in spleen and lung. Detected in liver, heart, small intestine, colon, thymus, prostate, skeletal muscle, peripheral blood leukocytes, kidney and testis. No expression in the brain. {ECO:0000269|PubMed:15498465}. | Protease | Brain inflammation
Cerebral ischemia Diabetic retinopathy Inflammation | Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis. {ECO:0000269|PubMed:15498465, ECO:0000269|PubMed:7876192}. | Caspase-1 negative modulator: Minocycline | 15.11 | ||
| dfaCASP3 | Caspase-3 | 6 | 1364 | 90.81 | 88.12 | ND | 0.76 | 0.83 | 0.6 | Mammalian | Highly expressed in lung, spleen, heart, liver and kidney. Moderate levels in brain and skeletal muscle, and low in testis. Also found in many cell lines, highest expression in cells of the immune system. | Protease | Chronic experimental allergic encephalomyelitis
Dysregulation of apoptosis Multiple sclerosis Neurodegenerative diseases | Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop- helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage. {ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:7596430}. | Caspase-3 negative modulator: Minocycline | 16.04 | ||
| dfaCASP6 | Caspase-6 | 4 | 160 | 97.66 | 96.24 | ND | 0.69 | 0.72 | 0.4 | Mammalian | Protease | Not Available | Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. | 16.04 | ||||
| dfaCASP7 | Caspase-7 | 3 | 348 | 96.46 | 96.08 | ND | 0.66 | 0.78 | 0.7 | Mammalian | Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain. | Protease | Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly- 217' bond. Overexpression promotes programmed cell death. | 15.11 | ||||
| dfaCASP8 | Caspase-8 | 2 | 328 | 95.97 | 95.76 | ND | 0.80 | 0.82 | 0.6 | Mammalian | Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle. | Protease | Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. {ECO:0000269|PubMed:12353035}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:9006941}. | 15.11 | |||
| dfaCASR | Extracellular calcium-sensing receptor | 7 | 424 | 95.05 | 97.26 | ND | 0.55 | 0.64 | 0.7 | Mammalian | Expressed in the temporal lobe, frontal lobe, parietal lobe, hippocampus, and cerebellum. Also found in kidney, lung, liver, heart, skeletal muscle, placenta. {ECO:0000269|PubMed:18756473}. | Family C G protein-coupled receptor | Hypocalciuric hypercalcemia, familial 1 (HHC1) [MIM:145980]: A form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. It is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level. Hypermagnesemia is typically present. Affected individuals are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults. {ECO:0000269|PubMed:11762699, ECO:0000269|PubMed:15572418, ECO:0000269|PubMed:15579740, ECO:0000269|PubMed:15879434, ECO:0000269|PubMed:16598859, ECO:0000269|PubMed:17473068, ECO:0000269|PubMed:17698911, ECO:0000269|PubMed:21643651, ECO:0000269|PubMed:7673400, ECO:0000269|PubMed:7726161, ECO:0000269|PubMed:7916660, ECO:0000269|PubMed:9298824}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hyperparathyroidism, neonatal severe (NSHPT) [MIM:239200]: A disorder characterized by severe hypercalcemia, bone demineralization, and failure to thrive usually manifesting in the first 6 months of life. If untreated, NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. {ECO:0000269|PubMed:8675635, ECO:0000269|PubMed:9253359}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypocalcemia, autosomal dominant 1 (HYPOC1) [MIM:601198]: A disorder of mineral homeostasis characterized by blood calcium levels below normal, and low or normal serum parathyroid hormone concentrations. Disease manifestations include mild or asymptomatic hypocalcemia, paresthesias, carpopedal spasm, seizures, hypercalciuria with nephrocalcinosis or kidney stones, and ectopic and basal ganglia calcifications. Few patients manifest hypocalcemia and features of Bartter syndrome, including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. {ECO:0000269|PubMed:10487661, ECO:0000269|PubMed:12050233, ECO:0000269|PubMed:12107202, ECO:0000269|PubMed:12241879, ECO:0000269|PubMed:12574188, ECO:0000269|PubMed:12915654, ECO:0000269|PubMed:15551332, ECO:0000269|PubMed:16608894, ECO:0000269|PubMed:7874174, ECO:0000269|PubMed:8733126, ECO:0000269|PubMed:8813042, ECO:0000269|PubMed:9253358, ECO:0000269|PubMed:9661634, ECO:0000269|PubMed:9920108}. Note=The disease is caused by mutations affecting the gene represented in this entry. Epilepsy, idiopathic generalized 8 (EIG8) [MIM:612899]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Seizure types are variable, but include myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:18756473}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Homozygous defects in CASR can be a cause of primary hyperparathyroidism in adulthood. Patients suffer from osteoporosis and renal calculi, have marked hypercalcemia and increased serum PTH concentrations. | Senses changes in the extracellular concentration of calcium ions. The activity of this receptor is mediated by a G- protein that activates a phosphatidylinositol-calcium second messenger system. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 16.04 | ||
| dfaCATB | Cathepsin B | 2 | 1262 | 94.52 | 91.26 | ND | 0.65 | 0.68 | 0.7 | Mammalian | Protease | Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis. | 15.11 | |||||
| dfaCATC | Dipeptidyl peptidase 1 | 4 | 85 | 94.88 | 84.60 | ND | 0.53 | 0.67 | 0.8 | Mammalian | Ubiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas. {ECO:0000269|PubMed:9092576}. | Protease | Papillon-Lefevre syndrome (PLS) [MIM:245000]: An autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees. {ECO:0000269|PubMed:10581027, ECO:0000269|PubMed:10662808, ECO:0000269|PubMed:11106356, ECO:0000269|PubMed:11158173, ECO:0000269|PubMed:11180012, ECO:0000269|PubMed:11180601, ECO:0000269|PubMed:11886537, ECO:0000269|PubMed:12112662, ECO:0000269|PubMed:12809647, ECO:0000269|PubMed:14974080, ECO:0000269|PubMed:15108292, ECO:0000269|PubMed:15991336, ECO:0000269|PubMed:25799584}. Note=The disease is caused by mutations affecting the gene represented in this entry. Haim-Munk syndrome (HMS) [MIM:245010]: An autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis. {ECO:0000269|PubMed:10662807}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodontititis, aggressive, 1 (AP1) [MIM:170650]: A disease characterized by severe and protracted gingival infections, generalized or localized, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting. {ECO:0000269|PubMed:10662808, ECO:0000269|PubMed:14974080}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B. Can also activate neuraminidase and factor XIII. {ECO:0000269|PubMed:1586157}. | 15.11 | |||
| dfaCATD | Cathepsin D | 6 | 733 | 96.16 | 97.52 | ND | 0.67 | 0.70 | 0.5 | Mammalian | Expressed in the aorta extrcellular space (at protein level). {ECO:0000269|PubMed:20551380}. | Protease | Ceroid lipofuscinosis, neuronal, 10 (CLN10) [MIM:610127]: A form of neuronal ceroid lipofuscinosis with onset at birth or early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. {ECO:0000269|PubMed:16670177, ECO:0000269|PubMed:16685649, ECO:0000269|PubMed:21990111}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Acid protease active in intracellular protein breakdown. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease. | Cathepsin D : Insulin Regular, Insulin, porcine | 16.04 | ||
| dfaCATF | Cathepsin F | 2 | 47 | 99.84 | 87.59 | ND | 0.81 | 0.57 | 0.6 | Mammalian | High expression levels in heart, skeletal muscle, brain, testis and ovary; moderate levels in prostate, placenta, liver and colon; and no detectable expression in peripheral leukocytes and thymus. | Protease | Ceroid lipofuscinosis, neuronal, 13 (CLN13) [MIM:615362]: A form of neuronal ceroid lipofuscinosis characterized by adult onset of progressive cognitive decline and motor dysfunction leading to dementia and often early death. Some patients develop seizures. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material. {ECO:0000269|PubMed:23297359}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis. | 16.04 | |||
| dfaCATG | Cathepsin G | 3 | 208 | 96.81 | 92.24 | ND | 0.72 | 0.70 | 0.7 | Mammalian | Protease | Alpha 1 Antitrypsin Deficiency
Atopic Dermatitis Chronic Obstructive Pulmonary Disease (COPD) | Serine protease with trypsin- and chymotrypsin-like specificity. Cleaves complement C3. Has antibacterial activity against the Gram-negative bacterium P.aeruginosa, antibacterial activity is inhibited by LPS from P.aeruginosa, Z-Gly-Leu-Phe- CH2Cl and phenylmethylsulfonyl fluoride. {ECO:0000269|PubMed:1861080, ECO:0000269|PubMed:1937776, ECO:0000269|PubMed:8194606}. | 15.11 | ||||
| dfaCATK | Cathepsin K | 1 | 1569 | 97.03 | 87.45 | ND | 0.67 | 0.53 | 0.8 | Mammalian | Predominantly expressed in osteoclasts (bones). | Protease | Pycnodysostosis (PKND) [MIM:265800]: A rare autosomal recessive bone disorder characterized by deformity of the skull, maxilla and phalanges, osteosclerosis, and fragility of bone. {ECO:0000269|PubMed:10491211, ECO:0000269|PubMed:10878663, ECO:0000269|PubMed:22822386, ECO:0000269|PubMed:25731711, ECO:0000269|PubMed:8703060, ECO:0000269|PubMed:9529353}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. | 15.11 | |||
| dfaCATL1 | Cathepsin L1 | 6 | 1350 | 92.47 | 91.24 | ND | 0.52 | 0.65 | 0.8 | Mammalian | Protease | Autoimmune diseases
Melanoma | Important for the overall degradation of proteins in lysosomes. | 15.11 | ||||
| dfaCATL2 | Cathepsin L2 | 7 | 114 | 97.49 | 98.10 | ND | 0.75 | 0.76 | 0.5 | Mammalian | Predominantly expressed in the thymus and testis. Also expressed in corneal epithelium, and to a lesser extent in conjunctival epithelium and skin. {ECO:0000269|PubMed:10029531, ECO:0000269|PubMed:9563472, ECO:0000269|PubMed:9727401}. | Protease | Cysteine protease. May have an important role in corneal physiology. {ECO:0000269|PubMed:10029531, ECO:0000269|PubMed:9727401}. | 16.04 | ||||
| dfaCATS | Cathepsin S | 5 | 1412 | 93.07 | 95.55 | ND | 0.61 | 0.05 | 0.6 | Mammalian | Protease | Autoimmune diseases
Psoriasis and Psoriatic Disorders | Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules. The bond- specificity of this proteinase is in part similar to the specificities of cathepsin L and cathepsin N. | 15.11 | ||||
| dfaCBP | CREB-binding protein | 4 | 135 | 89.30 | 88.85 | ND | 0.70 | 0.03 | 0.3 | Mammalian | Writer | Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Rubinstein-Taybi syndrome 1 (RSTS1) [MIM:180849]: A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. {ECO:0000269|PubMed:11331617, ECO:0000269|PubMed:12114483, ECO:0000269|PubMed:12566391, ECO:0000269|PubMed:15706485, ECO:0000269|PubMed:20684013, ECO:0000269|PubMed:25388907}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK- ARNTL/BMAL1 heterodimers. Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). {ECO:0000269|PubMed:11154691, ECO:0000269|PubMed:12738767, ECO:0000269|PubMed:12929931, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:24939902, ECO:0000269|PubMed:9707565}. | 16.04 | ||||
| dfaCBPA1 | Carboxypeptidase A1 | 2 | 136 | 96.19 | 93.71 | ND | 0.58 | 0.54 | 0.5 | Mammalian | Pancreas. {ECO:0000269|PubMed:7556081}. | Protease | Carboxypeptidase that catalyzes the release of a C- terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro. {ECO:0000250}. | 15.11 | ||||
| dfaCBPB1 | Carboxypeptidase B | 3 | 77 | 92.41 | 81.32 | ND | 0.71 | 0.64 | 0.8 | Mammalian | Protease | 15.11 | ||||||
| dfaCBPB2 | Carboxypeptidase B2 | 2 | 87 | 99.05 | 98.12 | ND | 0.84 | 0.71 | 0.5 | Mammalian | Plasma; synthesized in the liver. | Protease | Thrombosis | Cleaves C-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities. Down- regulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin. {ECO:0000269|PubMed:10574983}. | 15.11 | |||
| dfaCBX7 | Chromobox protein homolog 7 | 1 | 120 | 99.81 | 99.88 | ND | 0.37 | 0.67 | 0.2 | Mammalian | Reader | Component of a Polycomb group (PcG) multiprotein PRC1- like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Promotes histone H3 trimethylation at 'Lys-9' (H3K9me3). Binds to trimethylated lysine residues in histones, and possibly also other proteins. Regulator of cellular lifespan by maintaining the repression of CDKN2A, but not by inducing telomerase activity. {ECO:0000269|PubMed:19636380, ECO:0000269|PubMed:21047797, ECO:0000269|PubMed:21060834, ECO:0000269|PubMed:21282530}. | 15.11 | |||||
| dfaCCKAR | Cholecystokinin receptor type A | 5 | 1188 | 97.86 | 98.74 | ND | 0.64 | 0.66 | 0.7 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Acid-related diseases
Alcoholism Gastroesophageal Reflux Disease (GERD) Gastrointestinal Diseases and Disorders, miscellaneous Gastrointestinal motility disorders Irritable Bowel Syndrome (IBS) Obesity Pancreatic Cancer | Receptor for cholecystokinin. Mediates pancreatic growth and enzyme secretion, smooth muscle contraction of the gall bladder and stomach. Has a 1000-fold higher affinity for CCK rather than for gastrin. It modulates feeding and dopamine-induced behavior in the central and peripheral nervous system. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. | Cholecystokinin receptor type A inducer: Ceruletide | 16.04 | ||
| dfaCCR1 | C-C chemokine receptor type 1 | 3 | 568 | 95.28 | 93.72 | ND | 0.56 | 0.65 | 0.7 | Mammalian | Widely expressed in different hematopoietic cells. | Family A G protein-coupled receptor | Autoimmune diseases
Chronic inflammatory diseases Ovarian cancer Renal fibrosis | Receptor for a C-C type chemokine. Binds to MIP-1-alpha, MIP-1-delta, RANTES, and MCP-3 and, less efficiently, to MIP-1- beta or MCP-1 and subsequently transduces a signal by increasing the intracellular calcium ions level. Responsible for affecting stem cell proliferation. | 16.04 | |||
| dfaCCR2 | C-C chemokine receptor type 2 | 1 | 1204 | 97.41 | 87.03 | ND | 0.63 | 0.52 | 0.6 | Mammalian | Family A G protein-coupled receptor | Inflammatory demyelination
Multiple Sclerosis (MS) Obese Insulin-resistant Subjects Rheumatoid arthritis | Receptor for the CCL2, CCL7 and CCL13 chemokines. Transduces a signal by increasing intracellular calcium ion levels. Alternative coreceptor with CD4 for HIV-1 infection. {ECO:0000269|PubMed:23408426}. | 16.04 | ||||
| dfaCCR3 | C-C chemokine receptor type 3 | 3 | 865 | 97.70 | 97.69 | ND | 0.77 | 0.81 | 0.6 | Mammalian | In eosinophils as well as trace amounts in neutrophils and monocytes. | Family A G protein-coupled receptor | Allergic diseases | Receptor for a C-C type chemokine. Binds to eotaxin, eotaxin-3, MCP-3, MCP-4, RANTES and MIP-1 delta. Subsequently transduces a signal by increasing the intracellular calcium ions level. Alternative coreceptor with CD4 for HIV-1 infection. | 16.04 | |||
| dfaCCR4 | C-C chemokine receptor type 4 | 6 | 311 | 95.79 | 97.82 | ND | 0.62 | 0.72 | 0.6 | Mammalian | Predominantly expressed in the thymus, in peripheral blood leukocytes, including T-cells, mostly CD4+ cells, and basophils, and in platelets; at lower levels, in the spleen and in monocytes. Detected also in macrophages, IL-2-activated natural killer cells and skin-homing memory T-cells, mostly the ones expressing the cutaneous lymphocyte antigen (CLA). Expressed in brain microvascular and coronary artery endothelial cells. {ECO:0000269|PubMed:10754297}. | Family A G protein-coupled receptor | Asthma | High affinity receptor for the C-C type chemokines CCL17/TARC, CCL22/MDC and CKLF isoform 1/CKLF1. The activity of this receptor is mediated by G(i) proteins which activate a phosphatidylinositol-calcium second messenger system. Can function as a chemoattractant homing receptor on circulating memory lymphocytes and as a coreceptor for some primary HIV-2 isolates. In the CNS, could mediate hippocampal-neuron survival. {ECO:0000269|PubMed:10466728, ECO:0000269|PubMed:10754297, ECO:0000269|PubMed:16137713, ECO:0000269|PubMed:9169480, ECO:0000269|PubMed:9430724}. | 16.04 | |||
| dfaCCR5 | C-C chemokine receptor type 5 | 1 | 1648 | 98.58 | 96.22 | ND | 0.67 | 0.57 | 0.6 | Mammalian | Highly expressed in spleen, thymus, in the myeloid cell line THP-1, in the promyeloblastic cell line KG-1a and on CD4+ and CD8+ T-cells. Medium levels in peripheral blood leukocytes and in small intestine. Low levels in ovary and lung. {ECO:0000269|PubMed:8639485, ECO:0000269|PubMed:8663314}. | Family A G protein-coupled receptor | Diabetes mellitus, insulin-dependent, 22 (IDDM22) [MIM:612522]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:19073967}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for a number of inflammatory CC-chemokines including MIP-1-alpha, MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a role in the control of granulocytic lineage proliferation or differentiation. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 R5 isolates. {ECO:0000269|PubMed:11323418, ECO:0000269|PubMed:8639485, ECO:0000269|PubMed:8649511, ECO:0000269|PubMed:8649512, ECO:0000269|PubMed:8663314, ECO:0000269|PubMed:8699119}. (Microbial infection) Acts as a receptor for human immunodeficiency virus-1/HIV-1. {ECO:0000269|PubMed:21763489, ECO:0000269|PubMed:9632396}. | C-C chemokine receptor type 5 antagonist: Maraviroc | 15.11 | ||
| dfaCCR6 | C-C chemokine receptor type 6 | 4 | 53 | 99.24 | 84.35 | ND | 0.07 | 0.60 | 0.1 | Mammalian | Spleen, lymph nodes, appendix, and fetal liver. Expressed in lymphocytes, T-cells and B-cells but not in natural killer cells, monocytes or granulocytes. | Family A G protein-coupled receptor | Receptor for a C-C type chemokine. Binds to MIP-3- alpha/LARC and subsequently transduces a signal by increasing the intracellular calcium ions level. {ECO:0000269|PubMed:9169459}. | 16.04 | ||||
| dfaCCR8 | C-C chemokine receptor type 8 | 3 | 163 | 98.64 | 95.26 | ND | 0.62 | 0.57 | 0.6 | Mammalian | Family A G protein-coupled receptor | Allergic diseases | Receptor for the chemokine CCL1/SCYA1/I-309. May regulate monocyte chemotaxis and thymic cell line apoptosis. Alternative coreceptor with CD4 for HIV-1 infection. {ECO:0000269|PubMed:10540332, ECO:0000269|PubMed:9207005, ECO:0000269|PubMed:9469461, ECO:0000269|PubMed:9521068}. | 16.04 | ||||
| dfaCD11A | Cyclin-dependent kinase 11A | 4 | 64 | 99.82 | 93.84 | ND | 0.62 | 0.93 | 0.3 | Mammalian | Expressed ubiquitously. Some evidence of isoform-specific tissue distribution. {ECO:0000269|PubMed:8195233, ECO:0000269|PubMed:9750192}. | Kinase | Appears to play multiple roles in cell cycle progression, cytokinesis and apoptosis. The p110 isoforms have been suggested to be involved in pre-mRNA splicing, potentially by phosphorylating the splicing protein SFRS7. The p58 isoform may act as a negative regulator of normal cell cycle progression. {ECO:0000269|PubMed:12501247, ECO:0000269|PubMed:12624090}. | 16.04 | ||||
| dfaCD11B | Cyclin-dependent kinase 11B | 4 | 64 | 93.38 | 92.33 | ND | 0.02 | 0.93 | 0.8 | Mammalian | Expressed ubiquitously. Some evidence of isoform-specific tissue distribution. {ECO:0000269|PubMed:8195233, ECO:0000269|PubMed:9750192}. | Kinase | Plays multiple roles in cell cycle progression, cytokinesis and apoptosis. Involved in pre-mRNA splicing in a kinase activity-dependent manner. Isoform 7 may act as a negative regulator of normal cell cycle progression. {ECO:0000269|PubMed:12501247, ECO:0000269|PubMed:12624090, ECO:0000269|PubMed:18216018, ECO:0000269|PubMed:2217177}. | 16.04 | ||||
| dfaCDC7 | Cell division cycle 7-related protein kinase | 8 | 458 | 95.35 | 96.97 | ND | 0.71 | 0.70 | 0.5 | Mammalian | Kinase | Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3. {ECO:0000269|PubMed:12065429}. | 15.11 | |||||
| dfaCDK1 | Cyclin-dependent kinase 1 | 6 | 1149 | 93.09 | 90.58 | ND | 0.65 | 0.69 | 0.6 | Mammalian | Isoform 2 is found in breast cancer tissues. | Kinase | Cancer, unspecific
Malaria | Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins. Required in higher cells for entry into S-phase and mitosis. Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl- xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SIRT2 and RUNX2. CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs. Essential for early stages of embryonic development. During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation. Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis. Inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation upon DNA damage to stop cell cycle and genome replication at the G2 checkpoint thus facilitating DNA repair. Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C- mediated dephosphorylation and restoring cell cycle progression. In proliferating cells, CDK1-mediated FOXO1 phosphorylation at the G2-M phase represses FOXO1 interaction with 14-3-3 proteins and thereby promotes FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons. The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis. NEDD1 phosphorylation promotes PLK1-mediated NEDD1 phosphorylation and subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis. The phosphorylation of Bcl- xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis. In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration. CDK1-cyclin-B complex phosphorylates NCKAP5L and mediates its dissociation from centrosomes during mitosis (PubMed:26549230). {ECO:0000269|PubMed:16371510, ECO:0000269|PubMed:16407259, ECO:0000269|PubMed:16933150, ECO:0000269|PubMed:17459720, ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:18480403, ECO:0000269|PubMed:19509060, ECO:0000269|PubMed:19917720, ECO:0000269|PubMed:20171170, ECO:0000269|PubMed:20360007, ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20935635, ECO:0000269|PubMed:20937773, ECO:0000269|PubMed:21063390, ECO:0000269|PubMed:26549230}. | 16.04 | |||
| dfaCDK14 | Cyclin-dependent kinase 14 | 7 | 64 | 97.02 | 93.18 | ND | 0.06 | 0.94 | 0.6 | Mammalian | Highly expressed in brain, pancreas, kidney, heart, testis and ovary. Also detected at lower levels in other tissues except in spleen and thymus where expression is barely detected. {ECO:0000269|PubMed:11313143}. | Kinase | Serine/threonine-protein kinase involved in the control of the eukaryotic cell cycle, whose activity is controlled by an associated cyclin. Acts as a cell-cycle regulator of Wnt signaling pathway during G2/M phase by mediating the phosphorylation of LRP6 at 'Ser-1490', leading to the activation of the Wnt signaling pathway. Acts as a regulator of cell cycle progression and cell proliferation via its interaction with CCDN3. Phosphorylates RB1 in vitro, however the relevance of such result remains to be confirmed in vivo. May also play a role in meiosis, neuron differentiation and may indirectly act as a negative regulator of insulin-responsive glucose transport. {ECO:0000269|PubMed:16461467, ECO:0000269|PubMed:17517622, ECO:0000269|PubMed:19524571, ECO:0000269|PubMed:20059949}. | 16.04 | ||||
| dfaCDK15 | Cyclin-dependent kinase 15 | 3 | 61 | 95.70 | 89.88 | ND | 0.08 | 0.95 | 0.4 | Mammalian | Kinase | Serine/threonine-protein kinase that acts like an antiapoptotic protein that counters TRAIL/TNFSF10-induced apoptosis by inducing phosphorylation of BIRC5 at 'Thr-34'. {ECO:0000269|PubMed:24866247}. | 16.04 | |||||
| dfaCDK16 | Cyclin-dependent kinase 16 | 5 | 66 | 88.31 | 87.14 | ND | 0.67 | 0.94 | 0.4 | Mammalian | Detected in pancreas islets (at protein level). Detected in brain and pancreas. {ECO:0000269|PubMed:22798068}. | Kinase | Protein kinase that plays a role in vesicle-mediated transport processes and exocytosis. Regulates GH1 release by brain neurons. Phosphorylates NSF, and thereby regulates NSF oligomerization. Required for normal spermatogenesis. Regulates neuron differentiation and dendrite development (By similarity). Plays a role in the regulation of insulin secretion in response to changes in blood glucose levels. Can phosphorylate CCNY at 'Ser- 336' (in vitro). {ECO:0000250, ECO:0000269|PubMed:22184064, ECO:0000269|PubMed:22796189, ECO:0000269|PubMed:22798068}. | 16.04 | ||||
| dfaCDK18 | Cyclin-dependent kinase 18 | 4 | 64 | 99.42 | 98.29 | ND | 0.42 | 0.95 | 0.5 | Mammalian | Isoform 3 expression is limited to several subcortical nuclei of the basal gangli and the spinal cord. Isoform 2 is widely expressed. {ECO:0000269|PubMed:15019984}. | Kinase | May play a role in signal transduction cascades in terminally differentiated cells. | 16.04 | ||||
| dfaCDK19 | Cyclin-dependent kinase 19 | 4 | 97 | 92.58 | 95.66 | ND | 0.15 | 0.79 | 0.8 | Mammalian | Kinase | 16.04 | ||||||
| dfaCDK2 | Cyclin-dependent kinase 2 | 6 | 1916 | 93.40 | 91.02 | ND | 0.65 | 0.70 | 0.7 | Mammalian | Kinase | Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML) Advanced Solid tumors B-cell malignancies Cancer, unspecific Cardiovascular disease, unspecified Chronic lymphocytic leukemia (CLL) Hepatocellular Carcinoma (HCC) Nasopharyngeal Cancer (NPC) Non-Hodgkin's Lymphoma Non-small Cell Lung Cancer Solid tumors Viral infection, unspecified | Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Interacts with cyclins A, B1, B3, D, or E. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT- mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). {ECO:0000250|UniProtKB:P97377, ECO:0000269|PubMed:10499802, ECO:0000269|PubMed:10884347, ECO:0000269|PubMed:10995386, ECO:0000269|PubMed:10995387, ECO:0000269|PubMed:11051553, ECO:0000269|PubMed:11113184, ECO:0000269|PubMed:15800615, ECO:0000269|PubMed:17495531, ECO:0000269|PubMed:18372919, ECO:0000269|PubMed:19966300, ECO:0000269|PubMed:20079829, ECO:0000269|PubMed:20147522, ECO:0000269|PubMed:20195506, ECO:0000269|PubMed:20935635, ECO:0000269|PubMed:21262353, ECO:0000269|PubMed:21319273, ECO:0000269|PubMed:21596315}. | Cyclin-dependent kinase 2 inhibitor: Bosutinib | 15.11 | |||
| dfaCDK3 | Cyclin-dependent kinase 3 | 2 | 68 | 99.12 | 99.85 | ND | 0.03 | 0.43 | 0.6 | Mammalian | Expressed in cancer cell lines and glioblastoma tissue. {ECO:0000269|PubMed:18794154}. | Kinase | Serine/threonine-protein kinase that plays a critical role in the control of the eukaryotic cell cycle; involved in G0- G1 and G1-S cell cycle transitions. Interacts with CCNC/cyclin-C during interphase. Phosphorylates histone H1, ATF1, RB1 and CABLES1. ATF1 phosphorylation triggers ATF1 transactivation and transcriptional activities, and promotes cell proliferation and transformation. CDK3/cyclin-C mediated RB1 phosphorylation is required for G0-G1 transition. Promotes G1-S transition probably by contributing to the activation of E2F1, E2F2 and E2F3 in a RB1- independent manner. {ECO:0000269|PubMed:15084261, ECO:0000269|PubMed:18794154, ECO:0000269|PubMed:8846921}. | 16.04 | ||||
| dfaCDK4 | Cyclin-dependent kinase 4 | 6 | 528 | 96.98 | 97.30 | ND | 0.61 | 0.70 | 0.6 | Mammalian | Kinase | Melanoma, cutaneous malignant 3 (CMM3) [MIM:609048]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:7652577, ECO:0000269|PubMed:8528263, ECO:0000269|PubMed:9311594, ECO:0000269|PubMed:9425228}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. {ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:18827403, ECO:0000269|PubMed:9003781}. | Cyclin-dependent kinase 4 Inhibitor: Palbociclib | 16.04 | |||
| dfaCDK5 | Cyclin-dependent-like kinase 5 | 7 | 625 | 89.21 | 87.90 | ND | 0.62 | 0.66 | 0.6 | Mammalian | Isoform 1 is ubiquitously expressed. Accumulates in cortical neurons (at protein level). Isoform 2 has only been detected in testis, skeletal muscle, colon, bone marrow and ovary. {ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:19693690}. | Kinase | Lissencephaly 7, with cerebellar hypoplasia (LIS7) [MIM:616342]: A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six- layered cortex. LIS7 patients manifest lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy. {ECO:0000269|PubMed:25560765}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3- type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma- dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin- dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1- EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution. {ECO:0000269|PubMed:12393264, ECO:0000269|PubMed:12691662, ECO:0000269|PubMed:15992363, ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:17121855, ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17611284, ECO:0000269|PubMed:17671990, ECO:0000269|PubMed:18042622, ECO:0000269|PubMed:19081376, ECO:0000269|PubMed:19693690, ECO:0000269|PubMed:20061803, ECO:0000269|PubMed:20213743, ECO:0000269|PubMed:20826806, ECO:0000269|PubMed:21209322, ECO:0000269|PubMed:21220307, ECO:0000269|PubMed:21442427, ECO:0000269|PubMed:21465480, ECO:0000269|PubMed:21499257, ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:9822744}. | 15.11 | |||
| dfaCDK7 | Cyclin-dependent kinase 7 | 3 | 293 | 85.49 | 87.07 | ND | 0.58 | 0.76 | 0.5 | Mammalian | Ubiquitous. | Kinase | B-cell malignancies
Cancer, unspecific Solid tumors | Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. Cyclin- dependent kinases (CDKs) are activated by the binding to a cyclin and mediate the progression through the cell cycle. Each different complex controls a specific transition between 2 subsequent phases in the cell cycle. Required for both activation and complex formation of CDK1/cyclin-B during G2-M transition, and for activation of CDK2/cyclins during G1-S transition (but not complex formation). CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Phosphorylates SPT5/SUPT5H, SF1/NR5A1, POLR2A, p53/TP53, CDK1, CDK2, CDK4, CDK6 and CDK11B/CDK11. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation, thus regulating cell cycle progression. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Phosphorylation of POLR2A in complex with DNA promotes transcription initiation by triggering dissociation from DNA. Its expression and activity are constant throughout the cell cycle. Upon DNA damage, triggers p53/TP53 activation by phosphorylation, but is inactivated in turn by p53/TP53; this feedback loop may lead to an arrest of the cell cycle and of the transcription, helping in cell recovery, or to apoptosis. Required for DNA-bound peptides-mediated transcription and cellular growth inhibition. {ECO:0000269|PubMed:10024882, ECO:0000269|PubMed:11113184, ECO:0000269|PubMed:16327805, ECO:0000269|PubMed:17373709, ECO:0000269|PubMed:17386261, ECO:0000269|PubMed:17901130, ECO:0000269|PubMed:19015234, ECO:0000269|PubMed:19071173, ECO:0000269|PubMed:19136461, ECO:0000269|PubMed:19450536, ECO:0000269|PubMed:19667075, ECO:0000269|PubMed:20360007, ECO:0000269|PubMed:9372954, ECO:0000269|PubMed:9840937}. | 15.11 | |||
| dfaCDK8 | Cyclin-dependent kinase 8 | 8 | 264 | 87.72 | 89.03 | ND | 0.66 | 0.69 | 0.6 | Mammalian | Kinase | Cancer, unspecific | Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. {ECO:0000269|PubMed:10993082, ECO:0000269|PubMed:15546612}. | 15.11 | ||||
| dfaCDK9 | Cyclin-dependent kinase 9 | 6 | 264 | 85.83 | 86.83 | ND | 0.40 | 0.72 | 0.7 | Mammalian | Ubiquitous. | Kinase | Note=Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy, and confers predisposition to heart failure. | Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single- stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation. {ECO:0000269|PubMed:10393184, ECO:0000269|PubMed:10574912, ECO:0000269|PubMed:10757782, ECO:0000269|PubMed:10912001, ECO:0000269|PubMed:11112772, ECO:0000269|PubMed:11145967, ECO:0000269|PubMed:11575923, ECO:0000269|PubMed:11809800, ECO:0000269|PubMed:11884399, ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:14701750, ECO:0000269|PubMed:15564463, ECO:0000269|PubMed:16109376, ECO:0000269|PubMed:16109377, ECO:0000269|PubMed:17956865, ECO:0000269|PubMed:18362169, ECO:0000269|PubMed:19575011, ECO:0000269|PubMed:19844166, ECO:0000269|PubMed:20081228, ECO:0000269|PubMed:20493174, ECO:0000269|PubMed:20930849, ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:21127351, ECO:0000269|PubMed:9857195}. | 15.11 | |||
| dfaCDKL2 | Cyclin-dependent kinase-like 2 | 2 | 59 | 86.11 | 97.45 | ND | 0.78 | 0.98 | 0.2 | Mammalian | Expressed in testis and kidney, and at lower level in brain and lung. {ECO:0000269|PubMed:9000130}. | Kinase | 15.11 | |||||
| dfaCDKL5 | Cyclin-dependent kinase-like 5 | 4 | 60 | 99.08 | 99.54 | ND | 0.90 | 0.99 | 0.2 | Mammalian | Expressed in brain, lung, kidney, prostate, ovary, placenta, pancreas and testis. | Kinase | Note=Chromosomal aberrations involving CDKL5 are found in patients manifesting early-onset seizures and spams and psychomotor impairment. Translocation t(X;6)(p22.3;q14); translocation t(X;7)(p22.3;p15). Epileptic encephalopathy, early infantile, 2 (EIEE2) [MIM:300672]: A severe form of epilepsy characterized by seizures or spasms beginning in infancy. Patients with epileptic encephalopathy early infantile type 2 manifest features resembling Rett syndrome such as microcephaly, lack of speech development, stereotypic hand movements. However, EIEE2 and Rett syndrome are considered two distinct entities. {ECO:0000269|PubMed:12736870, ECO:0000269|PubMed:15492925, ECO:0000269|PubMed:15499549, ECO:0000269|PubMed:15689447, ECO:0000269|PubMed:15917271, ECO:0000269|PubMed:16015284, ECO:0000269|PubMed:16611748, ECO:0000269|PubMed:17993579, ECO:0000269|PubMed:18790821, ECO:0000269|PubMed:18809835, ECO:0000269|PubMed:19241098, ECO:0000269|PubMed:19253388, ECO:0000269|PubMed:24564546}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates phosphorylation of MECP2. {ECO:0000269|PubMed:15917271, ECO:0000269|PubMed:16935860}. | 16.04 | |||
| dfaCEGT | Ceramide glucosyltransferase | 4 | 112 | 97.52 | 94.26 | ND | 0.89 | 0.78 | 0.4 | Mammalian | Found in all tissues examined. {ECO:0000269|PubMed:8643456}. | Transferase | Sphingolipid storage disorders | Catalyzes the first glycosylation step in glycosphingolipid biosynthesis, the transfer of glucose to ceramide. May also serve as a "flippase". {ECO:0000269|PubMed:8643456}. | Ceramide glucosyltransferase antagonist: Eliglustat Ceramide glucosyltransferase inhibitor: Miglustat | 16.04 | ||
| dfaCEL | Bile salt-activated lipase | 2 | 63 | 92.16 | 86.51 | ND | 0.26 | 0.80 | 0.8 | Mammalian | Enzyme | Catalyzes fat and vitamin absorption. Acts in concert with pancreatic lipase and colipase for the complete digestion of dietary triglycerides. | 15.11 | |||||
| dfaCEL2A | Chymotrypsin-like elastase family member 2A | 7 | 50 | 82.16 | 82.20 | ND | 0.81 | 0.80 | 0.5 | Mammalian | Pancreas. Not detected in keratinocytes. {ECO:0000269|PubMed:10620133}. | Acts upon elastin. | 16.04 | |||||
| dfaCETP | Cholesteryl ester transfer protein {ECO:0000303|PubMed:3600759} | 7 | 676 | 96.87 | 97.81 | ND | 0.65 | 0.61 | 0.6 | Mammalian | Expressed by the liver and secreted in plasma. | Other ion channel | Hyperalphalipoproteinemia 1 (HALP1) [MIM:143470]: A condition characterized by high levels of high density lipoprotein (HDL) and increased HDL cholesterol levels. {ECO:0000269|PubMed:12091484, ECO:0000269|PubMed:2215607, ECO:0000269|PubMed:8408659}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles. Allows the net movement of cholesteryl ester from high density lipoproteins/HDL to triglyceride-rich very low density lipoproteins/VLDL, and the equimolar transport of triglyceride from VLDL to HDL (PubMed:3600759, PubMed:24293641). Regulates the reverse cholesterol transport, by which excess cholesterol is removed from peripheral tissues and returned to the liver for elimination (PubMed:17237796). {ECO:0000269|PubMed:24293641, ECO:0000303|PubMed:17237796, ECO:0000305|PubMed:3600759}. | 15.11 | |||
| dfaCFTR | Cystic fibrosis transmembrane conductance regulator | 6 | 131 | 97.22 | 99.79 | ND | 0.83 | 0.88 | 0.4 | Mammalian | Expressed in the respiratory airway, including bronchial epithelium, and in the female reproductive tract, including oviduct (at protein level). {ECO:0000269|PubMed:22207244}. | Other ion channel | Cystic fibrosis (CF) [MIM:219700]: A common generalized disorder of the exocrine glands which impairs clearance of secretions in a variety of organs. It is characterized by the triad of chronic bronchopulmonary disease (with recurrent respiratory infections), pancreatic insufficiency (which leads to malabsorption and growth retardation) and elevated sweat electrolytes. It is the most common genetic disease in Caucasians, with a prevalence of about 1 in 2'000 live births. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10094564, ECO:0000269|PubMed:1284466, ECO:0000269|PubMed:1284468, ECO:0000269|PubMed:1284529, ECO:0000269|PubMed:1284530, ECO:0000269|PubMed:1695717, ECO:0000269|PubMed:1710600, ECO:0000269|PubMed:2236053, ECO:0000269|PubMed:7504969, ECO:0000269|PubMed:7505694, ECO:0000269|PubMed:7513296, ECO:0000269|PubMed:7517264, ECO:0000269|PubMed:7520022, ECO:0000269|PubMed:7522211, ECO:0000269|PubMed:7524909, ECO:0000269|PubMed:7524913, ECO:0000269|PubMed:7525450, ECO:0000269|PubMed:7537150, ECO:0000269|PubMed:7541273, ECO:0000269|PubMed:7541510, ECO:0000269|PubMed:7543567, ECO:0000269|PubMed:7544319, ECO:0000269|PubMed:7581407, ECO:0000269|PubMed:7680525, ECO:0000269|PubMed:7683628, ECO:0000269|PubMed:7683954, ECO:0000269|PubMed:8081395, ECO:0000269|PubMed:8522333, ECO:0000269|PubMed:8723693, ECO:0000269|PubMed:8723695, ECO:0000269|PubMed:8800923, ECO:0000269|PubMed:8829633, ECO:0000269|PubMed:8956039, ECO:0000269|PubMed:9101301, ECO:0000269|PubMed:9222768, ECO:0000269|PubMed:9375855, ECO:0000269|PubMed:9401006, ECO:0000269|PubMed:9443874, ECO:0000269|PubMed:9452048, ECO:0000269|PubMed:9452054, ECO:0000269|PubMed:9452073, ECO:0000269|PubMed:9482579, ECO:0000269|PubMed:9521595, ECO:0000269|PubMed:9554753, ECO:0000269|PubMed:9736778, ECO:0000269|PubMed:9921909}. Note=The disease is caused by mutations affecting the gene represented in this entry. Congenital bilateral absence of the vas deferens (CBAVD) [MIM:277180]: Important cause of sterility in men and could represent an incomplete form of cystic fibrosis, as the majority of men suffering from cystic fibrosis lack the vas deferens. {ECO:0000269|PubMed:10651488, ECO:0000269|PubMed:7529962, ECO:0000269|PubMed:7539342, ECO:0000269|PubMed:9067761, ECO:0000269|Ref.77}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO1. Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation. {ECO:0000269|PubMed:22178883}. | Cystic fibrosis transmembrane conductance regulator antagonist: Bumetanide, Crofelemer, Glyburide Cystic fibrosis transmembrane conductance regulator inhibitor: Ibuprofen Cystic fibrosis transmembrane conductance regulator potentiator: Ivacaftor | 16.04 | ||
| dfaCHK1 | Serine/threonine-protein kinase Chk1 | 7 | 1722 | 95.47 | 96.05 | ND | 0.65 | 0.00 | 0.7 | Mammalian | Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon. {ECO:0000269|PubMed:9278511, ECO:0000269|PubMed:9382850}. | Kinase | Solid tumors | Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser- 124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell- cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest. Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition. | 15.11 | |||
| dfaCHK2 | Serine/threonine-protein kinase Chk2 | 5 | 528 | 94.81 | 94.25 | ND | 0.71 | 0.73 | 0.6 | Mammalian | High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues. | Kinase | Li-Fraumeni syndrome 2 (LFS2) [MIM:609265]: A highly penetrant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers. {ECO:0000269|PubMed:11719428}. Note=The disease is caused by mutations affecting the gene represented in this entry. Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:12533788}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Osteogenic sarcoma (OSRC) [MIM:259500]: A sarcoma originating in bone-forming cells, affecting the ends of long bones. Note=The gene represented in this entry may be involved in disease pathogenesis. Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:12094328, ECO:0000269|PubMed:21618645, ECO:0000269|PubMed:25619829}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. {ECO:0000269|PubMed:12094328}. | Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X- R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition (PubMed:25361978). {ECO:0000250|UniProtKB:Q9Z265, ECO:0000269|PubMed:10097108, ECO:0000269|PubMed:10724175, ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:12402044, ECO:0000269|PubMed:12607004, ECO:0000269|PubMed:12717439, ECO:0000269|PubMed:12810724, ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:17101782, ECO:0000269|PubMed:17380128, ECO:0000269|PubMed:17715138, ECO:0000269|PubMed:18317453, ECO:0000269|PubMed:18644861, ECO:0000269|PubMed:18728393, ECO:0000269|PubMed:20364141, ECO:0000269|PubMed:25361978, ECO:0000269|PubMed:25619829, ECO:0000269|PubMed:9836640, ECO:0000269|PubMed:9889122}. | 15.11 | |||
| dfaCHKA | Choline kinase alpha | 3 | 77 | 99.40 | 99.23 | ND | 0.27 | 0.58 | 0.4 | Mammalian | Enzyme | Cancer, unspecific
Proliferative diseases Ras-dependent tumourigenesis | Has a key role in phospholipid biosynthesis and may contribute to tumor cell growth. Catalyzes the first step in phosphatidylcholine biosynthesis. Contributes to phosphatidylethanolamine biosynthesis. Phosphorylates choline and ethanolamine. Has higher activity with choline. {ECO:0000269|PubMed:19915674}. | Choline kinase alpha substrate: Choline | 15.11 | |||
| dfaCHLE | Cholinesterase | 4 | 2662 | 91.98 | 85.13 | ND | 0.71 | 0.75 | 0.7 | Mammalian | Detected in blood plasma (at protein level). Present in most cells except erythrocytes. {ECO:0000269|PubMed:19368529, ECO:0000269|PubMed:19542320}. | Bradycardia Salivary hypersecretion | Hydrolase | Butyrylcholinesterase deficiency (BChE deficiency) [MIM:177400]: A metabolic disorder characterized by prolonged apnea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnea varies significantly depending on the extent of the enzyme deficiency. {ECO:0000269|PubMed:10404729, ECO:0000269|PubMed:11928765, ECO:0000269|PubMed:12881446, ECO:0000269|PubMed:1306123, ECO:0000269|PubMed:1349196, ECO:0000269|PubMed:1415224, ECO:0000269|PubMed:15563885, ECO:0000269|PubMed:15781196, ECO:0000269|PubMed:1611188, ECO:0000269|PubMed:16788378, ECO:0000269|PubMed:17700357, ECO:0000269|PubMed:18075469, ECO:0000269|PubMed:18300943, ECO:0000269|PubMed:25054547, ECO:0000269|PubMed:25264279, ECO:0000269|PubMed:2915989, ECO:0000269|PubMed:7634491, ECO:0000269|PubMed:8554068, ECO:0000269|PubMed:8680411, ECO:0000269|PubMed:9110359, ECO:0000269|PubMed:9191541, ECO:0000269|PubMed:9388484, ECO:0000269|PubMed:9543549, ECO:0000269|PubMed:9694584}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters. {ECO:0000269|PubMed:19452557, ECO:0000269|PubMed:19542320}. | Cholinesterase inhibitor: Pegvisomant | 15.11 | |
| dfaCLAT | Choline O-acetyltransferase | 1 | 44 | 99.73 | 99.96 | ND | 0.10 | 0.29 | 0.8 | Mammalian | Enzyme | Myasthenic syndrome, congenital, 6, presynaptic (CMS6) [MIM:254210]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS6 affected individuals have myasthenic symptoms since birth or early infancy, negative tests for anti-AChR antibodies, and abrupt episodic crises with increased weakness, bulbar paralysis, and apnea precipitated by undue exertion, fever, or excitement. CMS6 inheritance is autosomal recessive. {ECO:0000269|PubMed:11172068, ECO:0000269|PubMed:12756141}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. | Choline O-acetyltransferase substrate: Choline | 16.04 | |||
| dfaCLK1 | Dual specificity protein kinase CLK1 | 5 | 402 | 89.80 | 89.94 | ND | 0.53 | 0.58 | 0.7 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA. {ECO:0000269|PubMed:10480872, ECO:0000269|PubMed:19168442}. | 15.11 | ||||
| dfaCLK2 | Dual specificity protein kinase CLK2 | 1 | 483 | 89.43 | 88.30 | ND | 0.52 | 0.69 | 0.5 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. {ECO:0000269|PubMed:10480872, ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:8910305, ECO:0000269|PubMed:9637771}. | 15.11 | ||||
| dfaCLK3 | Dual specificity protein kinase CLK3 | 1 | 138 | 92.60 | 98.46 | ND | 0.43 | 0.58 | 0.3 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Phosphorylates SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. {ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:9637771}. | 15.11 | ||||
| dfaCLK4 | Dual specificity protein kinase CLK4 | 4 | 1195 | 87.80 | 89.14 | ND | 0.52 | 0.71 | 0.7 | Mammalian | Expressed in liver, kidney, heart, muscle, brain and endothelial cells. {ECO:0000269|PubMed:11170754, ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates SRSF1 and SRSF3. Required for the regulation of alternative splicing of MAPT/TAU. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. {ECO:0000269|PubMed:11170754, ECO:0000269|PubMed:19168442}. | 16.04 | ||||
| dfaCLTR1 | Cysteinyl leukotriene receptor 1 | 1 | 385 | 99.07 | 99.26 | ND | 0.81 | 0.75 | 0.5 | Mammalian | Widely expressed, with highest levels in spleen and peripheral blood leukocytes. Lower expression in several tissues, such as lung (mostly in smooth muscle bundles and alveolar macrophages), placenta, small intestine, pancreas, colon and heart. | Family A G protein-coupled receptor | Asthma | Receptor for cysteinyl leukotrienes mediating bronchoconstriction of individuals with and without asthma. Stimulation by LTD4 results in the contraction and proliferation of smooth muscle, edema, eosinophil migration and damage to the mucus layer in the lung. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The rank order of affinities for the leukotrienes is LTD4 >> LTE4 = LTC4 >> LTB4. | Cysteinyl leukotriene receptor 1 antagonist: Cinalukast, Montelukast, Pranlukast, Zafirlukast Cysteinyl leukotriene receptor 1 suppressor: Nedocromil | 16.04 | ||
| dfaCMA1 | Chymase | 5 | 297 | 95.57 | 98.64 | ND | 0.64 | 0.51 | 0.5 | Mammalian | Mast cells in lung, heart, skin and placenta. Expressed in both normal skin and in urticaria pigmentosa lesions. {ECO:0000269|PubMed:8144971}. | Protease | Asthma
Atopic dermatitis Cardiovascular disease, unspecified Inflammation Myocardial infarction | Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion. | 16.04 | |||
| dfaCNR1 | Cannabinoid receptor 1 | 1 | 4328 | 96.74 | 90.92 | ND | 0.59 | 0.00 | 0.8 | Nature11159 | Mammalian | Widely expressed. {ECO:0000269|PubMed:15620723}. | Family A G protein-coupled receptor | Analgesics
Inflammatory bowel disease Migraine Pain, unspecified | Involved in cannabinoid-induced CNS effects. Acts by inhibiting adenylate cyclase. Could be a receptor for anandamide. Inhibits L-type Ca(2+) channel current. Isoform 2 and isoform 3 have altered ligand binding. {ECO:0000269|PubMed:15620723}. | Cannabinoid receptor 1 agonist: Dronabinol Cannabinoid receptor 1 antagonist: Rimonabant Cannabinoid receptor 1 partial agonist: Nabilone | 16.04 | |
| dfaCNR2 | Cannabinoid receptor 2 | 5 | 3624 | 95.01 | 89.27 | ND | 0.59 | 0.00 | 0.7 | Mammalian | Preferentially expressed in cells of the immune system with higher expression in B-cells and NK cells (at protein level). Expressed in skin in suprabasal layers and hair follicles (at protein level). Highly expressed in tonsil and to a lower extent in spleen, peripheral blood mononuclear cells, and thymus. PubMed:14657172 could not detect expression in normal brain. Expressed in brain by perivascular microglial cells and dorsal root ganglion sensory neurons (at protein level). Two isoforms are produced by alternative promoter usage and differ only in the 5' UTR: isoform CB2A is observed predominantly in testis with some expression in brain, while isoform CB2B is predominant in spleen and leukocytes. {ECO:0000269|PubMed:12153574, ECO:0000269|PubMed:12511587, ECO:0000269|PubMed:14657172, ECO:0000269|PubMed:15266552, ECO:0000269|PubMed:18692962, ECO:0000269|PubMed:19496827, ECO:0000269|PubMed:7556170}. | Family A G protein-coupled receptor | Analgesics
Pain, unspecified | Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis. {ECO:0000269|PubMed:10051546, ECO:0000269|PubMed:12663043, ECO:0000269|PubMed:12711605, ECO:0000269|PubMed:18692962}. | Cannabinoid receptor 2 agonist: Dronabinol Cannabinoid receptor 2 partial agonist: Nabilone | 16.04 | ||
| dfaCOMT | Catechol O-methyltransferase | 3 | 82 | 94.73 | 92.89 | ND | 0.95 | 0.83 | 0.3 | Mammalian | Brain, liver, placenta, lymphocytes and erythrocytes. | Transferase | Parkinson's disease | Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol. | Catechol O-methyltransferase cofactor: S-Adenosylmethionine | 15.11 | ||
| dfaCP17A | Steroid 17-alpha-hydroxylase/17,20 lyase | 3 | 420 | 94.53 | 87.43 | ND | 0.65 | 0.57 | 0.5 | Mammalian | Cytochrome P450 | Adrenal hyperplasia 5 (AH5) [MIM:202110]: A form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late- onset (NC or LOAH)and 'cryptic' (asymptomatic). {ECO:0000269|PubMed:10720067, ECO:0000269|PubMed:11549685, ECO:0000269|PubMed:11836339, ECO:0000269|PubMed:12466376, ECO:0000269|PubMed:14671162, ECO:0000269|PubMed:1515452, ECO:0000269|PubMed:1714904, ECO:0000269|PubMed:1740503, ECO:0000269|PubMed:19793597, ECO:0000269|PubMed:24140098, ECO:0000269|PubMed:24498484, ECO:0000269|PubMed:25650406, ECO:0000269|PubMed:2808364, ECO:0000269|PubMed:8027220, ECO:0000269|PubMed:8245018, ECO:0000269|PubMed:8345056, ECO:0000269|PubMed:8396144, ECO:0000269|PubMed:8550762, ECO:0000269|Ref.20}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Conversion of pregnenolone and progesterone to their 17- alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty. {ECO:0000269|PubMed:22266943}. | Steroid 17-alpha-hydroxylase/17,20 lyase inhibitor: Progesterone | 15.11 | |||
| dfaCP1A1 | Cytochrome P450 1A1 | 5 | 202 | 96.06 | 93.19 | ND | 0.84 | 0.76 | 0.4 | Mammalian | Lung, lymphocytes and placenta. | Cytochrome P450 | Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. | Cytochrome P450 1A1 inducer: Cytochrome P450 1A1 inhibitor: Vitamin A | 15.11 | |||
| dfaCP1B1 | Cytochrome P450 1B1 | 3 | 106 | 97.41 | 98.39 | ND | 0.60 | 0.50 | 0.3 | Mammalian | Expressed in many tissues. {ECO:0000269|PubMed:8175734}. | Cytochrome P450 | Peters anomaly (PETAN) [MIM:604229]: Consists of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and a variable degree of iris and lenticular attachments to the central aspect of the posterior cornea. {ECO:0000269|PubMed:11403040}. Note=The disease is caused by mutations affecting the gene represented in this entry. Glaucoma 3, primary congenital, A (GLC3A) [MIM:231300]: An autosomal recessive form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. {ECO:0000269|PubMed:10227395, ECO:0000269|PubMed:10655546, ECO:0000269|PubMed:11184479, ECO:0000269|PubMed:11527932, ECO:0000269|PubMed:11980847, ECO:0000269|PubMed:12036985, ECO:0000269|PubMed:12525557, ECO:0000269|PubMed:14635112, ECO:0000269|PubMed:14640114, ECO:0000269|PubMed:15255109, ECO:0000269|PubMed:15342693, ECO:0000269|PubMed:15475877, ECO:0000269|PubMed:16490498, ECO:0000269|PubMed:16735994, ECO:0000269|PubMed:9463332, ECO:0000269|PubMed:9497261}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Glaucoma, primary open angle (POAG) [MIM:137760]: A complex and genetically heterogeneous ocular disorder characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. In some cases, POAG shows digenic inheritance involving mutations in CYP1B1 and MYOC genes. {ECO:0000269|PubMed:11774072, ECO:0000269|PubMed:15342693, ECO:0000269|PubMed:16688110, ECO:0000269|PubMed:16862072}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. CYP1B1 mutations have been reported to pose a significant risk for early-onset POAG and also modify glaucoma phenotype in patients who do not carry a MYOC mutation (PubMed:15342693). {ECO:0000269|PubMed:15342693}. Glaucoma 1, open angle, A (GLC1A) [MIM:137750]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. {ECO:0000269|PubMed:11774072}. Note=The gene represented in this entry acts as a disease modifier. Digenic mutations in CYP1B1 and MYOC have been found in a family segregating both primary adult- onset and juvenile forms of open angle glaucoma (PubMed:11774072). All affected family members with mutations in both MYOC and CYP1B1 had juvenile glaucoma, whereas those with only the MYOC mutation had the adult-onset form (PubMed:11774072). {ECO:0000269|PubMed:11774072}. | Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, retinoid and xenobiotics. Preferentially oxidizes 17beta- estradiol to the carcinogenic 4-hydroxy derivative, and a variety of procarcinogenic compounds to their activated forms, including polycyclic aromatic hydrocarbons. Promotes angiogenesis by removing cellular oxygenation products, thereby decreasing oxidative stress, release of antiangiogenic factor THBS2, then allowing endothelial cells migration, cell adhesion and capillary morphogenesis. These changes are concommitant with the endothelial nitric oxide synthase activity and nitric oxide synthesis. Plays an important role in the regulation of perivascular cell proliferation, migration, and survival through modulation of the intracellular oxidative state and NF-kappa-B expression and/or activity, during angiogenesis. Contributes to oxidative homeostasis and ultrastructural organization and function of trabecular meshwork tissue through modulation of POSTN expression. {ECO:0000269|PubMed:10426814, ECO:0000269|PubMed:15258110, ECO:0000269|PubMed:22888116, ECO:0000269|PubMed:23821647}. | Cytochrome P450 1B1 inducer: Biotin | 15.11 | ||
| dfaCP24A | 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial | 4 | 41 | 98.78 | 99.46 | ND | 0.89 | 0.89 | 0.3 | Mammalian | Cytochrome P450 | Has a role in maintaining calcium homeostasis. Catalyzes the NADPH-dependent 24-hydroxylation of calcidiol (25- hydroxyvitamin D(3)) and calcitriol (1-alpha,25-dihydroxyvitamin D(3)). The enzyme can perform up to 6 rounds of hydroxylation of calcitriol leading to calcitroic acid. | 15.11 | |||||
| dfaCP26A | Cytochrome P450 26A1 | 3 | 97 | 99.70 | 99.90 | ND | 0.39 | 0.48 | 0.4 | Mammalian | Highest levels in adult liver, heart, pituitary gland, adrenal gland, placenta and regions of the brain. {ECO:0000269|PubMed:9826557}. | Cytochrome P450 | Cardiovascular disease, unspecified
Eye diseases Hyperproliferative disorders Inflammatory diseases Neurodegenerative diseases Noninsulin-dependent diabetes mellitus Skin diseases | Plays a key role in retinoic acid metabolism. Acts on retinoids, including all-trans-retinoic acid (RA) and its stereoisomer 9-cis-RA. Capable of both 4-hydroxylation and 18- hydroxylation. Responsible for generation of several hydroxylated forms of RA, including 4-OH-RA, 4-oxo-RA and 18-OH-RA. | Cytochrome P450 26A1 inducer: Vitamin A Cytochrome P450 26A1 inhibitor: Ketoconazole Cytochrome P450 26A1 substrate: Acitretin | 16.04 | ||
| dfaCP2C8 | Cytochrome P450 2C8 | 1 | 328 | 87.86 | 86.94 | ND | 0.65 | 0.68 | 0.5 | Mammalian | Cytochrome P450 | Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol). {ECO:0000269|PubMed:7574697}. | Cytochrome P450 2C8 inhibitor: Cyclosporine | 15.11 | ||||
| dfaCP51A | Lanosterol 14-alpha demethylase | 6 | 52 | 80.31 | 85.30 | ND | 0.49 | 0.69 | 0.3 | Mammalian | Ubiquitously expressed with highest levels in testis, ovary, adrenal, prostate, liver, kidney and lung. {ECO:0000269|PubMed:8619637}. | Cytochrome P450 | Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol. {ECO:0000269|PubMed:20149798}. | 15.11 | ||||
| dfaCRFR1 | Corticotropin-releasing factor receptor 1 | 2 | 1755 | 99.41 | 98.37 | ND | 0.53 | 0.51 | 0.6 | Nature11159 | Mammalian | Predominantly expressed in the cerebellum, pituitary, cerebral cortex and olfactory lobe. {ECO:0000269|PubMed:8243652}. | Family B G protein-coupled receptor | Anxiety Disorders
Depression Innate anxiety Irritable Bowel Syndrome (IBS) Obesity Stress-related disorders | G-protein coupled receptor for CRH (corticotropin- releasing factor) and UCN (urocortin). Has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. Inhibits the activity of the calcium channel CACNA1H. Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli. {ECO:0000269|PubMed:18292205, ECO:0000269|PubMed:18801728, ECO:0000269|PubMed:23576434, ECO:0000269|PubMed:23863939}. | 15.11 | ||
| dfaCSF1R | Macrophage colony-stimulating factor 1 receptor | 7 | 875 | 94.73 | 94.61 | ND | 0.65 | 0.72 | 0.7 | Mammalian | Expressed in bone marrow and in differentiated blood mononuclear cells. | Kinase | Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers. Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection. Leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:221820]: An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes. {ECO:0000269|PubMed:22197934, ECO:0000269|PubMed:24532199}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5- trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP- 1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:12882960, ECO:0000269|PubMed:15117969, ECO:0000269|PubMed:16170366, ECO:0000269|PubMed:16337366, ECO:0000269|PubMed:16648572, ECO:0000269|PubMed:17121910, ECO:0000269|PubMed:18467591, ECO:0000269|PubMed:18814279, ECO:0000269|PubMed:19193011, ECO:0000269|PubMed:19934330, ECO:0000269|PubMed:20489731, ECO:0000269|PubMed:20504948, ECO:0000269|PubMed:20829061, ECO:0000269|PubMed:7683918}. | Macrophage colony-stimulating factor 1 receptor antagonist: Imatinib | 15.11 | ||
| dfaCSK | Tyrosine-protein kinase CSK | 2 | 160 | 87.12 | 86.17 | ND | 0.26 | 0.81 | 0.5 | Mammalian | Expressed in lung and macrophages. {ECO:0000269|PubMed:1371489}. | Kinase | Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T- cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK. {ECO:0000269|PubMed:1639064, ECO:0000269|PubMed:9281320}. | 15.11 | ||||
| dfaCSK21 | Casein kinase II subunit alpha | 6 | 400 | 86.17 | 84.06 | ND | 0.77 | 0.74 | 0.6 | Mammalian | Expressed in gastric carcinoma tissue and the expression gradually increases with the progression of the carcinoma (at protein level). {ECO:0000269|PubMed:24962073}. | Kinase | Breast cancer
Cancer, unspecific | Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV. Phosphorylates PML at 'Ser-565' and primes it for ubiquitin- mediated degradation. Plays an important role in the circadian clock function by phosphorylating ARNTL/BMAL1 at 'Ser-90' which is pivotal for its interaction with CLOCK and which controls CLOCK nuclear entry (PubMed:11239457, PubMed:11704824, PubMed:16193064, PubMed:19188443, PubMed:20625391, PubMed:22406621). Phosphorylates CCAR2 at 'Thr-454' in gastric carcinoma tissue (PubMed:24962073). {ECO:0000269|PubMed:11239457, ECO:0000269|PubMed:11704824, ECO:0000269|PubMed:16193064, ECO:0000269|PubMed:19188443, ECO:0000269|PubMed:20625391, ECO:0000269|PubMed:22406621, ECO:0000269|PubMed:24962073}. | 15.11 | |||
| dfaCSK22 | Casein kinase II subunit alpha' | 5 | 101 | 94.29 | 93.08 | ND | 0.90 | 0.81 | 0.3 | Mammalian | Kinase | Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV. {ECO:0000269|PubMed:11239457, ECO:0000269|PubMed:11704824, ECO:0000269|PubMed:16193064}. | 15.11 | |||||
| dfaCTRA | Chymotrypsinogen A | 4 | 206 | 91.46 | 89.02 | ND | 0.63 | 0.74 | 0.7 | Mammalian | Protease | 15.11 | ||||||
| dfaCTRB1 | Chymotrypsinogen B | 5 | 84 | 99.15 | 96.66 | ND | 0.41 | 0.85 | 0.9 | Mammalian | Protease | 16.04 | ||||||
| dfaCTRC | Chymotrypsin-C | 5 | 90 | 96.68 | 85.58 | ND | 0.71 | 0.53 | 0.5 | Mammalian | Pancreas. | Protease | Pancreatitis, hereditary (PCTT) [MIM:167800]: A disease characterized by pancreas inflammation, permanent destruction of the pancreatic parenchyma, maldigestion, and severe abdominal pain attacks. {ECO:0000269|PubMed:18059268, ECO:0000269|PubMed:18172691, ECO:0000269|PubMed:22580415, ECO:0000269|PubMed:22942235}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Loss-of-function CTRC variants predispose to pancreatitis by diminishing its protective trypsin-degrading activity (PubMed:18059268). They cause loss of function by one or more of three mechanisms: reduced secretion, catalytic defect and increased degradation by trypsin (PubMed:22942235). {ECO:0000269|PubMed:18059268, ECO:0000269|PubMed:22942235}. | Regulates activation and degradation of trypsinogens and procarboxypeptidases by targeting specific cleavage sites within their zymogen precursors. Has chymotrypsin-type protease activity and hypocalcemic activity. {ECO:0000269|PubMed:23430245}. | 16.04 | |||
| dfaCTRO | Citron Rho-interacting kinase | 4 | 65 | 89.48 | 92.73 | ND | 0.24 | 0.99 | 0.2 | Mammalian | Kinase | Plays a role in cytokinesis. Required for KIF14 localization to the central spindle and midbody. Putative RHO/RAC effector that binds to the GTP-bound forms of RHO and RAC1. It probably binds p21 with a tighter specificity in vivo. Displays serine/threonine protein kinase activity. Plays an important role in the regulation of cytokinesis and the development of the central nervous system. Phosphorylates MYL9/MLC2. {ECO:0000269|PubMed:16236794, ECO:0000269|PubMed:16431929, ECO:0000269|PubMed:21457715}. | 16.04 | |||||
| dfaCX3C1 | CX3C chemokine receptor 1 | 1 | 41 | 99.97 | 100.00 | ND | 0.31 | 0.58 | 0.4 | Mammalian | Expressed in lymphoid and neural tissues. | Family A G protein-coupled receptor | Macular degeneration, age-related, 12 (ARMD12) [MIM:613784]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:15208270}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for the CX3C chemokine fractalkine and mediates both its adhesive and migratory functions. Acts as coreceptor with CD4 for HIV-1 virus envelope protein (in vitro). Isoform 2 and isoform 3 seem to be more potent HIV-1 coreceptors than isoform 1. | 16.04 | |||
| dfaCXCR1 | C-X-C chemokine receptor type 1 | 4 | 184 | 98.38 | 97.69 | ND | 0.72 | 0.73 | 0.5 | Mammalian | Family A G protein-coupled receptor | Acute respiratory distress syndrome
Asthma Human cytomegalovirus infections Lung injury | Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activate a phosphatidylinositol-calcium second messenger system. This receptor binds to IL-8 with a high affinity and to MGSA (GRO) with a low affinity. | C-X-C chemokine receptor type 1 other: Ketoprofen | 16.04 | |||
| dfaCXCR2 | C-X-C chemokine receptor type 2 | 4 | 442 | 98.07 | 95.33 | ND | 0.65 | 0.75 | 0.6 | Mammalian | Family A G protein-coupled receptor | Acute respiratory distress syndrome
Asthma Chronic Obstructive Pulmonary Disease (COPD) Colorectal cancer Lung injury | Receptor for interleukin-8 which is a powerful neutrophil chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. Binds to IL-8 with high affinity. Also binds with high affinity to CXCL3, GRO/MGSA and NAP-2. | 16.04 | ||||
| dfaCXCR3 | C-X-C chemokine receptor type 3 | 7 | 697 | 96.75 | 94.63 | ND | 0.59 | 0.63 | 0.7 | Mammalian | Isoform 1 and isoform 2 are mainly expressed in heart, kidney, liver and skeletal muscle. Isoform 1 is also expressed in placenta. Isoform 2 is expressed in endothelial cells. Expressed in T-cells (at protein level). {ECO:0000269|PubMed:12782716, ECO:0000269|PubMed:23121557}. | Family A G protein-coupled receptor | Autoimmune diseases
Focal stroke Inflammatory Disorders, Unspecified Insulin-dependent diabetes mellitus Multiple sclerosis Psoriasis and Psoriatic Disorders | Isoform 1: Receptor for the C-X-C chemokine CXCL9, CXCL10 and CXCL11 and mediates the proliferation, survival and angiogenic activity of human mesangial cells (HMC) through a heterotrimeric G-protein signaling pathway (PubMed:12782716). Binds to CCL21. Probably promotes cell chemotaxis response. {ECO:0000269|PubMed:12782716}. Isoform 2: Receptor for the C-X-C chemokine CXCL4 and also mediates the inhibitory activities of CXCL9, CXCL10 and CXCL11 on the proliferation, survival and angiogenic activity of human microvascular endothelial cells (HMVEC) through a cAMP- mediated signaling pathway (PubMed:12782716). Does not promote cell chemotaxis respons. Interaction with CXCL4 or CXCL10 leads to activation of the p38MAPK pathway and contributes to inhibition of angiogenesis. Overexpression in renal cancer cells down-regulates expression of the anti-apoptotic protein HMOX1 and promotes apoptosis. {ECO:0000269|PubMed:12782716}. Isoform 3: Mediates the activity of CXCL11. | 16.04 | |||
| dfaCXCR4 | C-X-C chemokine receptor type 4 | 5 | 168 | 98.88 | 99.62 | ND | 0.47 | 0.72 | 0.7 | Mammalian | Expressed in numerous tissues, such as peripheral blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex and medulla (in microglia as well as in astrocytes), brain microvascular, coronary artery and umbilical cord endothelial cells. Isoform 1 is predominant in all tissues tested. {ECO:0000269|PubMed:11276205}. | Family A G protein-coupled receptor | WHIM syndrome (WHIMS) [MIM:193670]: Immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. {ECO:0000269|PubMed:12692554}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival. {ECO:0000269|PubMed:10074102, ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:17197449, ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:20228059, ECO:0000269|PubMed:20505072, ECO:0000269|PubMed:8752280, ECO:0000269|PubMed:8752281}. (Microbial infection) Acts as a coreceptor (CD4 being the primary receptor) for human immunodeficiency virus-1/HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus (PubMed:9427609, PubMed:10074122, PubMed:10756055). Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). {ECO:0000269|PubMed:10074122, ECO:0000269|PubMed:10756055, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:9427609}. | C-X-C chemokine receptor type 4 antagonist: Framycetin, Plerixafor | 16.04 | ||
| dfaDAPK1 | Death-associated protein kinase 1 | 7 | 72 | 99.01 | 96.60 | ND | 0.68 | 0.82 | 0.7 | Mammalian | Isoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas. {ECO:0000269|PubMed:18422656}. | Kinase | Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript- selective translation inhibition. Isoform 2 cannot induce apoptosis but can induce membrane blebbing. | 15.11 | ||||
| dfaDAPK3 | Death-associated protein kinase 3 | 4 | 364 | 89.54 | 89.44 | ND | 0.43 | 0.58 | 0.6 | Mammalian | Widely expressed. Isoform 1 and isoform 2 are expressed in the bladder smooth muscle. {ECO:0000269|PubMed:15292222, ECO:0000269|PubMed:17126281}. | Kinase | Serine/threonine kinase which is involved in the regulation of apoptosis, autophagy, transcription, translation and actin cytoskeleton reorganization. Involved in the regulation of smooth muscle contraction. Regulates both type I (caspase- dependent) apoptotic and type II (caspase-independent) autophagic cell deaths signal, depending on the cellular setting. Involved in regulation of starvation-induced autophagy. Regulates myosin phosphorylation in both smooth muscle and non-muscle cells. In smooth muscle, regulates myosin either directly by phosphorylating MYL12B and MYL9 or through inhibition of smooth muscle myosin phosphatase (SMPP1M) via phosphorylation of PPP1R12A; the inhibition of SMPP1M functions to enhance muscle responsiveness to Ca(2+) and promote a contractile state. Phosphorylates MYL12B in non-muscle cells leading to reorganization of actin cytoskeleton. Isoform 2 can phosphorylate myosin, PPP1R12A and MYL12B. Overexpression leads to condensation of actin stress fibers into thick bundles. Involved in actin filament focal adhesion dynamics. The function in both reorganization of actin cytoskeleton and focal adhesion dissolution is modulated by RhoD. Positively regulates canonical Wnt/beta-catenin signaling through interaction with NLK and TCF7L2. Phosphorylates RPL13A on 'Ser-77' upon interferon-gamma activation which is causing RPL13A release from the ribosome, RPL13A association with the GAIT complex and its subsequent involvement in transcript-selective translation inhibition. Enhances transcription from AR-responsive promoters in a hormone- and kinase-dependent manner. Involved in regulation of cell cycle progression and cell proliferation. May be a tumor suppressor. {ECO:0000269|PubMed:10356987, ECO:0000269|PubMed:11384979, ECO:0000269|PubMed:11781833, ECO:0000269|PubMed:12917339, ECO:0000269|PubMed:15096528, ECO:0000269|PubMed:15367680, ECO:0000269|PubMed:16219639, ECO:0000269|PubMed:17126281, ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:18995835, ECO:0000269|PubMed:21169990, ECO:0000269|PubMed:21408167, ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:21487036, ECO:0000269|PubMed:23454120}. | 15.11 | ||||
| dfaDCAM | S-adenosylmethionine decarboxylase proenzyme | 3 | 53 | 99.56 | 99.76 | ND | 0.45 | 0.62 | 0.8 | Mammalian | Enzyme | Cancer, unspecific
Parasitic diseases Proliferative diseases | Essential for biosynthesis of the polyamines spermidine and spermine. Promotes maintenance and self-renewal of embryonic stem cells, by maintaining spermine levels (By similarity). {ECO:0000250}. | S-adenosylmethionine decarboxylase proenzyme cofactor: S-Adenosylmethionine | 15.11 | |||
| dfaDCK | Deoxycytidine kinase | 3 | 94 | 99.28 | 99.53 | ND | 0.86 | 0.88 | 0.4 | Mammalian | Enzyme | Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents. {ECO:0000269|PubMed:18377927, ECO:0000269|PubMed:20614893}. | Deoxycytidine kinase substrate: Cladribine | 15.11 | ||||
| dfaDCLK1 | Serine/threonine-protein kinase DCLK1 | 4 | 106 | 82.77 | 89.11 | ND | 0.19 | 0.87 | 0.4 | Mammalian | In fetal tissues, highly expressed in brain, detectable in lung and liver, but not in kidney. In adult tissues, expressed ubiquitously in the brain, detectable in the heart, liver, spleen, thymus, prostate, testis, ovary, small intestine and colon. The type A isoforms seem to be expressed predominantly in fetal brain whereas type B isoforms are expressed abundantly in both fetal and adult brain. {ECO:0000269|PubMed:10051403}. | Kinase | Probable kinase that may be involved in a calcium- signaling pathway controlling neuronal migration in the developing brain. May also participate in functions of the mature nervous system. | 16.04 | ||||
| dfaDCLK3 | Serine/threonine-protein kinase DCLK3 | 2 | 65 | 86.32 | 80.92 | ND | 0.15 | 0.62 | 0.6 | Mammalian | Kinase | 16.04 | ||||||
| dfaDCMC | Malonyl-CoA decarboxylase, mitochondrial | 1 | 209 | 99.58 | 96.87 | ND | 0.60 | 0.71 | 0.6 | Mammalian | Expressed in fibroblasts and hepatoblastoma cells (at protein level). Expressed strongly in heart, liver, skeletal muscle, kidney and pancreas. Expressed in myotubes. Expressed weakly in brain, placenta, spleen, thymus, testis, ovary and small intestine. {ECO:0000269|PubMed:10455107, ECO:0000269|PubMed:18314420}. | Enzyme | Malonyl-CoA decarboxylase deficiency (MLYCD deficiency) [MIM:248360]: Autosomal recessive disease characterized by abdominal pain, chronic constipation, episodic vomiting, metabolic acidosis and malonic aciduria. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of malonyl-CoA to acetyl-CoA. In the fatty acid biosynthesis MCD selectively removes malonyl-CoA and thus assures that methyl-malonyl-CoA is the only chain elongating substrate for fatty acid synthase and that fatty acids with multiple methyl side chains are produced. In peroxisomes it may be involved in degrading intraperoxisomal malonyl-CoA, which is generated by the peroxisomal beta-oxidation of odd chain-length dicarboxylic fatty acids. Plays a role in the metabolic balance between glucose and lipid oxidation in muscle independent of alterations in insulin signaling. May play a role in controlling the extent of ischemic injury by promoting glucose oxidation. {ECO:0000269|PubMed:10455107, ECO:0000269|PubMed:15003260, ECO:0000269|PubMed:18314420, ECO:0000269|PubMed:23482565}. | 15.11 | |||
| dfaDDR1 | Epithelial discoidin domain-containing receptor 1 | 4 | 101 | 91.48 | 94.64 | ND | 0.64 | 0.80 | 0.6 | Mammalian | Detected in T-47D, MDA-MB-175 and HBL-100 breast carcinoma cells, A-431 epidermoid carcinoma cells, SW48 and SNU-C2B colon carcinoma cells and Hs 294T melanoma cells (at protein level). Expressed at low levels in most adult tissues and is highest in the brain, lung, placenta and kidney. Lower levels of expression are detected in melanocytes, heart, liver, skeletal muscle and pancreas. Abundant in breast carcinoma cell lines. In the colonic mucosa, expressed in epithelia but not in the connective tissue of the lamina propria. In the thyroid gland, expressed in the epithelium of the thyroid follicles. In pancreas, expressed in the islets of Langerhans cells, but not in the surrounding epithelial cells of the exocrine pancreas. In kidney, expressed in the epithelia of the distal tubules. Not expressed in connective tissue, endothelial cells, adipose tissue, muscle cells or cells of hematopoietic origin. {ECO:0000269|PubMed:7845687, ECO:0000269|PubMed:7848919, ECO:0000269|PubMed:8247543}. | Kinase | Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11. {ECO:0000250, ECO:0000269|PubMed:12065315, ECO:0000269|PubMed:16234985, ECO:0000269|PubMed:16337946, ECO:0000269|PubMed:19401332, ECO:0000269|PubMed:20093046, ECO:0000269|PubMed:20432435, ECO:0000269|PubMed:20884741, ECO:0000269|PubMed:21044884, ECO:0000269|PubMed:9659899}. | Epithelial discoidin domain-containing receptor 1 antagonist: Imatinib | 15.11 | |||
| dfaDDR2 | Discoidin domain-containing receptor 2 | 4 | 121 | 95.36 | 98.53 | ND | 0.62 | 0.56 | 0.6 | Mammalian | Detected in osteocytes, osteoblastic cells in subchondral bone, bone lining cells, tibia and cartilage (at protein level). Detected at high levels in heart and lung, and at low levels in brain, placenta, liver, skeletal muscle, pancreas, and kidney. {ECO:0000269|PubMed:17665456, ECO:0000269|PubMed:20564243, ECO:0000269|PubMed:8247548}. | Kinase | Spondyloepimetaphyseal dysplasia short limb-hand type (SEMD-SL) [MIM:271665]: A bone disease characterized by short- limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping. {ECO:0000269|PubMed:19110212, ECO:0000269|PubMed:20223752, ECO:0000269|PubMed:26463668}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing. {ECO:0000269|PubMed:16186104, ECO:0000269|PubMed:16186108, ECO:0000269|PubMed:17665456, ECO:0000269|PubMed:18201965, ECO:0000269|PubMed:20004161, ECO:0000269|PubMed:20564243, ECO:0000269|PubMed:20734453, ECO:0000269|PubMed:9659899}. | Discoidin domain-containing receptor 2 inhibitor: Regorafenib | 16.04 | ||
| dfaDEFM | Peptide deformylase, mitochondrial | 1 | 45 | 99.70 | 84.52 | ND | 0.73 | 0.29 | 0.7 | Mammalian | Ubiquitous. | Enzyme | Removes the formyl group from the N-terminal Met of newly synthesized proteins. {ECO:0000250}. | 15.11 | ||||
| dfaDGAT1 | Diacylglycerol O-acyltransferase 1 | 5 | 571 | 98.30 | 99.14 | ND | 0.50 | 0.59 | 0.6 | Mammalian | Enzyme | Diarrhea 7 (DIAR7) [MIM:615863]: A life-threatening disease characterized by severe, intractable, watery diarrhea. {ECO:0000269|PubMed:23114594}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. In contrast to DGAT2 it is not essential for survival. May be involved in VLDL (very low density lipoprotein) assembly. In liver, plays a role in esterifying exogenous fatty acids to glycerol. Functions as the major acyl-CoA retinol acyltransferase (ARAT) in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity leading to skin and hair disorders. {ECO:0000269|PubMed:16214399, ECO:0000269|PubMed:9756920}. | 16.04 | ||||
| dfaDHB1 | Estradiol 17-beta-dehydrogenase 1 | 1 | 298 | 97.69 | 97.13 | ND | 0.64 | 0.67 | 0.5 | Mammalian | Enzyme | Breast cancer (hormone-sensitive) | Favors the reduction of estrogens and androgens. Also has 20-alpha-HSD activity. Uses preferentially NADH. | 15.11 | ||||
| dfaDHB2 | Estradiol 17-beta-dehydrogenase 2 | 2 | 273 | 98.42 | 97.54 | ND | 0.43 | 0.54 | 0.4 | Mammalian | Enzyme | Capable of catalyzing the interconversion of testosterone and androstenedione, as well as estradiol and estrone. Also has 20-alpha-HSD activity. Uses NADH while EDH17B3 uses NADPH. | 16.04 | |||||
| dfaDHB3 | Testosterone 17-beta-dehydrogenase 3 | 4 | 146 | 96.24 | 84.22 | ND | 0.50 | 0.56 | 0.7 | Mammalian | Testis. | Enzyme | Male pseudohermaphrodism with gynecomastia (MPH) [MIM:264300]: These individuals have unambiguous female external genitalia at birth, but fail to menstruate at the time of expected puberty and instead virilize as evidenced by growth of the phallus. Breast development may or may not take place. {ECO:0000269|PubMed:11158067, ECO:0000269|PubMed:26545797, ECO:0000269|PubMed:8075637, ECO:0000269|PubMed:8550739, ECO:0000269|PubMed:9709959, ECO:0000269|PubMed:9758445}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Favors the reduction of androstenedione to testosterone. Uses NADPH while the two other EDH17B enzymes use NADH. {ECO:0000269|PubMed:26545797}. | 16.04 | |||
| dfaDHI1 | Corticosteroid 11-beta-dehydrogenase isozyme 1 | 5 | 1757 | 91.46 | 87.89 | ND | 0.67 | 0.69 | 0.6 | Mammalian | Widely expressed at low levels. Highest expression in liver. {ECO:0000269|PubMed:10699594}. | Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7- ketocholesterol to 7-beta-hydroxycholesterol (By similarity). {ECO:0000250, ECO:0000269|PubMed:10699594}. | 15.11 | |||||
| dfaDHI2 | Corticosteroid 11-beta-dehydrogenase isozyme 2 | 7 | 348 | 92.81 | 92.75 | ND | 0.60 | 0.68 | 0.5 | Mammalian | Expressed in kidney, pancreas, prostate, ovary, small intestine and colon. At midgestation, expressed at high levels in placenta and in fetal kidney and, at much lower levels, in fetal lung and testis (PubMed:8530071). {ECO:0000269|PubMed:8530071}. | Enzyme | Apparent mineralocorticoid excess (AME) [MIM:218030]: An autosomal recessive form of low-renin hypertension. It is usually diagnosed within the first years of life and is characterized by polyuria and polydipsia, failure to thrive, hypernatremia, severe hypertension with low renin and aldosterone levels, profound hypokalemia with metabolic alkalosis, and most often nephrocalcinosis. {ECO:0000269|PubMed:12788846, ECO:0000269|PubMed:17314322, ECO:0000269|PubMed:7593417, ECO:0000269|PubMed:7608290, ECO:0000269|PubMed:9661590}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of cortisol to the inactive metabolite cortisone. Modulates intracellular glucocorticoid levels, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids. | 16.04 | |||
| dfaDHSO | Sorbitol dehydrogenase | 1 | 66 | 99.82 | 99.88 | ND | 0.42 | 0.63 | 0.6 | Mammalian | Expressed in kidney and epithelial cells of both benign and malignant prostate tissue. Expressed in epididymis (at protein level). {ECO:0000269|PubMed:16278369, ECO:0000269|PubMed:19423711, ECO:0000269|PubMed:20372835}. | Enzyme | Diabetic complications
Myocardial ischemia | Converts sorbitol to fructose. Part of the polyol pathway that plays an important role in sperm physiology. May play a role in the sperm motility by providing an energetic source for sperm. {ECO:0000250|UniProtKB:Q64442, ECO:0000269|PubMed:16278369}. | 15.11 | |||
| dfaDMPK | Myotonin-protein kinase | 2 | 73 | 96.74 | 94.56 | ND | 0.03 | 0.63 | 0.8 | Mammalian | Most isoforms are expressed in many tissues including heart, skeletal muscle, liver and brain, except for isoform 2 which is only found in the heart and skeletal muscle, and isoform 14 which is only found in the brain, with high levels in the striatum, cerebellar cortex and pons. {ECO:0000269|PubMed:7488138}. | Kinase | Dystrophia myotonica 1 (DM1) [MIM:160900]: A muscular disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness and cardiac arrhythmias. {ECO:0000269|PubMed:1302022, ECO:0000269|PubMed:1310900, ECO:0000269|PubMed:1546326, ECO:0000269|PubMed:19514047}. Note=The disease is caused by mutations affecting the gene represented in this entry. The causative mutation is a CTG expansion in the 3'- UTR of the DMPK gene. A length exceeding 50 CTG repeats is pathogenic, while normal individuals have 5 to 37 repeats. Intermediate alleles with 35-49 triplets are not disease-causing but show instability in intergenerational transmissions. Disease severity varies with the number of repeats: mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with congenital onset can have more than 2,000 repeats. {ECO:0000269|PubMed:1310900, ECO:0000269|PubMed:19514047}. | Non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function. May play a role in myocyte differentiation and survival by regulating the integrity of the nuclear envelope and the expression of muscle-specific genes. May also phosphorylate PPP1R12A and inhibit the myosin phosphatase activity to regulate myosin phosphorylation. Also critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction activity probably through the regulation of cellular calcium homeostasis. Phosphorylates PLN, a regulator of calcium pumps and may regulate sarcoplasmic reticulum calcium uptake in myocytes. May also phosphorylate FXYD1/PLM which is able to induce chloride currents. May also play a role in synaptic plasticity. {ECO:0000269|PubMed:10811636, ECO:0000269|PubMed:10913253, ECO:0000269|PubMed:11287000, ECO:0000269|PubMed:15598648, ECO:0000269|PubMed:21457715, ECO:0000269|PubMed:21949239}. | 15.11 | |||
| dfaDOPO | Dopamine beta-hydroxylase | 1 | 77 | 92.84 | 84.15 | ND | 0.43 | 0.33 | 0.5 | Mammalian | Enzyme | Dopamine beta-hydroxylase deficiency (DBH deficiency) [MIM:223360]: Characterized by profound deficits in autonomic and cardiovascular function, but apparently only subtle signs, if any, of central nervous system dysfunction. {ECO:0000269|PubMed:11857564}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Conversion of dopamine to noradrenaline. | Dopamine beta-hydroxylase : Vitamin C Dopamine beta-hydroxylase inhibitor: Capsaicin, Disulfiram, Propylthiouracil Dopamine beta-hydroxylase ligand: Dopamine Dopamine beta-hydroxylase substrate: Dopamine | 16.04 | |||
| dfaDOT1L | Histone-lysine N-methyltransferase, H3 lysine-79 specific | 2 | 61 | 99.93 | 99.92 | ND | 0.85 | 0.60 | 0.6 | Mammalian | Writer | Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA. | 15.11 | |||||
| dfaDPEP1 | Dipeptidase 1 | 2 | 132 | 97.97 | 99.85 | ND | 0.73 | 0.81 | 0.4 | Mammalian | Protease | Bacterial infections | Hydrolyzes a wide range of dipeptides. Implicated in the renal metabolism of glutathione and its conjugates. Converts leukotriene D4 to leukotriene E4; it may play an important role in the regulation of leukotriene activity. | Dipeptidase 1 inhibitor: Cilastatin | 15.11 | |||
| dfaDPOLA | DNA polymerase alpha catalytic subunit | 3 | 82 | 80.51 | 82.78 | ND | 0.21 | 0.83 | 0.5 | Mammalian | Transferase | Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. {ECO:0000269|PubMed:9518481}. | DNA polymerase alpha catalytic subunit inhibitor: Cladribine | 15.11 | ||||
| dfaDPP2 | Dipeptidyl peptidase 2 | 5 | 1200 | 95.45 | 96.22 | ND | 0.73 | 0.49 | 0.6 | Mammalian | Detected in seminal plasma (at protein level). {ECO:0000269|PubMed:15487984}. | Protease | Plays an important role in the degradation of some oligopeptides. {ECO:0000269|PubMed:15487984}. | 15.11 | ||||
| dfaDPP4 | Dipeptidyl peptidase 4 | 6 | 3051 | 97.31 | 97.57 | ND | 0.70 | 0.00 | 0.6 | Mammalian | Expressed specifically in lymphatic vessels but not in blood vessels in the skin, small intestine, esophagus, ovary, breast and prostate glands. Not detected in lymphatic vessels in the lung, kidney, uterus, liver and stomach (at protein level). Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon. {ECO:0000269|PubMed:1677636, ECO:0000269|PubMed:18708048}. | Protease | Autoimmune diseases
Diabetes mellitus Malignancies Noninsulin-dependent diabetes mellitus Obesity | Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF- kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline. {ECO:0000269|PubMed:10570924, ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:10900005, ECO:0000269|PubMed:10951221, ECO:0000269|PubMed:11772392, ECO:0000269|PubMed:14691230, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17287217, ECO:0000269|PubMed:17549790, ECO:0000269|PubMed:18708048}. | Dipeptidyl peptidase 4 inhibitor: Atorvastatin | 15.11 | ||
| dfaDPP8 | Dipeptidyl peptidase 8 | 5 | 1229 | 96.28 | 95.87 | ND | 0.77 | 0.81 | 0.6 | Mammalian | Ubiquitously expressed, with highest levels in testis, placenta, prostate, muscle and brain. {ECO:0000269|PubMed:11012666, ECO:0000269|PubMed:12662155}. | Protease | Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. May play a role in T-cell activation and immune function. {ECO:0000269|PubMed:11012666}. | 16.04 | ||||
| dfaDPP9 | Dipeptidyl peptidase 9 | 4 | 900 | 97.41 | 91.12 | ND | 0.67 | 0.83 | 0.8 | Mammalian | Ubiquitously expressed, with highest levels in liver, heart and muscle, and lowest levels in brain. {ECO:0000269|PubMed:12459266, ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:15245913}. | Protease | Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. | 16.04 | ||||
| dfaDRD1 | D(1A) dopamine receptor | 5 | 1985 | 87.10 | 84.55 | ND | 0.68 | 0.67 | 0.6 | Nature11159 | Mammalian | Detected in caudate, nucleus accumbens and in the olfactory tubercle. {ECO:0000269|PubMed:2144334}. | Agranulocytosis Akathisia Amenorrhoea Cataract Cholestasis Corneal opacity Corneal pigmentation Dermatitis allergic Dermatitis exfoliative Dry mouth Dyskinesia Dystonia Ejaculation disorder Electrocardiogram change Endocrine disorder Extrapyramidal disorder Eyelash discolouration Fibrocystic breast disease Galactorrhoea Gynaecomastia Hypercholesterolaemia Hyperprolactinaemia Hyperthermia Hypothermia Insomnia Lenticular opacities Lipid metabolism disorder Menstrual disorder Miosis Mydriasis Nasal congestion Neuroleptic malignant syndrome Neutropenia Orthostatic hypotension Parkinsonism Photosensitivity reaction Tachycardia Tardive dyskinesia Weight increased | Family A G protein-coupled receptor | Parkinson's disease | Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase. | D(1A) dopamine receptor agonist: Apomorphine, Bromocriptine, Cabergoline, Dopamine, Ergotamine, Fenoldopam, Levodopa, Minaprine, Pergolide, Ropinirole, Rotigotine D(1A) dopamine receptor antagonist: Acepromazine, Acetophenazine, Amoxapine, Aripiprazole, Asenapine, Chlorpromazine, Chlorprothixene, Clozapine, Ergoloid mesylate, Flupentixol, Fluphenazine, Haloperidol, Iloperidone, Lisuride, Methotrimeprazine, Methylergometrine, Olanzapine, Paliperidone, Perphenazine, Pipotiazine, Promazine, Propericiazine, Propiomazine, Quetiapine, Risperidone, Thioproperazine, Thioridazine, Thiothixene, Triflupromazine, Ziprasidone, Zuclopenthixol D(1A) dopamine receptor binder: Cinnarizine, Imipramine, Loxapine, Mianserin, Mirtazapine, Trimipramine D(1A) dopamine receptor partial agonist: Phenylpropanolamine D(1A) dopamine receptor unknown: Pramipexole | 16.04 |
| dfaDRD2 | D(2) dopamine receptor | 6 | 7695 | 87.85 | 85.86 | ND | 0.50 | 0.45 | 0.6 | Nature11159 | Mammalian | Akathisia Amenorrhoea Cataract Cholestasis Constipation Convulsion Corneal opacity Corneal pigmentation Dermatitis allergic Dermatitis exfoliative Dry mouth Dyskinesia Dystonia Ejaculation disorder Electrocardiogram change Endocrine disorder Erectile dysfunction Extrapyramidal disorder Eyelash discolouration Fibrocystic breast disease Galactorrhoea Gynaecomastia Hypercholesterolaemia Hyperprolactinaemia Hyperthermia Hypothermia Insomnia Lenticular opacities Lipid metabolism disorder Menstrual disorder Miosis Mydriasis Nasal congestion Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Sexual dysfunction Tachycardia Tardive dyskinesia Urinary retention Vision blurred Weight increased | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Attention deficit hyperactivity disorder Cocaine dependence Cognitive deficits Delusional disorder Depression Disabling peak-dose dyskinesias Erectile dysfunction Gastric emptying disorders Gilles de la Tourette's disorder Nausea and vomiting Neuroleptic malignant syndrome Neurological diseases Parkinson's disease Psychiatric illness Respiratory diseases Schizophrenia Vomiting | Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. {ECO:0000269|PubMed:21645528}. | D(2) dopamine receptor agonist: Amantadine, Apomorphine, Brexpiprazole, Bromocriptine, Cabergoline, Cariprazine, Dopamine, Ergotamine, Ketamine, Levodopa, Lisuride, Memantine, Minaprine, Pergolide, Pramipexole, Ropinirole, Rotigotine D(2) dopamine receptor antagonist: Acepromazine, Acetophenazine, Alizapride, Amisulpride, Amoxapine, Aripiprazole, Asenapine, Bromopride, Buspirone, Chlorpromazine, Chlorprothixene, Clozapine, Domperidone, Doxepin, Droperidol, Ergoloid mesylate, Flupentixol, Fluphenazine, Fluspirilene, Haloperidol, Iloperidone, Loxapine, Lurasidone, Mesoridazine, Methotrimeprazine, Metoclopramide, Mianserin, Molindone, Nortriptyline, Olanzapine, Paliperidone, Perphenazine, Pimozide, Pipotiazine, Prochlorperazine, Promazine, Promethazine, Propiomazine, Quetiapine, Remoxipride, Risperidone, Sertindole, Sulpiride, Thioproperazine, Thioridazine, Thiothixene, Trifluoperazine, Triflupromazine, Yohimbine, Ziprasidone, Zuclopenthixol D(2) dopamine receptor binder: Amphetamine, Desipramine, Imipramine, Maprotiline, Mirtazapine D(2) dopamine receptor inhibitor: Tetrabenazine D(2) dopamine receptor other/unknown: Cinnarizine, Trimipramine D(2) dopamine receptor partial agonist: | 16.04 | |
| dfaDRD3 | D(3) dopamine receptor | 2 | 2792 | 89.05 | 89.55 | ND | 0.55 | 0.56 | 0.8 | Nature11159 | Mammalian | Brain. | Akathisia Amenorrhoea Dyskinesia Dystonia Ejaculation disorder Electrocardiogram change Extrapyramidal disorder Galactorrhoea Gynaecomastia Hyperprolactinaemia Hyperthermia Hypothermia Menstrual disorder Nasal congestion Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tardive dyskinesia Weight increased | Family A G protein-coupled receptor | Tremor, hereditary essential 1 (ETM1) [MIM:190300]: A common movement disorder mainly characterized by postural tremor of the arms. Head, legs, trunk, voice, jaw, and facial muscles also may be involved. The condition can be aggravated by emotions, hunger, fatigue and temperature extremes, and may cause a functional disability or even incapacitation. Inheritance is autosomal dominant. {ECO:0000269|PubMed:16650084, ECO:0000269|PubMed:16809426}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation. {ECO:0000269|PubMed:19520868}. | D(3) dopamine receptor antagonist: Ziprasidone | 15.11 |
| dfaDRD4 | D(4) dopamine receptor | 3 | 1693 | 96.17 | 90.90 | ND | 0.54 | 0.01 | 0.7 | Nature11159 | Mammalian | Akathisia Amenorrhoea Dyskinesia Dystonia Ejaculation disorder Electrocardiogram change Extrapyramidal disorder Galactorrhoea Hypercholesterolaemia Hyperprolactinaemia Hyperthermia Hypothermia Lipid metabolism disorder Menstrual disorder Mydriasis Nasal congestion Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tardive dyskinesia | Family A G protein-coupled receptor | Parkinson's disease
Psychiatric illness Respiratory diseases | Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins which inhibit adenylyl cyclase. Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells (By similarity). {ECO:0000250}. | D(4) dopamine receptor agonist: Apomorphine, Cabergoline, Dopamine, Levodopa, Lisuride, Pergolide, Pramipexole, Ropinirole, Rotigotine D(4) dopamine receptor antagonist: Amoxapine, Aripiprazole, Asenapine, Bromocriptine, Clozapine, Flibanserin, Iloperidone, Methotrimeprazine, Olanzapine, Paliperidone, Promazine, Propiomazine, Quetiapine, Remoxipride, Risperidone, Ziprasidone D(4) dopamine receptor binder: Chlorpromazine, Loxapine D(4) dopamine receptor partial agonist: | 16.04 | |
| dfaDRD5 | D(1B) dopamine receptor | 4 | 309 | 93.85 | 94.95 | ND | 0.70 | 0.75 | 0.7 | Mammalian | Neuron-specific, localized primarily within limbic regions of the brain. {ECO:0000269|PubMed:1834671}. | Akathisia Amenorrhoea Dyskinesia Dystonia Electrocardiogram change Extrapyramidal disorder Galactorrhoea Hypothermia Nasal congestion Neuroleptic malignant syndrome Parkinsonism Tardive dyskinesia | Family A G protein-coupled receptor | Benign essential blepharospasm (BEB) [MIM:606798]: A primary focal dystonia affecting the orbicularis oculi muscles. Dystonia is defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. BEB usually begins in middle age. Initial symptoms include eye irritation and frequent blinking, progressing to involuntary spasms of eyelid closure. Patients have normal eyes. The visual disturbance is due solely to the forced closure of the eyelids. In severe cases, this can lead to functional blindness. {ECO:0000269|PubMed:11781417}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. | Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase. {ECO:0000269|PubMed:1834671}. | D(1B) dopamine receptor : Chlorpromazine D(1B) dopamine receptor agonist: Apomorphine, Bromocriptine, Cabergoline, Dopamine, Fenoldopam, Levodopa, Pergolide, Ropinirole, Rotigotine D(1B) dopamine receptor antagonist: Aripiprazole, Lisuride, Methotrimeprazine, Olanzapine, Quetiapine, Ziprasidone, Zuclopenthixol D(1B) dopamine receptor binder: Loxapine D(1B) dopamine receptor partial agonist: D(1B) dopamine receptor unknown: Pramipexole | 16.04 | |
| dfaDUS22 | Dual specificity protein phosphatase 22 | 3 | 40 | 99.97 | 100.00 | ND | 0.50 | 0.73 | 0.3 | Mammalian | Ubiquitous. Highest expression seen in heart, placenta, lung, liver, kidney and pancreas. {ECO:0000269|PubMed:11717427}. | Phosphatase | Activates the Jnk signaling pathway. Dephosphorylates and deactivates p38 and stress-activated protein kinase/c-Jun N- terminal kinase (SAPK/JNK) (By similarity). {ECO:0000250, ECO:0000269|PubMed:11717427}. | 15.11 | ||||
| dfaDUSTY | Dual serine/threonine and tyrosine protein kinase | 2 | 58 | 99.55 | 99.22 | ND | 0.31 | 0.70 | 0.4 | Mammalian | Predominantly expressed in skeletal muscle and testis. Expressed in basolateral and apical membranes of all tubular epithelia. Expressed in thin ascending limb of the loop of Henle and the distal convoluted tubule. Expressed in all layers of transitional ureteric epithelium and in the ureteric smooth-muscle cells. Weakly expressed in heart, brain, placenta, kidney, pancreas, spleen, thymus, prostate, uterus, small intestine, white blood cells, stomach, spinal cord and adrenal gland. Is widely distributed in the CNS. Also detected in several tumor cell lines. {ECO:0000269|PubMed:15178406, ECO:0000269|PubMed:17123648, ECO:0000269|PubMed:23862974}. | Enzyme | Congenital anomalies of the kidney and urinary tract 1 (CAKUT1) [MIM:610805]: A disorder encompassing a broad spectrum of renal and urinary tract malformations that include renal agenesis, kidney hypodysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. Congenital anomalies of kidney and urinary tract are the commonest cause of chronic kidney disease in children. {ECO:0000269|PubMed:23862974}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation. May induce both caspase-dependent apoptosis and caspase-independent cell death. {ECO:0000269|PubMed:15178406, ECO:0000269|PubMed:23862974}. | 16.04 | |||
| dfaDUT | Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial | 4 | 117 | 99.70 | 98.94 | ND | 0.90 | 0.89 | 0.3 | Mammalian | Found in a variety of tissues. Isoform 3 expression is constitutive, while isoform 2 expression correlates with the onset of DNA replication (at protein level). Isoform 2 degradation coincides with the cessation of nuclear DNA replication (at protein level). {ECO:0000269|PubMed:9228092}. | Enzyme | This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA. {ECO:0000269|PubMed:8805593}. | 15.11 | ||||
| dfaDYN1 | Dynamin-1 | 5 | 112 | 99.77 | 99.11 | ND | 0.76 | 0.74 | 0.2 | Mammalian | Enzyme | Epileptic encephalopathy, early infantile, 31 (EIEE31) [MIM:616346]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:25262651, ECO:0000269|PubMed:25533962}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Most probably involved in vesicular trafficking processes. Involved in receptor-mediated endocytosis. | 16.04 | ||||
| dfaDYR | Dihydrofolate reductase | 1 | 1500 | 98.33 | 95.30 | ND | 0.55 | 0.00 | 0.9 | Mammalian | Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain. {ECO:0000269|PubMed:21310276}. | Oxidoreductase | Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]: An inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms. {ECO:0000269|PubMed:21310276, ECO:0000269|PubMed:21310277}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1. {ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:21876188}. | Dihydrofolate reductase inhibitor: Pyrimethamine | 15.11 | ||
| dfaDYR1A | Dual specificity tyrosine-phosphorylation-regulated kinase 1A | 5 | 1928 | 84.57 | 83.11 | ND | 0.61 | 0.60 | 0.5 | Mammalian | Ubiquitous. Highest levels in skeletal muscle, testis, fetal lung and fetal kidney. {ECO:0000269|PubMed:10329007, ECO:0000269|PubMed:8769099, ECO:0000269|PubMed:8872470, ECO:0000269|PubMed:8975710}. | Kinase | Mental retardation, autosomal dominant 7 (MRD7) [MIM:614104]: A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21294719}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Modulates alternative splicing by phosphorylating the splice factor SRSF6 (By similarity). Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates such as CRY2, FOXO1, SRSF6 and SIRT1. Exhibits a sugstrate preference for proline at position P+1 and arginine at position P-3. {ECO:0000250, ECO:0000269|PubMed:20981014, ECO:0000269|PubMed:21127067, ECO:0000269|PubMed:23665168, ECO:0000269|PubMed:8769099}. | 15.11 | |||
| dfaDYR1B | Dual specificity tyrosine-phosphorylation-regulated kinase 1B | 3 | 324 | 82.79 | 88.24 | ND | 0.75 | 0.80 | 0.5 | Mammalian | Highest expression in skeletal muscle, testis, heart and brain with little expression in colon or lung. Expressed in a variety of tumor cell lines. {ECO:0000269|PubMed:10910078}. | Kinase | Abdominal obesity-metabolic syndrome 3 (AOMS3) [MIM:615812]: A form of abdominal obesity-metabolic syndrome, a disorder characterized by abdominal obesity, high triglycerides, low levels of high density lipoprotein cholesterol, high blood pressure, and elevated fasting glucose levels. AOMS3 is characterized by early-onset coronary artery disease, central obesity, hypertension, and diabetes. {ECO:0000269|PubMed:24827035}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. Enhances the transcriptional activity of TCF1/HNF1A and FOXO1. Inhibits epithelial cell migration. Mediates colon carcinoma cell survival in mitogen-poor environments. Inhibits the SHH and WNT1 pathways, thereby enhancing adipogenesis. In addition, promotes expression of the gluconeogenic enzyme glucose-6-phosphatase (G6PC). {ECO:0000269|PubMed:10910078, ECO:0000269|PubMed:11980910, ECO:0000269|PubMed:14500717, ECO:0000269|PubMed:24827035}. | 16.04 | |||
| dfaDYRK2 | Dual specificity tyrosine-phosphorylation-regulated kinase 2 | 5 | 141 | 88.48 | 90.82 | ND | 0.55 | 0.74 | 0.4 | Mammalian | Testis, after the onset of spermatogenesis. {ECO:0000269|PubMed:9748265}. | Kinase | Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser- 641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457', promoting TERT ubiquitination by the EDVP complex. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro). {ECO:0000269|PubMed:11311121, ECO:0000269|PubMed:12588975, ECO:0000269|PubMed:14593110, ECO:0000269|PubMed:15910284, ECO:0000269|PubMed:16511445, ECO:0000269|PubMed:16611631, ECO:0000269|PubMed:17349958, ECO:0000269|PubMed:18455992, ECO:0000269|PubMed:18599021, ECO:0000269|PubMed:19287380, ECO:0000269|PubMed:22307329, ECO:0000269|PubMed:22878263, ECO:0000269|PubMed:23362280, ECO:0000269|PubMed:9748265}. | 15.11 | ||||
| dfaDYRK3 | Dual specificity tyrosine-phosphorylation-regulated kinase 3 | 6 | 182 | 88.37 | 86.43 | ND | 0.41 | 0.73 | 0.5 | Mammalian | Isoform 1 and isoform 2 are highly expressed in testis and in hematopoietic tissue such as fetal liver, and bone marrow. Isoform 2 is the predominant form in testis. Isoform 1 is the predominant form in fetal liver and bone marrow. Isoform 1 and isoform 2 are present at low levels in heart, pancreas, lymph node, and thymus. {ECO:0000269|PubMed:10779429}. | Kinase | Negative regulator of EPO-dependent erythropoiesis, may place an upper limit on red cell production during stress erythropoiesis. Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells. May act by regulating CREB/CRE signaling. {ECO:0000269|PubMed:10779429}. | 16.04 | ||||
| dfaDYRK4 | Dual specificity tyrosine-phosphorylation-regulated kinase 4 | 8 | 73 | 92.22 | 87.34 | ND | 0.71 | 0.88 | 0.3 | Mammalian | Enzyme | Possible non-essential role in spermiogenesis. {ECO:0000250}. | 16.04 | |||||
| dfaE2AK1 | Eukaryotic translation initiation factor 2-alpha kinase 1 | 3 | 88 | 91.85 | 94.63 | ND | 0.71 | 0.79 | 0.5 | Mammalian | Expressed predominantly in erythroid cells. At much lower levels, expressed in hepatocytes (at protein level). {ECO:0000269|PubMed:20071449}. | Kinase | Inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. Exerts its function through the phosphorylation of EIF2S1 at 'Ser- 48' and 'Ser-51', thus preventing its recycling. Binds hemin forming a 1:1 complex through a cysteine thiolate and histidine nitrogenous coordination. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. Thus plays an essential protective role for RBC survival in anemias of iron deficiency. Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes. May also contain ER stress during acute heme-deficient conditions (By similarity). {ECO:0000250}. | 16.04 | ||||
| dfaE2AK2 | Interferon-induced, double-stranded RNA-activated protein kinase | 6 | 136 | 94.37 | 92.57 | ND | 0.56 | 0.64 | 0.5 | Mammalian | Highly expressed in thymus, spleen and bone marrow compared to non-hematopoietic tissues such as small intestine, liver, or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer disease (AD) brain. Elevated levels seen in breast and colon carcinomas,and which correlates with tumor progression and invasiveness or risk of progression. {ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:23403623}. | Kinase | IFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation. Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1). Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (EIF2S1), this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser- 312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin. {ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380, ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853, ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191, ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114, ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651, ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662, ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035}. | 15.11 | ||||
| dfaE2AK3 | Eukaryotic translation initiation factor 2-alpha kinase 3 | 2 | 64 | 98.73 | 89.49 | ND | 0.69 | 0.78 | 0.9 | Mammalian | Ubiquitous. A high level expression is seen in secretory tissues. | Kinase | Wolcott-Rallison syndrome (WRS) [MIM:226980]: A rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, mental retardation and cardiovascular abnormalities. {ECO:0000269|PubMed:10932183}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function (By similarity). {ECO:0000250}. | 15.11 | |||
| dfaE2AK4 | eIF-2-alpha kinase GCN2 {ECO:0000250|UniProtKB:Q9QZ05} | 7 | 68 | 98.42 | 97.45 | ND | 0.83 | 0.97 | 0.4 | Mammalian | Widely expressed (PubMed:10504407). Expressed in lung, smooth muscle cells and macrophages (PubMed:24292273). {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:24292273}. | Kinase | Pulmonary venoocclusive disease 2, autosomal recessive (PVOD2) [MIM:234810]: A disease characterized by widespread fibrous obstruction and intimal thickening of septal veins and preseptal venules, a low diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and nodular ground-glass opacities, septal lines and lymph node enlargement showed by high-resolution computed tomography of the chest. It is frequently associated with pulmonary capillary dilatation and proliferation, and is a rare and devastating cause of pulmonary hypertension. {ECO:0000269|PubMed:24135949, ECO:0000269|PubMed:24292273}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' in response to low amino acid availability (PubMed:25329545). Plays a role as an activator of the integrated stress response (ISR) required for adapatation to amino acid starvation. Converts phosphorylated eIF- 2-alpha/EIF2S1 either to a competitive inhibitor of the translation initiation factor eIF-2B, leading to a global protein synthesis repression, and thus to a reduced overall utilization of amino acids, or to a translational initiation activation of specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Binds uncharged tRNAs (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress- activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity). {ECO:0000250|UniProtKB:P15442, ECO:0000250|UniProtKB:Q9QZ05, ECO:0000269|PubMed:25329545, ECO:0000269|PubMed:26102367}. (Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation (PubMed:24310610). {ECO:0000269|PubMed:24310610}. | 16.04 | |||
| dfaEAA1 | Excitatory amino acid transporter 1 | 2 | 66 | 99.58 | 85.06 | ND | 0.01 | 0.74 | 1.2 | Mammalian | Highly expressed in cerebellum, but also found in frontal cortex, hippocampus and basal ganglia. | Electrochemical transporter | Episodic ataxia 6 (EA6) [MIM:612656]: A disorder characterized by episodic ataxia, seizures, migraine and alternating hemiplegia. {ECO:0000269|PubMed:16116111}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transports L-glutamate and also L- and D-aspartate. Essential for terminating the postsynaptic action of glutamate by rapidly removing released glutamate from the synaptic cleft. Acts as a symport by cotransporting sodium. | 16.04 | |||
| dfaEAA2 | Excitatory amino acid transporter 2 | 1 | 63 | 93.17 | 89.04 | ND | 0.89 | 0.71 | 0.4 | Mammalian | Electrochemical transporter | Transports L-glutamate and also L- and D-aspartate. Essential for terminating the postsynaptic action of glutamate by rapidly removing released glutamate from the synaptic cleft. Acts as a symport by cotransporting sodium. | 16.04 | |||||
| dfaEAA3 | Excitatory amino acid transporter 3 | 2 | 67 | 99.81 | 99.96 | ND | 0.91 | 0.53 | 0.3 | Mammalian | Expressed in all tissues tested including liver, muscle, testis, ovary, retinoblastoma cell line, neurons and brain (in which there was dense expression in substantia nigra, red nucleus, hippocampus and in cerebral cortical layers). {ECO:0000269|PubMed:7521911, ECO:0000269|PubMed:7859077, ECO:0000269|PubMed:7914198}. | Electrochemical transporter | Dicarboxylic aminoaciduria (DCBXA) [MIM:222730]: An autosomal recessive disorder characterized by abnormal excretion of urinary glutamate and aspartate, resulting from the incomplete reabsorption of anionic amino acids from the glomerular filtrate in the kidney. It can be associated with mental retardation. {ECO:0000269|PubMed:21123949}. Note=The disease is caused by mutations affecting the gene represented in this entry. Schizophrenia 18 (SCZD18) [MIM:615232]: A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. {ECO:0000269|PubMed:21982423, ECO:0000269|PubMed:23341099}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A deletion at the chromosome 9p24.2 locus, including SLC1A1, has been identified in patients with psychotic disorders (PubMed:21982423). This 84 kb deletion is immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence, extends through exon 1 of the SLC1A1 mRNA, co-segregates with disease in an extended 5-generation pedigree and increases disease risk more than 18-fold for family members (PubMed:23341099). {ECO:0000269|PubMed:21982423, ECO:0000269|PubMed:23341099}. | Transports L-glutamate, L- and D-aspartate and L-cystein (PubMed:21123949). Essential for terminating the postsynaptic action of glutamate by rapidly removing released glutamate from the synaptic cleft. Acts as a symport by cotransporting sodium. Negatively regulated by ARL6IP5 (By similarity). {ECO:0000250|UniProtKB:P51906, ECO:0000250|UniProtKB:P51907, ECO:0000269|PubMed:21123949}. | Excitatory amino acid transporter 3 : L-Aspartic Acid Excitatory amino acid transporter 3 Other: Pregabalin | 16.04 | ||
| dfaEBP | 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase | 2 | 129 | 93.12 | 92.01 | ND | 0.73 | 0.80 | 0.6 | Mammalian | Enzyme | Chondrodysplasia punctata 2, X-linked dominant (CDPX2) [MIM:302960]: A clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. The key clinical features of CDPX2 are chondrodysplasia punctata, linear ichthyosis, cataracts and short stature. CDPX2 is a rare disorder of defective cholesterol biosynthesis, biochemically characterized by an increased amount of 8-dehydrocholesterol and cholest-8(9)- en-3-beta-ol in the plasma and tissues. {ECO:0000269|PubMed:10391218, ECO:0000269|PubMed:10391219, ECO:0000269|PubMed:10942423, ECO:0000269|PubMed:11493318, ECO:0000269|PubMed:18176751, ECO:0000269|PubMed:25814754}. Note=The disease is caused by mutations affecting the gene represented in this entry. MEND syndrome (MEND) [MIM:300960]: An X-linked recessive disorder associated with a defect in sterol biosynthesis. Disease manifestations and severity are highly variable. Clinical features include intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. {ECO:0000269|PubMed:12503101, ECO:0000269|PubMed:20949533, ECO:0000269|PubMed:24459067, ECO:0000269|PubMed:24700572}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of Delta(8)-sterols to their corresponding Delta(7)-isomers. | 16.04 | ||||
| dfaECE1 | Endothelin-converting enzyme 1 | 5 | 316 | 93.71 | 93.60 | ND | 0.50 | 0.46 | 0.7 | Mammalian | All isoforms are expressed in umbilical vein endothelial cells, polynuclear neutrophils, fibroblasts, atrium cardiomyocytes and ventricles. Isoforms A, B and C are also expressed in placenta, lung, heart, adrenal gland and phaeochromocytoma; isoforms A and C in liver, testis and small intestine; isoform B, C and D in endothelial cells and umbilical vein smooth muscle cells; isoforms C and D in saphenous vein cells, and isoform C in kidney. {ECO:0000269|PubMed:10491078, ECO:0000269|PubMed:9396733}. | Protease | Hirschsprung disease cardiac defects and autonomic dysfunction (HSCRCDAD) [MIM:613870]: A disorder characterized by skip-lesions Hirschsprung disease, craniofacial abnormalities and other dysmorphic features, cardiac defects including ductus arteriosus, small subaortic ventricular septal defect, small atrial septal defect, and autonomic dysfunction. {ECO:0000269|PubMed:9915973}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts big endothelin-1 to endothelin-1. {ECO:0000269|PubMed:9396733}. | 16.04 | |||
| dfaEDNRA | Endothelin-1 receptor | 6 | 1702 | 96.78 | 97.85 | ND | 0.66 | 0.65 | 0.7 | Nature11159 | Mammalian | Isoform 1, isoform 3 and isoform 4 are expressed in a variety of tissues, with highest levels in the aorta and cerebellum, followed by lung, atrium and cerebral cortex, lower levels in the placenta, kidney, adrenal gland, duodenum, colon, ventricle and liver but no expression in umbilical vein endothelial cells. Within the placenta, isoform 1, isoform 2, isoform 3 and isoform 4 are expressed in the villi and stem villi vessels. {ECO:0000269|PubMed:8611157, ECO:0000269|PubMed:9284755}. | Family A G protein-coupled receptor | Mandibulofacial dysostosis with alopecia (MFDA) [MIM:616367]: A form of mandibulofacial dysostosis, a disorder characterized by malar and mandibular hypoplasia, typically associated with abnormalities of the ears and eyelids. MFDA features include maxillary dysmorphism with dysplastic zygomatic arch, hypoplastic mandible, scalp alopecia, scant eyebrows and eyelashes, severe hypoplasia or aplasia of eyelids, small cupped dysplastic ears, conductive hearing loss, cleft palate, dental anomalies, micrognathia, and limited jaw mobility. {ECO:0000269|PubMed:25772936}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3. | Endothelin-1 receptor : Acetylsalicylic acid Endothelin-1 receptor antagonist: Ambrisentan, Bosentan, MACITENTAN, Sitaxentan | 16.04 | |
| dfaEDNRB | Endothelin B receptor | 2 | 1248 | 98.08 | 97.31 | ND | 0.73 | 0.77 | 0.6 | Nature11159 | Mammalian | Expressed in placental stem villi vessels, but not in cultured placental villi smooth muscle cells. {ECO:0000269|PubMed:9284755}. | Family A G protein-coupled receptor | Waardenburg syndrome 4A (WS4A) [MIM:277580]: A disorder characterized by the association of Waardenburg features (depigmentation and deafness) with the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease). {ECO:0000269|PubMed:12189494, ECO:0000269|PubMed:8634719}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hirschsprung disease 2 (HSCR2) [MIM:600155]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. {ECO:0000269|PubMed:8001158, ECO:0000269|PubMed:8630503, ECO:0000269|PubMed:8852659, ECO:0000269|PubMed:8852660}. Note=The disease is caused by mutations affecting the gene represented in this entry. ABCD syndrome (ABCDS) [MIM:600501]: An autosomal recessive syndrome characterized by albinism, black lock at temporal occipital region, bilateral deafness, aganglionosis of the large intestine and total absence of neurocytes and nerve fibers in the small intestine. {ECO:0000269|PubMed:11891690}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:7536888}. | Endothelin B receptor antagonist: Ambrisentan, Bosentan, MACITENTAN, Sitaxentan | 16.04 | |
| dfaEF2K | Eukaryotic elongation factor 2 kinase | 3 | 60 | 84.59 | 80.97 | ND | 0.21 | 0.60 | 0.5 | Mammalian | Kinase | Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation. Upon activation by a variety of upstream kinases including AMPK or TRPM7, phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced. {ECO:0000269|PubMed:14709557, ECO:0000269|PubMed:9144159}. | 16.04 | |||||
| dfaEGFR | Epidermal growth factor receptor | 4 | 4098 | 95.88 | 92.89 | ND | 0.62 | 0.56 | 0.8 | Mammalian | Ubiquitously expressed. Isoform 2 is also expressed in ovarian cancers. {ECO:0000269|PubMed:17671655}. | Decreased appetite | Kinase | Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:15118125, ECO:0000269|PubMed:16533793, ECO:0000269|PubMed:16672372}. Note=The gene represented in this entry is involved in disease pathogenesis. Inflammatory skin and bowel disease, neonatal, 2 (NISBD2) [MIM:616069]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269|PubMed:24691054}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS- RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin. Isoform 2 may act as an antagonist of EGF action. | Epidermal growth factor receptor antagonist: Cetuximab | 15.11 | |
| dfaEGLN1 | Egl nine homolog 1 | 4 | 245 | 94.28 | 93.04 | ND | 0.78 | 0.87 | 0.8 | Mammalian | According to PubMed:11056053, widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to PubMed:12351678 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. According to PubMed:12788921; expressed in adult and fetal heart, brain, liver, lung, skeletal muscle and kidney. Also expressed in placenta. Highest levels in adult heart, brain, lung and liver and fetal brain, heart spleen and skeletal muscle. {ECO:0000269|PubMed:11056053, ECO:0000269|PubMed:12163023, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:12788921}. | Enzyme | Erythrocytosis, familial, 3 (ECYT3) [MIM:609820]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels. {ECO:0000269|PubMed:16407130, ECO:0000269|PubMed:17579185}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:15897452, ECO:0000269|PubMed:19339211, ECO:0000269|PubMed:21792862, ECO:0000269|PubMed:25129147}. | 15.11 | |||
| dfaEGLN2 | Egl nine homolog 2 | 1 | 53 | 100.00 | 100.00 | ND | 0.93 | 0.56 | 0.4 | Mammalian | Expressed in adult and fetal heart, brain, liver, lung, skeletal muscle, and kidney. Also expressed in testis and placenta. Highest levels in adult brain, placenta, lung, kidney, and testis. Expressed in hormone responsive tissues, including normal and cancerous mammary, ovarian and prostate epithelium. {ECO:0000269|PubMed:12163023}. | Enzyme | Anemia
Kidney Disease | Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB activation in hypoxic conditions. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:16509823, ECO:0000269|PubMed:17114296, ECO:0000269|PubMed:19339211, ECO:0000269|PubMed:23932902}. | 16.04 | |||
| dfaEGLN3 | Egl nine homolog 3 | 5 | 67 | 93.28 | 98.71 | ND | 0.10 | 0.81 | 0.6 | Mammalian | Widely expressed at low levels. Expressed at higher levels in adult heart (cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle), lung and placenta, and in fetal spleen, heart and skeletal muscle. Also expressed in pancreas. Localized to pancreatic acini and islet cells. {ECO:0000269|PubMed:12163023, ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:21575608}. | Enzyme | Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:16098468, ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:20849813, ECO:0000269|PubMed:20978507, ECO:0000269|PubMed:21317538, ECO:0000269|PubMed:21483450, ECO:0000269|PubMed:21575608, ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22797300}. | 16.04 | ||||
| dfaELNE | Neutrophil elastase | 5 | 1193 | 94.95 | 93.06 | ND | 0.65 | 0.77 | 0.8 | Mammalian | Bone marrow cells. | Protease | Cyclic haematopoiesis (CH) [MIM:162800]: Autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency. {ECO:0000269|PubMed:10581030, ECO:0000269|PubMed:11001877, ECO:0000269|PubMed:14962902, ECO:0000269|PubMed:23463630}. Note=The disease is caused by mutations affecting the gene represented in this entry. Neutropenia, severe congenital 1, autosomal dominant (SCN1) [MIM:202700]: A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. {ECO:0000269|PubMed:11001877, ECO:0000269|PubMed:11675333, ECO:0000269|PubMed:12091371, ECO:0000269|PubMed:14962902, ECO:0000269|PubMed:17436313, ECO:0000269|PubMed:18946670, ECO:0000269|PubMed:19036076, ECO:0000269|PubMed:19415009, ECO:0000269|PubMed:19927291, ECO:0000269|PubMed:20220065, ECO:0000269|PubMed:20803142, ECO:0000269|PubMed:21425445, ECO:0000269|PubMed:23463630}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis. {ECO:0000269|PubMed:15140022}. | 15.11 | |||
| dfaELOV6 | Elongation of very long chain fatty acids protein 6 {ECO:0000255|HAMAP-Rule:MF_03206, ECO:0000305} | 3 | 100 | 99.54 | 99.95 | ND | 0.39 | 0.44 | 0.5 | Mammalian | Ubiquitous. {ECO:0000269|PubMed:20937905}. | Enzyme | Catalyzes the first and rate-limiting reaction of the four that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. Condensing enzyme that elongates fatty acids with 12, 14 and 16 carbons with higher activity toward C16:0 acyl-CoAs. Catalyzes the synthesis of unsaturated C16 long chain fatty acids and, to a lesser extent, C18:0 and those with low desaturation degree. May participate to the production of saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. {ECO:0000255|HAMAP- Rule:MF_03206, ECO:0000269|PubMed:20937905}. | 16.04 | ||||
| dfaENPL | Endoplasmin | 6 | 55 | 99.60 | 98.93 | ND | 0.81 | 0.95 | 0.4 | Mammalian | Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors (By similarity). Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity. {ECO:0000250, ECO:0000269|PubMed:18264092}. | Endoplasmin other/unknown: Rifabutin | 15.11 | |||||
| dfaENPP2 | Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 | 6 | 140 | 98.29 | 98.58 | ND | 0.60 | 0.57 | 0.5 | Mammalian | Expressed in brain and adipose tissue. {ECO:0000269|PubMed:18175805}. | Note=May contribute to obesity (PubMed:15700135). {ECO:0000269|PubMed:15700135}. | Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility- related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Tumor cell motility-stimulating factor. {ECO:0000269|PubMed:17208043, ECO:0000269|PubMed:21240269}. | 15.11 | ||||
| dfaEPHA2 | Ephrin type-A receptor 2 | 4 | 221 | 93.47 | 94.61 | ND | 0.70 | 0.79 | 0.6 | Mammalian | Expressed in brain and glioma tissue and glioma cell lines (at protein level). Expressed most highly in tissues that contain a high proportion of epithelial cells, e.g. skin, intestine, lung, and ovary. {ECO:0000269|PubMed:17332925}. | Kinase | Cataract 6, multiple types (CTRCT6) [MIM:116600]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT6 includes posterior polar and age- related cortical cataracts, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. Age-related cortical cataract is a developmental punctate opacity restricted to the cortex. The cataract is white or cerulean, increases in number with age, but rarely affects vision. {ECO:0000269|PubMed:19005574, ECO:0000269|PubMed:19306328, ECO:0000269|PubMed:19649315}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Overexpressed in several cancer types and promotes malignancy. {ECO:0000269|PubMed:19573808}. | Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand- independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:16236711, ECO:0000269|PubMed:18339848, ECO:0000269|PubMed:19573808, ECO:0000269|PubMed:20679435, ECO:0000269|PubMed:20861311, ECO:0000269|PubMed:23358419}. | Ephrin type-A receptor 2 antagonist: Dasatinib Ephrin type-A receptor 2 inhibitor: Regorafenib | 16.04 | ||
| dfaEPHA3 | Ephrin type-A receptor 3 | 6 | 86 | 84.52 | 88.40 | ND | 0.54 | 0.91 | 0.5 | Mammalian | Widely expressed. Highest level in placenta. | Kinase | Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:12738854}. Note=The gene represented in this entry may be involved in disease pathogenesis. | Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development. {ECO:0000269|PubMed:11870224}. | 15.11 | |||
| dfaEPHA6 | Ephrin type-A receptor 6 | 3 | 65 | 91.34 | 94.96 | ND | 0.69 | 0.93 | 0.4 | Mammalian | Expressed in brain and testis. {ECO:0000269|PubMed:14726470}. | Kinase | Receptor tyrosine kinase which binds promiscuously GPI- anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling (By similarity). {ECO:0000250}. | 16.04 | ||||
| dfaEPHA7 | Ephrin type-A receptor 7 | 4 | 69 | 99.74 | 99.74 | ND | 0.82 | 0.87 | 0.2 | Mammalian | Widely expressed. | Kinase | Receptor tyrosine kinase which binds promiscuously GPI- anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Among GPI-anchored ephrin-A ligands, EFNA5 is a cognate/functional ligand for EPHA7 and their interaction regulates brain development modulating cell-cell adhesion and repulsion. Has a repellent activity on axons and is for instance involved in the guidance of corticothalamic axons and in the proper topographic mapping of retinal axons to the colliculus. May also regulate brain development through a caspase(CASP3)-dependent proapoptotic activity. Forward signaling may result in activation of components of the ERK signaling pathway including MAP2K1, MAP2K2, MAPK1 AND MAPK3 which are phosphorylated upon activation of EPHA7. {ECO:0000269|PubMed:17726105}. | 15.11 | ||||
| dfaEPHA8 | Ephrin type-A receptor 8 | 5 | 66 | 87.28 | 85.62 | ND | 0.47 | 0.92 | 0.5 | Mammalian | Kinase | Receptor tyrosine kinase which binds promiscuously GPI- anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. The GPI-anchored ephrin-A EFNA2, EFNA3, and EFNA5 are able to activate EPHA8 through phosphorylation. With EFNA5 may regulate integrin-mediated cell adhesion and migration on fibronectin substrate but also neurite outgrowth. During development of the nervous system plays also a role in axon guidance. Downstream effectors of the EPHA8 signaling pathway include FYN which promotes cell adhesion upon activation by EPHA8 and the MAP kinases in the stimulation of neurite outgrowth (By similarity). {ECO:0000250}. | 16.04 | |||||
| dfaEPHB1 | Ephrin type-B receptor 1 | 2 | 72 | 83.15 | 81.73 | ND | 0.28 | 0.90 | 0.4 | Mammalian | Preferentially expressed in brain. | Kinase | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. In addition to its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively. {ECO:0000269|PubMed:12223469, ECO:0000269|PubMed:12925710, ECO:0000269|PubMed:18034775, ECO:0000269|PubMed:9430661, ECO:0000269|PubMed:9499402}. | 16.04 | ||||
| dfaEPHB2 | Ephrin type-B receptor 2 | 4 | 102 | 97.19 | 96.36 | ND | 0.34 | 0.85 | 0.5 | Mammalian | Brain, heart, lung, kidney, placenta, pancreas, liver and skeletal muscle. Preferentially expressed in fetal brain. | Kinase | Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:15300251, ECO:0000269|PubMed:16155194}. Note=The gene represented in this entry may be involved in disease pathogenesis. EPHB2 mutations have been found in a prostate cancer cell line derived from a brain metastasis. | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. In addition to axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor. {ECO:0000269|PubMed:15300251}. | 15.11 | |||
| dfaEPHB3 | Ephrin type-B receptor 3 | 3 | 97 | 99.37 | 99.47 | ND | 0.53 | 0.53 | 0.5 | Mammalian | Ubiquitous. | Kinase | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Generally has an overlapping and redundant function with EPHB2. Like EPHB2, functions in axon guidance during development regulating for instance the neurons forming the corpus callosum and the anterior commissure, 2 major interhemispheric connections between the temporal lobes of the cerebral cortex. In addition to its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and the formation of excitatory synapses. Controls other aspects of development through regulation of cell migration and positioning. This includes angiogenesis, palate development and thymic epithelium development for instance. Forward and reverse signaling through the EFNB2/EPHB3 complex also regulate migration and adhesion of cells that tubularize the urethra and septate the cloaca. Finally, plays an important role in intestinal epithelium differentiation segregating progenitor from differentiated cells in the crypt. {ECO:0000269|PubMed:15536074}. | 16.04 | ||||
| dfaEPHB4 | Ephrin type-B receptor 4 | 6 | 421 | 96.98 | 98.19 | ND | 0.71 | 0.70 | 0.5 | Mammalian | Abundantly expressed in placenta but also detected in kidney, liver, lung, pancreas, skeletal muscle and heart. Expressed in primitive and myeloid, but not lymphoid, hematopoietic cells. Also observed in cell lines derived from liver, breast, colon, lung, melanocyte and cervix. {ECO:0000269|PubMed:8188704}. | Kinase | Lung Cancer
Solid tumors | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4- mediated forward signaling controls cellular repulsion and segregation form EFNB2-expressing cells. Plays also a role in postnatal blood vessel remodeling, morphogenesis and permeability and is thus important in the context of tumor angiogenesis. {ECO:0000269|PubMed:12734395, ECO:0000269|PubMed:16424904}. | 15.11 | |||
| dfaERBB2 | Receptor tyrosine-protein kinase erbB-2 | 1 | 1458 | 94.49 | 89.45 | ND | 0.69 | 0.49 | 0.7 | Mammalian | Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth. {ECO:0000269|PubMed:15380516}. | Kinase | Hereditary diffuse gastric cancer (HDGC) [MIM:137215]: A cancer predisposition syndrome with increased susceptibility to diffuse gastric cancer. Diffuse gastric cancer is a malignant disease characterized by poorly differentiated infiltrating lesions resulting in thickening of the stomach. Malignant tumors start in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. Note=The gene represented in this entry is involved in disease pathogenesis. Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. Note=The gene represented in this entry is involved in disease pathogenesis. Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Note=The gene represented in this entry is involved in disease pathogenesis. Gastric cancer (GASC) [MIM:613659]: A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. Note=The gene represented in this entry is involved in disease pathogenesis. Note=Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2. | Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth. | Receptor tyrosine-protein kinase erbB-2 antagonist: Lapatinib Receptor tyrosine-protein kinase erbB-2 antibody: Pertuzumab, Trastuzumab, ado-trastuzumab emtansine Receptor tyrosine-protein kinase erbB-2 inhibitor: Afatinib | 16.04 | ||
| dfaERBB4 | Receptor tyrosine-protein kinase erbB-4 | 4 | 186 | 94.13 | 95.56 | ND | 0.59 | 0.79 | 0.8 | Mammalian | Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart. {ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:9334263}. | Kinase | Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:24119685}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis. {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:10358079, ECO:0000269|PubMed:10722704, ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:11390655, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:8617750, ECO:0000269|PubMed:9135143, ECO:0000269|PubMed:9168115, ECO:0000269|PubMed:9334263}. | Receptor tyrosine-protein kinase erbB-4 inhibitor: Afatinib | 15.11 | ||
| dfaERCC5 | DNA repair protein complementing XP-G cells | 2 | 52 | 92.85 | 93.87 | ND | 0.90 | 0.96 | 0.6 | Mammalian | Other nuclear protein | Xeroderma pigmentosum complementation group G (XP-G) [MIM:278780]: An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling and other pigmentation abnormalities. Some XP-G patients present features of Cockayne syndrome, cachectic dwarfism, pigmentary retinopathy, ataxia, decreased nerve conduction velocities. The phenotype combining xeroderma pigmentosum and Cockayne syndrome traits is referred to as XP-CS complex. {ECO:0000269|PubMed:11228268, ECO:0000269|PubMed:11841555, ECO:0000269|PubMed:12060391, ECO:0000269|PubMed:23255472, ECO:0000269|PubMed:7951246, ECO:0000269|PubMed:9096355}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cerebro-oculo-facio-skeletal syndrome 3 (COFS3) [MIM:616570]: A disorder of prenatal onset characterized by microcephaly, congenital cataracts, facial dysmorphism, neurogenic arthrogryposis, growth failure and severe psychomotor retardation. COFS is considered to be part of the nucleotide-excision repair disorders spectrum that include also xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome. {ECO:0000269|PubMed:24700531}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Single-stranded structure-specific DNA endonuclease involved in DNA excision repair. Makes the 3'incision in DNA nucleotide excision repair (NER). Acts as a cofactor for a DNA glycosylase that removes oxidized pyrimidines from DNA. May also be involved in transcription-coupled repair of this kind of damage, in transcription by RNA polymerase II, and perhaps in other processes too. | 16.04 | ||||
| dfaERG1 | Squalene monooxygenase | 2 | 72 | 99.83 | 99.75 | ND | 0.20 | 0.43 | 0.5 | Mammalian | Enzyme | Catalyzes the first oxygenation step in sterol biosynthesis and is suggested to be one of the rate-limiting enzymes in this pathway. | Squalene monooxygenase inhibitor: Butenafine, Naftifine, Terbinafine | 16.04 | ||||
| dfaERG7 | Lanosterol synthase | 4 | 144 | 91.22 | 93.39 | ND | 0.53 | 0.69 | 0.8 | Mammalian | Enzyme | Hypercholesterolemia | Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus. {ECO:0000269|PubMed:7639730}. | 15.11 | ||||
| dfaERN1 | Serine/threonine-protein kinase/endoribonuclease IRE1 | 3 | 93 | 88.93 | 87.02 | ND | 0.52 | 0.75 | 0.6 | Mammalian | Ubiquitously expressed. High levels observed in pancreatic tissue. {ECO:0000269|PubMed:9637683}. | Enzyme | Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto- activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis. {ECO:0000250|UniProtKB:Q9EQY0, ECO:0000269|PubMed:11175748, ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:9637683}. | 15.11 | ||||
| dfaERR1 | Steroid hormone receptor ERR1 | 5 | 98 | 91.77 | 97.80 | ND | 0.67 | 0.69 | 0.4 | Mammalian | Nuclear receptor | Breast cancer
Diabetes mellitus Metabolic disorder, unspecified Obesity | Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle. {ECO:0000269|PubMed:12522104, ECO:0000269|PubMed:16150865, ECO:0000269|PubMed:17676930, ECO:0000269|PubMed:18063693, ECO:0000269|PubMed:23836911, ECO:0000269|PubMed:9271417}. | 15.11 | ||||
| dfaESR1 | Estrogen receptor | 1 | 1911 | 95.10 | 92.42 | ND | 0.60 | 0.58 | 0.8 | Nature11159 VirtualToxLab | Mammalian | Widely expressed. Isoform 3 is not expressed in the pituitary gland. {ECO:0000269|PubMed:10970861}. | Acne Blood urea increased Bone disorder Breast pain Chloasma Depression Electrolyte imbalance Embolism arterial Endometrial cancer Endometrial hyperplasia Epiphyses premature fusion Erythema multiforme Fibrocystic breast disease Gynaecomastia Hepatic function abnormal Hypercalcaemia Jaundice Menstrual disorder Metrorrhagia Neoplasm Oedema Porphyria non-acute Sodium retention Urticaria Uterine inflammation Weight increased | Nuclear receptor | Estrogen resistance (ESTRR) [MIM:615363]: A disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present. {ECO:0000269|PubMed:23841731, ECO:0000269|PubMed:8961262}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA- binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF- kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA- binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1. {ECO:0000269|PubMed:10681512, ECO:0000269|PubMed:10816575, ECO:0000269|PubMed:11477071, ECO:0000269|PubMed:11682626, ECO:0000269|PubMed:14764652, ECO:0000269|PubMed:15078875, ECO:0000269|PubMed:15891768, ECO:0000269|PubMed:16043358, ECO:0000269|PubMed:16617102, ECO:0000269|PubMed:16684779, ECO:0000269|PubMed:17922032, ECO:0000269|PubMed:17932106, ECO:0000269|PubMed:18247370, ECO:0000269|PubMed:19350539, ECO:0000269|PubMed:20074560, ECO:0000269|PubMed:20705611, ECO:0000269|PubMed:21330404, ECO:0000269|PubMed:22083956, ECO:0000269|PubMed:7651415, ECO:0000269|PubMed:9328340}. | Estrogen receptor agonist: Diethylstilbestrol | 15.11 |
| dfaESR2 | Estrogen receptor beta | 3 | 1459 | 93.98 | 93.89 | ND | 0.60 | 0.58 | 0.6 | Nature11159 VirtualToxLab | Mammalian | Isoform beta-1 is expressed in testis and ovary, and at a lower level in heart, brain, placenta, liver, skeletal muscle, spleen, thymus, prostate, colon, bone marrow, mammary gland and uterus. Also found in uterine bone, breast, and ovarian tumor cell lines, but not in colon and liver tumors. Isoform beta-2 is expressed in spleen, thymus, testis and ovary and at a lower level in skeletal muscle, prostate, colon, small intestine, leukocytes, bone marrow, mammary gland and uterus. Isoform beta-3 is found in testis. Isoform beta-4 is expressed in testis, and at a lower level in spleen, thymus, ovary, mammary gland and uterus. Isoform beta-5 is expressed in testis, placenta, skeletal muscle, spleen and leukocytes, and at a lower level in heart, lung, liver, kidney, pancreas, thymus, prostate, colon, small intestine, bone marrow, mammary gland and uterus. Not expressed in brain. | Acne Blood urea increased Bone disorder Breast pain Chloasma Depression Electrolyte imbalance Endometrial cancer Endometrial hyperplasia Epiphyses premature fusion Erythema multiforme Fibrocystic breast disease Gynaecomastia Hepatic function abnormal Hypercalcaemia Jaundice Menstrual disorder Metrorrhagia Neoplasm Oedema Porphyria non-acute Sodium retention Urticaria Uterine inflammation Weight increased | Nuclear receptor | Breast cancer
Cardiovascular disease, unspecified ER beta-positive prostate tumors Neurodegenerative diseases Vascular injury response | Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual. {ECO:0000269|PubMed:20074560}. | Estrogen receptor beta agonist: Diethylstilbestrol | 15.11 |
| dfaEST1 | Liver carboxylesterase 1 | 4 | 373 | 83.32 | 82.95 | ND | 0.65 | 0.70 | 0.9 | Mammalian | Expressed predominantly in liver with lower levels in heart and lung. {ECO:0000269|PubMed:10562416}. | Enzyme | Alzheimer's disease
Atherosclerosis Cardiovascular disease, unspecified Cocaine overdose Hypercholesterolaemia Protection against chemical weapons like Sarin, Soman and VX gas | Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester. Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine. Catalyzes the transesterification of cocaine to form cocaethylene. Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate. {ECO:0000269|PubMed:7980644, ECO:0000269|PubMed:9169443}. | Liver carboxylesterase 1 other: Oseltamivir | 15.11 | ||
| dfaEST2 | Cocaine esterase | 3 | 122 | 94.60 | 84.22 | ND | 0.80 | 0.73 | 0.5 | Mammalian | Preferentially expressed in intestine with moderate expression in liver. Within the intestine, highest expression is found in small intestine with lower expression in colon and rectum. {ECO:0000269|PubMed:9144407}. | Enzyme | Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Shows high catalytic efficiency for hydrolysis of cocaine, 4-methylumbelliferyl acetate, heroin and 6-monoacetylmorphine. {ECO:0000269|PubMed:9169443}. | Cocaine esterase : Mycophenolate mofetil Cocaine esterase substrate: Dabigatran etexilate, Irinotecan, Prasugrel | 16.04 | |||
| dfaEZH2 | Histone-lysine N-methyltransferase EZH2 | 2 | 43 | 99.28 | 100.00 | ND | 0.74 | 0.70 | 0.4 | Mammalian | Expressed in many tissues. Overexpressed in numerous tumor types including carcinomas of the breast, colon, larynx, lymphoma and testis. {ECO:0000269|PubMed:14532106}. | Writer | Weaver syndrome (WVS) [MIM:277590]: A syndrome of accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly. Distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand. {ECO:0000269|PubMed:22177091}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys- 27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Compared to EZH2-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-ARNTL/BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription. {ECO:0000269|PubMed:14532106, ECO:0000269|PubMed:15225548, ECO:0000269|PubMed:15231737, ECO:0000269|PubMed:15385962, ECO:0000269|PubMed:16179254, ECO:0000269|PubMed:16357870, ECO:0000269|PubMed:16618801, ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:16936726, ECO:0000269|PubMed:17210787, ECO:0000269|PubMed:17344414, ECO:0000269|PubMed:18285464, ECO:0000269|PubMed:19026781, ECO:0000269|PubMed:20935635, ECO:0000269|PubMed:23063525, ECO:0000269|PubMed:24474760}. | 16.04 | |||
| dfaF13A | Coagulation factor XIII A chain | 3 | 78 | 99.93 | 99.92 | ND | 0.49 | 0.15 | 0.5 | Mammalian | Aminoacyltransferase | Factor XIII subunit A deficiency (FA13AD) [MIM:613225]: An autosomal recessive hematologic disorder characterized by a life-long bleeding tendency, impaired wound healing and spontaneous abortion in affected women. {ECO:0000269|PubMed:1353995, ECO:0000269|PubMed:24286209, ECO:0000269|PubMed:24329762, ECO:0000269|PubMed:24889649}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor XIII is activated by thrombin and calcium ion to a transglutaminase that catalyzes the formation of gamma-glutamyl- epsilon-lysine cross-links between fibrin chains, thus stabilizing the fibrin clot. Also cross-link alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin. | Coagulation factor XIII A chain substrate: L-Glutamine | 16.04 | |||
| dfaF16P1 | Fructose-1,6-bisphosphatase 1 | 3 | 395 | 98.05 | 98.04 | ND | 0.80 | 0.78 | 0.5 | Mammalian | Expressed in pancreatic islets. {ECO:0000269|PubMed:18375435}. | Enzyme | Fructose-1,6-bisphosphatase deficiency (FBP1D) [MIM:229700]: An autosomal recessive metabolic disorder characterized by impaired gluconeogenesis, and episodes of hypoglycemia and metabolic acidosis that can be lethal in newborn infants or young children. {ECO:0000269|PubMed:12126934, ECO:0000269|PubMed:9382095}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations, acting as a rate-limiting enzyme in gluconeogenesis. Plays a role in regulating glucose sensing and insulin secretion of pancreatic beta-cells. Appears to modulate glycerol gluconeogenesis in liver. Important regulator of appetite and adiposity; increased expression of the protein in liver after nutrient excess increases circulating satiety hormones and reduces appetite-stimulating neuropeptides and thus seems to provide a feedback mechanism to limit weight gain. {ECO:0000269|PubMed:16497803, ECO:0000269|PubMed:18375435, ECO:0000269|PubMed:22517657}. | Fructose-1,6-bisphosphatase 1 antagonist: Adenosine monophosphate Fructose-1,6-bisphosphatase 1 inhibitory allosteric modulator: | 15.11 | ||
| dfaFA10 | Coagulation factor X | 4 | 4333 | 97.99 | 95.20 | ND | 0.70 | 0.00 | 0.7 | Mammalian | Plasma; synthesized in the liver. {ECO:0000269|PubMed:6587384}. | Protease | Factor X deficiency (FA10D) [MIM:227600]: A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis. {ECO:0000269|PubMed:10468877, ECO:0000269|PubMed:10746568, ECO:0000269|PubMed:11248282, ECO:0000269|PubMed:11728527, ECO:0000269|PubMed:12574802, ECO:0000269|PubMed:12945883, ECO:0000269|PubMed:15075089, ECO:0000269|PubMed:15650540, ECO:0000269|PubMed:17393015, ECO:0000269|PubMed:19135706, ECO:0000269|PubMed:1973167, ECO:0000269|PubMed:1985698, ECO:0000269|PubMed:25313940, ECO:0000269|PubMed:2790181, ECO:0000269|PubMed:7669671, ECO:0000269|PubMed:7860069, ECO:0000269|PubMed:8529633, ECO:0000269|PubMed:8845463, ECO:0000269|PubMed:8910490}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting. | Coagulation factor X activator: Antihemophilic Factor | 15.11 | ||
| dfaFA11 | Coagulation factor XI | 3 | 153 | 99.32 | 98.58 | ND | 0.66 | 0.79 | 0.8 | Mammalian | Isoform 2 is produced by platelets and megakaryocytes but absent from other blood cells. | Protease | Factor XI deficiency (FA11D) [MIM:612416]: A hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. {ECO:0000269|PubMed:10027710, ECO:0000269|PubMed:10606881, ECO:0000269|PubMed:11895778, ECO:0000269|PubMed:15026311, ECO:0000269|PubMed:15180874, ECO:0000269|PubMed:1547342, ECO:0000269|PubMed:15953011, ECO:0000269|PubMed:16607084, ECO:0000269|PubMed:18005151, ECO:0000269|PubMed:21457405, ECO:0000269|PubMed:21668437, ECO:0000269|PubMed:21999818, ECO:0000269|PubMed:22016685, ECO:0000269|PubMed:22159456, ECO:0000269|PubMed:22322133, ECO:0000269|PubMed:2813350, ECO:0000269|PubMed:7669672, ECO:0000269|PubMed:7888672, ECO:0000269|PubMed:9401068, ECO:0000269|PubMed:9787168}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. | Coagulation factor XI ligand: Coagulation Factor IX | 15.11 | ||
| dfaFA12 | Coagulation factor XII | 2 | 158 | 85.93 | 86.97 | ND | 0.34 | 0.51 | 0.5 | Mammalian | Protease | Factor XII deficiency (FA12D) [MIM:234000]: An asymptomatic anomaly of in vitro blood coagulation. Its diagnosis is based on finding a low plasma activity of the factor in coagulating assays. It is usually only accidentally discovered through pre-operative blood tests. Factor XII deficiency is divided into two categories, a cross-reacting material (CRM)- negative group (negative F12 antigen detection) and a CRM-positive group (positive F12 antigen detection). {ECO:0000269|PubMed:10361128, ECO:0000269|PubMed:11776307, ECO:0000269|PubMed:15205584, ECO:0000269|PubMed:15617741, ECO:0000269|PubMed:2510163, ECO:0000269|PubMed:2882793, ECO:0000269|PubMed:8049433, ECO:0000269|PubMed:8528215, ECO:0000269|PubMed:9354665}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hereditary angioedema 3 (HAE3) [MIM:610618]: An hereditary angioedema occurring only in women. Hereditary angioedema is an autosomal dominant disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. Hereditary angioedema type 3 differs from types 1 and 2 in that both concentration and function of C1 esterase inhibitor are normal. Hereditary angioedema type 3 is precipitated or worsened by high estrogen levels (e.g., during pregnancy or treatment with oral contraceptives). {ECO:0000269|PubMed:16638441, ECO:0000269|PubMed:17186468}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta- factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa. {ECO:0000269|PubMed:21304106}. | Coagulation factor XII activator: Ethanolamine Oleate | 16.04 | |||
| dfaFA7 | Coagulation factor VII | 1 | 298 | 98.99 | 99.65 | ND | 0.59 | 0.47 | 0.6 | Mammalian | Plasma. | Protease | Factor VII deficiency (FA7D) [MIM:227500]: A hemorrhagic disease with variable presentation. The clinical picture can be very severe, with the early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, moderate with cutaneous-mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by a surgical intervention. Finally, numerous subjects are completely asymptomatic despite very low factor VII levels. {ECO:0000269|PubMed:10862079, ECO:0000269|PubMed:11091194, ECO:0000269|PubMed:11129332, ECO:0000269|PubMed:12472587, ECO:0000269|PubMed:14717781, ECO:0000269|PubMed:1634227, ECO:0000269|PubMed:18976247, ECO:0000269|PubMed:19432927, ECO:0000269|PubMed:19751712, ECO:0000269|PubMed:2070047, ECO:0000269|PubMed:21206266, ECO:0000269|PubMed:21372693, ECO:0000269|PubMed:7974346, ECO:0000269|PubMed:7981691, ECO:0000269|PubMed:8043443, ECO:0000269|PubMed:8204879, ECO:0000269|PubMed:8364544, ECO:0000269|PubMed:8652821, ECO:0000269|PubMed:8844208, ECO:0000269|PubMed:8883260, ECO:0000269|PubMed:8940045, ECO:0000269|PubMed:9414278, ECO:0000269|PubMed:9452082, ECO:0000269|PubMed:9576180}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium. | 15.11 | |||
| dfaFA9 | Coagulation factor IX {ECO:0000303|PubMed:3857619} | 1 | 168 | 99.96 | 99.71 | ND | 0.72 | 0.69 | 0.5 | Mammalian | Detected in blood plasma (at protein level) (PubMed:3857619, PubMed:8295821, PubMed:2592373, PubMed:9169594, PubMed:19846852). Synthesized primarily in the liver and secreted in plasma. {ECO:0000269|PubMed:19846852, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:3857619}. | Protease | Hemophilia B (HEMB) [MIM:306900]: An X-linked blood coagulation disorder characterized by a permanent tendency to hemorrhage, due to factor IX deficiency. It is phenotypically similar to hemophilia A, but patients present with fewer symptoms. Many patients are asymptomatic until the hemostatic system is stressed by surgery or trauma. {ECO:0000269|PubMed:10094553, ECO:0000269|PubMed:10698280, ECO:0000269|PubMed:11122099, ECO:0000269|PubMed:12588353, ECO:0000269|PubMed:12604421, ECO:0000269|PubMed:1346975, ECO:0000269|PubMed:1615485, ECO:0000269|PubMed:1902289, ECO:0000269|PubMed:1958666, ECO:0000269|PubMed:2162822, ECO:0000269|PubMed:2339358, ECO:0000269|PubMed:2372509, ECO:0000269|PubMed:2472424, ECO:0000269|PubMed:25251685, ECO:0000269|PubMed:25470321, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:2713493, ECO:0000269|PubMed:2714791, ECO:0000269|PubMed:2738071, ECO:0000269|PubMed:2753873, ECO:0000269|PubMed:2773937, ECO:0000269|PubMed:2775660, ECO:0000269|PubMed:3009023, ECO:0000269|PubMed:3243764, ECO:0000269|PubMed:3401602, ECO:0000269|PubMed:3790720, ECO:0000269|PubMed:6603618, ECO:0000269|PubMed:7981722, ECO:0000269|PubMed:8076946, ECO:0000269|PubMed:8199596, ECO:0000269|PubMed:8257988, ECO:0000269|PubMed:8295821, ECO:0000269|PubMed:8680410, ECO:0000269|PubMed:9222764, ECO:0000269|PubMed:9452115, ECO:0000269|PubMed:9590153, ECO:0000269|PubMed:9600455}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide (PubMed:12588353, PubMed:2738071, PubMed:3009023, PubMed:8295821, PubMed:9169594, PubMed:9600455, PubMed:25251685). Mutation in position 93 (Alabama) probably fails to bind to cell membranes (PubMed:3790720). Mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya or Hilo) prevent cleavage of the activation peptide (PubMed:6603618, PubMed:8076946, PubMed:12588353, PubMed:2162822, PubMed:25251685, PubMed:2713493). {ECO:0000269|PubMed:12588353, ECO:0000269|PubMed:2162822, ECO:0000269|PubMed:25251685, ECO:0000269|PubMed:2713493, ECO:0000269|PubMed:2738071, ECO:0000269|PubMed:3009023, ECO:0000269|PubMed:3790720, ECO:0000269|PubMed:6603618, ECO:0000269|PubMed:8076946, ECO:0000269|PubMed:8295821, ECO:0000269|PubMed:9169594, ECO:0000269|PubMed:9600455}. Thrombophilia, X-linked, due to factor IX defect (THPH8) [MIM:300807]: A hemostatic disorder characterized by a tendency to thrombosis. {ECO:0000269|PubMed:19846852}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa. {ECO:0000269|PubMed:1730085, ECO:0000269|PubMed:19846852, ECO:0000269|PubMed:20121197, ECO:0000269|PubMed:20121198, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:8295821}. | Coagulation factor IX {ECO:0000303|PubMed:3857619} cofactor: Antihemophilic Factor | 15.11 | ||
| dfaFAAH1 | Fatty-acid amide hydrolase 1 | 4 | 1609 | 94.33 | 88.36 | ND | 0.62 | 0.62 | 0.8 | Mammalian | Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate. {ECO:0000269|PubMed:17015445}. | Enzyme | Analgesics
Anesthetic Anxiety disorder, unspecified Pain Sedation | Degrades bioactive fatty acid amides like oleamide, the endogenous cannabinoid, anandamide and myristic amide to their corresponding acids, thereby serving to terminate the signaling functions of these molecules. Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates. {ECO:0000269|PubMed:17015445}. | Fatty-acid amide hydrolase 1 inhibitor: Thiopental Fatty-acid amide hydrolase 1 substrate: Propofol | 16.04 | ||
| dfaFABP4 | Fatty acid-binding protein, adipocyte | 7 | 122 | 96.54 | 95.57 | ND | 0.78 | 0.84 | 0.6 | Mammalian | Fatty acid binding protein family | Atherosclerosis | Lipid transport protein in adipocytes. Binds both long chain fatty acids and retinoic acid. Delivers long-chain fatty acids and retinoic acid to their cognate receptors in the nucleus (By similarity). {ECO:0000250}. | 15.11 | ||||
| dfaFABPH | Fatty acid-binding protein, heart | 3 | 56 | 88.07 | 87.81 | ND | 0.69 | 0.62 | 0.3 | Mammalian | Fatty acid binding protein family | FABP are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters. | 15.11 | |||||
| dfaFAK1 | Focal adhesion kinase 1 | 3 | 579 | 93.62 | 95.60 | ND | 0.46 | 0.68 | 0.7 | Mammalian | Detected in B and T-lymphocytes. Isoform 1 and isoform 6 are detected in lung fibroblasts (at protein level). Ubiquitous. {ECO:0000269|PubMed:20109444, ECO:0000269|PubMed:7692878, ECO:0000269|PubMed:8247543, ECO:0000269|PubMed:8422239}. | Kinase | Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer. | Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:11331870, ECO:0000269|PubMed:11980671, ECO:0000269|PubMed:15166238, ECO:0000269|PubMed:15561106, ECO:0000269|PubMed:15895076, ECO:0000269|PubMed:16919435, ECO:0000269|PubMed:16927379, ECO:0000269|PubMed:17395594, ECO:0000269|PubMed:17431114, ECO:0000269|PubMed:17968709, ECO:0000269|PubMed:18006843, ECO:0000269|PubMed:18206965, ECO:0000269|PubMed:18256281, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:18497331, ECO:0000269|PubMed:18677107, ECO:0000269|PubMed:19138410, ECO:0000269|PubMed:19147981, ECO:0000269|PubMed:19224453, ECO:0000269|PubMed:20332118, ECO:0000269|PubMed:20495381, ECO:0000269|PubMed:21454698}. | 15.11 | |||
| dfaFAK2 | Protein-tyrosine kinase 2-beta | 4 | 257 | 89.82 | 85.79 | ND | 0.66 | 0.70 | 0.5 | Mammalian | Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes. {ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:9545257}. | Kinase | Note=Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer. | Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T- cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2. {ECO:0000269|PubMed:10022920, ECO:0000269|PubMed:12771146, ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:15050747, ECO:0000269|PubMed:15166227, ECO:0000269|PubMed:17634955, ECO:0000269|PubMed:18086875, ECO:0000269|PubMed:18339875, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18765415, ECO:0000269|PubMed:19086031, ECO:0000269|PubMed:19207108, ECO:0000269|PubMed:19244237, ECO:0000269|PubMed:19428251, ECO:0000269|PubMed:19648005, ECO:0000269|PubMed:19880522, ECO:0000269|PubMed:20001213, ECO:0000269|PubMed:20381867, ECO:0000269|PubMed:20521079, ECO:0000269|PubMed:21357692, ECO:0000269|PubMed:21533080, ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:8670418, ECO:0000269|PubMed:8849729}. | Protein-tyrosine kinase 2-beta antagonist: Leflunomide | 15.11 | ||
| dfaFAS | Fatty acid synthase | 5 | 933 | 87.06 | 85.61 | ND | 0.46 | 0.53 | 0.4 | Mammalian | Ubiquitous. Prominent expression in brain, lung, and liver. {ECO:0000269|PubMed:7567999, ECO:0000269|PubMed:7595075}. | Transferase | Endometrial carcinoma
Leukemia, unspecified Malaria Mesothelioma Metastatic osteosarcoma in the lung Obesity Prostate cancer Tumors | Fatty acid synthetase catalyzes the formation of long- chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein. | Fatty acid synthase inhibitor: Cerulenin | 15.11 | ||
| dfaFCER2 | Low affinity immunoglobulin epsilon Fc receptor | 2 | 56 | 99.94 | 99.93 | ND | 0.67 | 0.45 | 0.4 | Mammalian | Membrane receptor | Low-affinity receptor for immunoglobulin E (IgE) and CR2/CD21. Has essential roles in the regulation of IgE production and in the differentiation of B-cells (it is a B-cell-specific antigen). | 16.04 | |||||
| dfaFDFT | Squalene synthase | 3 | 597 | 93.71 | 92.62 | ND | 0.60 | 0.67 | 0.8 | Mammalian | Enzyme | Hypercholesterolemia
Hyperlipidemia Hypocholesterolemia | 15.11 | |||||
| dfaFEN1 | Flap endonuclease 1 {ECO:0000255|HAMAP-Rule:MF_03140} | 5 | 1059 | 90.85 | 90.11 | ND | 0.86 | 0.85 | 0.4 | Mammalian | Enzyme | Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double- stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA. {ECO:0000255|HAMAP-Rule:MF_03140, ECO:0000269|PubMed:10744741, ECO:0000269|PubMed:11986308, ECO:0000269|PubMed:18443037, ECO:0000269|PubMed:20729856, ECO:0000269|PubMed:7961795, ECO:0000269|PubMed:8621570}. | 16.04 | |||||
| dfaFER | Tyrosine-protein kinase Fer | 3 | 169 | 86.70 | 93.73 | ND | 0.49 | 0.66 | 0.5 | Mammalian | Isoform 1 is detected in normal colon and in fibroblasts (at protein level). Isoform 3 is detected in normal testis, in colon carcinoma-derived metastases in lung, liver and ovary, and in colon carcinoma and hepato carcinoma cell lines (at protein level). Isoform 3 is not detected in normal colon or in normal fibroblasts (at protein level). Widely expressed. {ECO:0000269|PubMed:18985748, ECO:0000269|PubMed:2156206, ECO:0000269|PubMed:22223638}. | Kinase | Tyrosine-protein kinase that acts downstream of cell surface receptors for growth factors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, lamellipodia formation, cell adhesion, cell migration and chemotaxis. Acts downstream of EGFR, KIT, PDGFRA and PDGFRB. Acts downstream of EGFR to promote activation of NF-kappa-B and cell proliferation. May play a role in the regulation of the mitotic cell cycle. Plays a role in the insulin receptor signaling pathway and in activation of phosphatidylinositol 3-kinase. Acts downstream of the activated FCER1 receptor and plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Plays a role in the regulation of mast cell degranulation. Plays a role in leukocyte recruitment and diapedesis in response to bacterial lipopolysaccharide (LPS). Plays a role in synapse organization, trafficking of synaptic vesicles, the generation of excitatory postsynaptic currents and neuron-neuron synaptic transmission. Plays a role in neuronal cell death after brain damage. Phosphorylates CTTN, CTNND1, PTK2/FAK1, GAB1, PECAM1 and PTPN11. May phosphorylate JUP and PTPN1. Can phosphorylate STAT3, but the biological relevance of this depends on cell type and stimulus. {ECO:0000269|PubMed:12972546, ECO:0000269|PubMed:14517306, ECO:0000269|PubMed:19147545, ECO:0000269|PubMed:19339212, ECO:0000269|PubMed:19738202, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21518868, ECO:0000269|PubMed:22223638, ECO:0000269|PubMed:7623846, ECO:0000269|PubMed:9722593}. | 16.04 | ||||
| dfaFES | Tyrosine-protein kinase Fes/Fps | 8 | 126 | 90.84 | 90.70 | ND | 0.69 | 0.90 | 0.4 | Mammalian | Widely expressed. Detected in adult colon epithelium. {ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:19051325}. | Kinase | Note=Has been shown to act as proto-oncogene in some types of cancer, possibly due to abnormal activation of the kinase. Has been shown to act as tumor suppressor in other types of cancer. Expressed and present as activated kinase in a subset of acute myeloid leukemia patients; promotes survival of leukemia cells (PubMed:20111072). Expression is absent in K562 leukemia cells; ectopic expression of FSP/FES restores myeloid differentiation (PubMed:2656706). May function as tumor suppressor in colorectal cancer; expression is reduced or absent in samples from some colon cancer patients (PubMed:16455651). Ectopic expression of FSP/FES suppresses anchorage-independent growth in colon cancer cell lines (PubMed:16455651). Up-regulated in prostate cancer, and might be a predictor of recurrence after radical surgery (PubMed:21563194). May promote growth of renal carcinoma cells (PubMed:19082481). {ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:19082481, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21563194, ECO:0000269|PubMed:2656706}. | Tyrosine-protein kinase that acts downstream of cell surface receptors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, cell attachment and cell spreading. Plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Acts down- stream of the activated FCER1 receptor and the mast/stem cell growth factor receptor KIT. Plays a role in the regulation of mast cell degranulation. Plays a role in the regulation of cell differentiation and promotes neurite outgrowth in response to NGF signaling. Plays a role in cell scattering and cell migration in response to HGF-induced activation of EZR. Phosphorylates BCR and down-regulates BCR kinase activity. Phosphorylates HCLS1/HS1, PECAM1, STAT3 and TRIM28. {ECO:0000269|PubMed:11509660, ECO:0000269|PubMed:15302586, ECO:0000269|PubMed:15485904, ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:17595334, ECO:0000269|PubMed:18046454, ECO:0000269|PubMed:19001085, ECO:0000269|PubMed:19051325, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:2656706, ECO:0000269|PubMed:8955135}. | 15.11 | |||
| dfaFFAR1 | Free fatty acid receptor 1 | 2 | 429 | 99.38 | 99.06 | ND | 0.58 | 0.56 | 0.4 | Mammalian | Detected in brain and pancreas. Detected in pancreatic beta cells. {ECO:0000269|PubMed:12496284, ECO:0000269|PubMed:16289108}. | Family A G protein-coupled receptor | G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis. Fatty acid binding increases glucose- stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (By similarity). Ligand binding leads to a conformation change that triggers signaling via G-proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration. Seems to act through a G(q) and G(i)-mediated pathway. {ECO:0000250|UniProtKB:Q76JU9, ECO:0000269|PubMed:12496284, ECO:0000269|PubMed:17699519, ECO:0000269|PubMed:24130766}. | Free fatty acid receptor 1 agonist: Icosapent | 15.11 | |||
| dfaFFAR2 | Free fatty acid receptor 2 | 1 | 68 | 99.53 | 99.95 | ND | 0.35 | 0.57 | 0.5 | Mammalian | Expressed at relatively high levels in peripheral blood leukocytes and, to lesser extent, in spleen. {ECO:0000269|PubMed:12496283, ECO:0000269|PubMed:12684041}. | Family A G protein-coupled receptor | G protein-coupled receptor that is activated by a major product of dietary fiber digestion, the short chain fatty acids (SCFAs), and that plays a role in the regulation of whole-body energy homeostasis and in intestinal immunity. In omnivorous mammals, the short chain fatty acids acetate, propionate and butyrate are produced primarily by the gut microbiome that metabolizes dietary fibers. SCFAs serve as a source of energy but also act as signaling molecules. That G protein-coupled receptor is probably coupled to the pertussis toxin-sensitive, G(i/o)-alpha family of G proteins but also to the Gq family (PubMed:12496283, PubMed:12711604, PubMed:23589301). Its activation results in the formation of inositol 1,4,5-trisphosphate, the mobilization of intracellular calcium, the phosphorylation of the MAPK3/ERK1 and MAPK1/ERK2 kinases and the inhibition of intracellular cAMP accumulation. May play a role in glucose homeostasis by regulating the secretion of GLP-1, in response to short-chain fatty acids accumulating in the intestine. May also regulate the production of LEP/Leptin, a hormone acting on the central nervous system to inhibit food intake. Finally, may also regulate whole-body energy homeostasis through adipogenesis regulating both differentiation and lipid storage of adipocytes. In parallel to its role in energy homeostasis, may also mediate the activation of the inflammatory and immune responses by SCFA in the intestine, regulating the rapid production of chemokines and cytokines. May also play a role in the resolution of the inflammatory response and control chemotaxis in neutrophils. In addition to SCFAs, may also be activated by the extracellular lectin FCN1 in a process leading to activation of monocytes and inducing the secretion of interleukin- 8/IL-8 in response to the presence of microbes (PubMed:21037097). Among SCFAs, the fatty acids containing less than 6 carbons, the most potent activators are probably acetate, propionate and butyrate (PubMed:12496283, PubMed:12711604). Exhibits a SCFA- independent constitutive G protein-coupled receptor activity (PubMed:23066016). {ECO:0000269|PubMed:12496283, ECO:0000269|PubMed:12684041, ECO:0000269|PubMed:12711604, ECO:0000269|PubMed:18801738, ECO:0000269|PubMed:21037097, ECO:0000269|PubMed:23066016, ECO:0000269|PubMed:23589301}. | 16.04 | ||||
| dfaFFAR4 | Free fatty acid receptor 4 | 1 | 55 | 99.32 | 97.54 | ND | 0.54 | 0.78 | 0.6 | Mammalian | Abundant expression in the intestinal tract. Highly expressed in adipose tissue, small intestine and pancreas. {ECO:0000269|PubMed:15619630, ECO:0000269|PubMed:17250804}. | Family A G protein-coupled receptor | Receptor for medium and long-chain free fatty acids (FFAs). Signals via a G(q)/G(11)-coupled pathway. Acts as a receptor for omega-3 fatty acids and mediates robust anti- inflammatory effects, particularly in macrophages and fat cells. The anti-inflammatory effects involve inhibition of TAK1 through a beta-arrestin 2 (ARRB2)/TAB1-dependent effect, but independent of the G(q)/G(11)-coupled pathway. Mediates potent insulin sensitizing and antidiabetic effects by repressing macrophage- induced tissue inflammation. May mediate the taste of fatty acids. Mediates FFA-induced inhibition of apoptosis in enteroendocrine cells. May play a role in the regulation of adipocyte development and differentiation. {ECO:0000269|PubMed:15619630}. | 16.04 | ||||
| dfaFGF1 | Fibroblast growth factor 1 | 2 | 26 | 99.96 | 99.03 | ND | 0.65 | 0.49 | 0.8 | Mammalian | Predominantly expressed in kidney and brain. Detected at much lower levels in heart and skeletal muscle. {ECO:0000269|PubMed:11964394, ECO:0000269|PubMed:7504343}. | Secreted protein | Hepatic fibrosis | Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. {ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:20145243, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor 1 antagonist: Pentosan Polysulfate | 15.11 | ||
| dfaFGFR1 | Fibroblast growth factor receptor 1 | 3 | 1091 | 93.13 | 93.31 | ND | 0.59 | 0.64 | 0.6 | Mammalian | Detected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform 17, isoform 18 and isoform 19 are not detected in these cells. {ECO:0000269|PubMed:1652059}. | Kinase | Pfeiffer syndrome (PS) [MIM:101600]: A syndrome characterized by the association of craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly of the fingers and toes. Three subtypes are known: mild autosomal dominant form (type 1); cloverleaf skull, elbow ankylosis, early death, sporadic (type 2); craniosynostosis, early demise, sporadic (type 3). {ECO:0000269|PubMed:7874169}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:147950]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:12627230, ECO:0000269|PubMed:15001591, ECO:0000269|PubMed:15605412, ECO:0000269|PubMed:15845591, ECO:0000269|PubMed:16606836, ECO:0000269|PubMed:16757108, ECO:0000269|PubMed:16764984, ECO:0000269|PubMed:16882753, ECO:0000269|PubMed:17154279, ECO:0000269|PubMed:19820032, ECO:0000269|PubMed:21700882, ECO:0000269|PubMed:22927827, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900, ECO:0000269|PubMed:26277103}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FGFR1 also have a mutation other HH-associated genes including DUSP6, FGF8, FGF17, FLRT3, GNRH1, GNRHR, HS6ST1, IL17RD, ANOS1, KISS1R, NSMF, PROKR2, SPRY4 and TACR3 (PubMed:23643382). {ECO:0000269|PubMed:23643382}. Osteoglophonic dysplasia (OGD) [MIM:166250]: Characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant. {ECO:0000269|PubMed:15625620, ECO:0000269|PubMed:16470795}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hartsfield syndrome (HRTFDS) [MIM:615465]: A syndrome characterized by the triad of holoprosencephaly, ectrodactyly, and cleft/lip palate. Profound mental retardation is also present. Multiple other congenital anomalies usually occur. {ECO:0000269|PubMed:23812909, ECO:0000269|PubMed:24888332}. Note=The disease is caused by mutations affecting the gene represented in this entry. Trigonocephaly 1 (TRIGNO1) [MIM:190440]: A keel-shaped deformation of the forehead, caused by premature fusion of the metopic sutures. It results in a triangular shape of the head. {ECO:0000269|PubMed:11173846}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with ZMYM2. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow. {ECO:0000269|PubMed:9716603}. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1OP. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity and be responsible for the transforming activity. {ECO:0000269|PubMed:10688839, ECO:0000269|PubMed:15034873, ECO:0000269|PubMed:16946300, ECO:0000269|PubMed:17389761, ECO:0000269|PubMed:9949182}. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(8;9)(p12;q33) with CNTRL. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein CNTRL-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation. {ECO:0000250|UniProtKB:P16092, ECO:0000269|PubMed:10830168, ECO:0000269|PubMed:11353842, ECO:0000269|PubMed:12181353, ECO:0000269|PubMed:1379697, ECO:0000269|PubMed:1379698, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19261810, ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:20133753, ECO:0000269|PubMed:20139426, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:8622701, ECO:0000269|PubMed:8663044}. | 15.11 | |||
| dfaFGFR2 | Fibroblast growth factor receptor 2 | 5 | 125 | 94.04 | 92.97 | ND | 0.30 | 0.78 | 0.7 | Mammalian | Kinase | Crouzon syndrome (CS) [MIM:123500]: An autosomal dominant syndrome characterized by craniosynostosis, hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism. {ECO:0000269|PubMed:10574673, ECO:0000269|PubMed:11173845, ECO:0000269|PubMed:11380921, ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7581378, ECO:0000269|PubMed:7655462, ECO:0000269|PubMed:7874170, ECO:0000269|PubMed:7987400, ECO:0000269|PubMed:8528214, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:8946174, ECO:0000269|PubMed:8956050, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9152842, ECO:0000269|PubMed:9521581, ECO:0000269|PubMed:9677057, ECO:0000269|Ref.10}. Note=The disease is caused by mutations affecting the gene represented in this entry. Jackson-Weiss syndrome (JWS) [MIM:123150]: An autosomal dominant craniosynostosis syndrome characterized by craniofacial abnormalities and abnormality of the feet: broad great toes with medial deviation and tarsal-metatarsal coalescence. {ECO:0000269|PubMed:7874170, ECO:0000269|PubMed:8528214, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:9385368, ECO:0000269|PubMed:9677057}. Note=The disease is caused by mutations affecting the gene represented in this entry. Apert syndrome (APRS) [MIM:101200]: A syndrome characterized by facio-cranio-synostosis, osseous and membranous syndactyly of the four extremities, and midface hypoplasia. The craniosynostosis is bicoronal and results in acrocephaly of brachysphenocephalic type. Syndactyly of the fingers and toes may be total (mitten hands and sock feet) or partial affecting the second, third, and fourth digits. Intellectual deficit is frequent and often severe, usually being associated with cerebral malformations. {ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7668257, ECO:0000269|PubMed:7719344, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9452027, ECO:0000269|PubMed:9677057}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pfeiffer syndrome (PS) [MIM:101600]: A syndrome characterized by the association of craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly of the fingers and toes. Three subtypes are known: mild autosomal dominant form (type 1); cloverleaf skull, elbow ankylosis, early death, sporadic (type 2); craniosynostosis, early demise, sporadic (type 3). {ECO:0000269|PubMed:10394936, ECO:0000269|PubMed:10945669, ECO:0000269|PubMed:11173845, ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7719333, ECO:0000269|PubMed:7719345, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9150725, ECO:0000269|PubMed:9693549, ECO:0000269|PubMed:9719378}. Note=The disease is caused by mutations affecting the gene represented in this entry. Beare-Stevenson cutis gyrata syndrome (BSTVS) [MIM:123790]: An autosomal dominant disease characterized by craniofacial anomalies, particularly craniosynostosis, and ear defects, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, and prominent umbilical stump. The skin furrows have a corrugated appearance and are widespread. Cutis gyrata variably affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet. {ECO:0000269|PubMed:12000365, ECO:0000269|PubMed:8696350}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial scaphocephaly syndrome (FSPC) [MIM:609579]: An autosomal dominant craniosynostosis syndrome characterized by scaphocephaly, macrocephaly, hypertelorism, maxillary retrusion, and mild intellectual disability. Scaphocephaly is the most common of the craniosynostosis conditions and is characterized by a long, narrow head. It is due to premature fusion of the sagittal suture or from external deformation. {ECO:0000269|PubMed:16061565}. Note=The disease is caused by mutations affecting the gene represented in this entry. Lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]: An autosomal dominant ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Lacrimo-auriculo-dento-digital syndrome is characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. {ECO:0000269|PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry. Antley-Bixler syndrome, without genital anomalies or disordered steroidogenesis (ABS2) [MIM:207410]: A rare syndrome characterized by craniosynostosis, radiohumeral synostosis present from the perinatal period, midface hypoplasia, choanal stenosis or atresia, femoral bowing and multiple joint contractures. Arachnodactyly and/or camptodactyly have also been reported. {ECO:0000269|PubMed:10633130}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bent bone dysplasia syndrome (BBDS) [MIM:614592]: A perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Dysmorphic facial features included low-set ears, hypertelorism, midface hypoplasia, prematurely erupted fetal teeth, and micrognathia. {ECO:0000269|PubMed:22387015}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1. {ECO:0000269|PubMed:12529371, ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:15629145, ECO:0000269|PubMed:16384934, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19103595, ECO:0000269|PubMed:19387476, ECO:0000269|PubMed:19410646, ECO:0000269|PubMed:21596750, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor receptor 2 binder: Palifermin | 15.11 | |||
| dfaFGFR3 | Fibroblast growth factor receptor 3 | 5 | 208 | 89.96 | 92.11 | ND | 0.68 | 0.09 | 0.4 | Mammalian | Expressed in brain, kidney and testis. Very low or no expression in spleen, heart, and muscle. In 20- to 22- week old fetuses it is expressed at high level in kidney, lung, small intestine and brain, and to a lower degree in spleen, liver, and muscle. Isoform 2 is detected in epithelial cells. Isoform 1 is not detected in epithelial cells. Isoform 1 and isoform 2 are detected in fibroblastic cells. {ECO:0000269|PubMed:1664411}. | Kinase | Achondroplasia (ACH) [MIM:100800]: A frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. {ECO:0000269|PubMed:7758520, ECO:0000269|PubMed:7847369, ECO:0000269|PubMed:8078586}. Note=The disease is caused by mutations affecting the gene represented in this entry. Crouzon syndrome with acanthosis nigricans (CAN) [MIM:612247]: Classic Crouzon disease which is caused by mutations in the FGFR2 gene is characterized by craniosynostosis (premature fusion of the skull sutures), and facial hypoplasia. Crouzon syndrome with acanthosis nigricans (a skin disorder characterized by pigmentation anomalies), CAN, is considered to be an independent disorder from classic Crouzon syndrome. CAN is characterized by additional more severe physical manifestation, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, and is caused by a specific mutation (Ala-391 to Glu) in the transmembrane domain of FGFR3. It is proposed to have an autosomal dominant mode of inheritance. {ECO:0000269|PubMed:17935505, ECO:0000269|PubMed:7493034}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thanatophoric dysplasia 1 (TD1) [MIM:187600]: A neonatal lethal skeletal dysplasia. Affected individuals manifest severe shortening of the limbs with macrocephaly, narrow thorax, short ribs, and curved femurs. {ECO:0000269|PubMed:10360402, ECO:0000269|PubMed:10671061, ECO:0000269|PubMed:7773297, ECO:0000269|PubMed:8589699, ECO:0000269|PubMed:8845844, ECO:0000269|PubMed:9790257}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thanatophoric dysplasia 2 (TD2) [MIM:187601]: A neonatal lethal skeletal dysplasia causing severe shortening of the limbs, narrow thorax and short ribs. Patients with thanatophoric dysplasia type 2 have straight femurs and cloverleaf skull. {ECO:0000269|PubMed:7773297}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypochondroplasia (HCH) [MIM:146000]: Autosomal dominant disease and is characterized by disproportionate short stature. It resembles achondroplasia, but with a less severe phenotype. {ECO:0000269|PubMed:10215410, ECO:0000269|PubMed:10777366, ECO:0000269|PubMed:11055896, ECO:0000269|PubMed:12707965, ECO:0000269|PubMed:7670477, ECO:0000269|PubMed:9452043}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. {ECO:0000269|PubMed:10471491, ECO:0000269|PubMed:11314002}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Somatic mutations can constitutively activate FGFR3. Cervical cancer (CERCA) [MIM:603956]: A malignant neoplasm of the cervix, typically originating from a dysplastic or premalignant lesion previously present at the active squamocolumnar junction. The transformation from mild dysplastic to invasive carcinoma generally occurs slowly within several years, although the rate of this process varies widely. Carcinoma in situ is particularly known to precede invasive cervical cancer in most cases. Cervical cancer is strongly associated with infection by oncogenic types of human papillomavirus. {ECO:0000269|PubMed:10471491}. Note=The gene represented in this entry is involved in disease pathogenesis. Camptodactyly tall stature and hearing loss syndrome (CATSHL syndrome) [MIM:610474]: Autosomal dominant syndrome characterized by permanent and irreducible flexion of one or more fingers of the hand and/or feet, tall stature, scoliosis and/or a pectus excavatum, and hearing loss. Affected individuals have developmental delay and/or mental retardation, and several of these have microcephaly. Radiographic findings included tall vertebral bodies with irregular borders and broad femoral metaphyses with long tubular shafts. On audiological exam, each tested member have bilateral sensorineural hearing loss and absent otoacoustic emissions. The hearing loss was congenital or developed in early infancy, progressed variably in early childhood, and range from mild to severe. Computed tomography and magnetic resonance imaging reveal that the brain, middle ear, and inner ear are structurally normal. {ECO:0000269|PubMed:17033969}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple myeloma (MM) [MIM:254500]: A malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. {ECO:0000269|PubMed:11529856, ECO:0000269|PubMed:9207791}. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving FGFR3 is found in multiple myeloma. Translocation t(4;14)(p16.3;q32.3) with the IgH locus. Lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]: An autosomal dominant ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Lacrimo-auriculo-dento-digital syndrome is characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. {ECO:0000269|PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry. Keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900]: Epidermal nevi of the common, non-organoid and non- epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. {ECO:0000269|PubMed:16841094}. Note=The disease is caused by mutations affecting the gene represented in this entry. Muenke syndrome (MNKS) [MIM:602849]: A condition characterized by premature closure of coronal suture of skull during development (coronal craniosynostosis), which affects the shape of the head and face. It may be uni- or bilateral. When bilateral, it is characterized by a skull with a small antero- posterior diameter (brachycephaly), often with a decrease in the depth of the orbits and hypoplasia of the maxillae. Unilateral closure of the coronal sutures leads to flattening of the orbit on the involved side (plagiocephaly). The intellect is normal. In addition to coronal craniosynostosis some affected individuals show skeletal abnormalities of hands and feet, sensorineural hearing loss, mental retardation and respiratory insufficiency. {ECO:0000269|PubMed:11746040, ECO:0000269|PubMed:9042914, ECO:0000269|PubMed:9950359}. Note=The disease is caused by mutations affecting the gene represented in this entry. Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:15772091}. Note=The disease is caused by mutations affecting the gene represented in this entry. Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:19855393}. Note=The gene represented in this entry may be involved in disease pathogenesis. Achondroplasia, severe, with developmental delay and acanthosis nigricans (SADDAN) [MIM:616482]: A severe form of achondroplasia associated with developmental delay and acanthosis nigricans. Patients manifest short-limb dwarfism, with a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. Acanthosis nigricans is a skin condition characterized by brown-pigmented, velvety verrucosities in body folds and creases. {ECO:0000269|PubMed:10053006}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:14534538, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17145761, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:19286672, ECO:0000269|PubMed:8663044}. | 15.11 | |||
| dfaFGFR4 | Fibroblast growth factor receptor 4 | 3 | 82 | 99.30 | 93.84 | ND | 0.03 | 0.88 | 0.4 | Mammalian | Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. {ECO:0000269|PubMed:10631118}. | Kinase | Obesity | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645, ECO:0000269|PubMed:8663044}. | 15.11 | |||
| dfaFGR | Tyrosine-protein kinase Fgr | 7 | 88 | 88.16 | 90.63 | ND | 0.74 | 0.91 | 0.4 | Mammalian | Detected in neutrophils, monocytes and natural killer cells (at protein level). Detected in monocytes and large lymphocytes. {ECO:0000269|PubMed:11078731, ECO:0000269|PubMed:2181286, ECO:0000269|PubMed:8327512}. | Kinase | Note=Mutations that cause aberrant kinase activation can confer oncogene activity and promote aberrant cell proliferation. | Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocyte, macrophage and mast cell functions, cytoskeleton remodeling in response to extracellular stimuli, phagocytosis, cell adhesion and migration. Promotes mast cell degranulation, release of inflammatory cytokines and IgE-mediated anaphylaxis. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as MS4A2/FCER1B, FCGR2A and/or FCGR2B. Acts downstream of ITGB1 and ITGB2, and regulates actin cytoskeleton reorganization, cell spreading and adhesion. Depending on the context, activates or inhibits cellular responses. Functions as negative regulator of ITGB2 signaling, phagocytosis and SYK activity in monocytes. Required for normal ITGB1 and ITGB2 signaling, normal cell spreading and adhesion in neutrophils and macrophages. Functions as positive regulator of cell migration and regulates cytoskeleton reorganization via RAC1 activation. Phosphorylates SYK (in vitro) and promotes SYK- dependent activation of AKT1 and MAP kinase signaling. Phosphorylates PLD2 in antigen-stimulated mast cells, leading to PLD2 activation and the production of the signaling molecules lysophosphatidic acid and diacylglycerol. Promotes activation of PIK3R1. Phosphorylates FASLG, and thereby regulates its ubiquitination and subsequent internalization. Phosphorylates ABL1. Promotes phosphorylation of CBL, CTTN, PIK3R1, PTK2/FAK1, PTK2B/PYK2 and VAV2. Phosphorylates HCLS1 that has already been phosphorylated by SYK, but not unphosphorylated HCLS1. {ECO:0000269|PubMed:10739672, ECO:0000269|PubMed:17164290, ECO:0000269|PubMed:1737799, ECO:0000269|PubMed:7519620}. | 16.04 | |||
| dfaFKB1A | Peptidyl-prolyl cis-trans isomerase FKBP1A | 2 | 474 | 96.41 | 98.25 | ND | 0.68 | 0.64 | 0.8 | Mammalian | Isomerase | Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. {ECO:0000269|PubMed:16720724, ECO:0000269|PubMed:9233797}. | Peptidyl-prolyl cis-trans isomerase FKBP1A potentiator: Pimecrolimus | 15.11 | ||||
| dfaFKBP4 | Peptidyl-prolyl cis-trans isomerase FKBP4 | 3 | 60 | 99.77 | 99.96 | ND | 0.36 | 0.61 | 0.4 | Mammalian | Widely expressed. {ECO:0000269|PubMed:1279700}. | Enzyme | Neurological diseases | Immunophilin protein with PPIase and co-chaperone activities. Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria. {ECO:0000269|PubMed:1279700, ECO:0000269|PubMed:1376003, ECO:0000269|PubMed:19945390, ECO:0000269|PubMed:21730050, ECO:0000269|PubMed:2378870}. | 15.11 | |||
| dfaFKBP5 | Peptidyl-prolyl cis-trans isomerase FKBP5 | 2 | 76 | 99.55 | 99.81 | ND | 0.12 | 0.65 | 0.7 | Mammalian | Widely expressed, enriched in testis compared to other tissues. | Enzyme | Immunophilin protein with PPIase and co-chaperone activities. Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). Plays a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors maintaining the complex into the cytoplasm when unliganded. | 15.11 | ||||
| dfaFLT3 | Receptor-type tyrosine-protein kinase FLT3 | 4 | 1224 | 93.43 | 93.58 | ND | 0.66 | 0.67 | 0.6 | Mammalian | Detected in bone marrow, in hematopoietic stem cells, in myeloid progenitor cells and in granulocyte/macrophage progenitor cells (at protein level). Detected in bone marrow, liver, thymus, spleen and lymph node, and at low levels in kidney and pancreas. Highly expressed in T-cell leukemia. {ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:7507245, ECO:0000269|PubMed:8394751, ECO:0000269|PubMed:8637232}. | Kinase | Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:11290608, ECO:0000269|PubMed:11442493, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:18305215, ECO:0000269|PubMed:8946930, ECO:0000269|PubMed:9737679}. Note=The gene represented in this entry may be involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase. | Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways. {ECO:0000269|PubMed:10080542, ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:16627759, ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21067588, ECO:0000269|PubMed:21262971, ECO:0000269|PubMed:21516120, ECO:0000269|PubMed:7507245}. | Receptor-type tyrosine-protein kinase FLT3 antagonist: Sorafenib | 15.11 | ||
| dfaFOLH1 | Glutamate carboxypeptidase 2 | 1 | 174 | 96.06 | 90.15 | ND | 0.56 | 0.40 | 1.1 | Mammalian | Highly expressed in prostate epithelium. Detected in urinary bladder, kidney, testis, ovary, fallopian tube, breast, adrenal gland, liver, esophagus, stomach, small intestine, colon and brain (at protein level). Detected in the small intestine, brain, kidney, liver, spleen, colon, trachea, spinal cord and the capillary endothelium of a variety of tumors. Expressed specifically in jejunum brush border membranes. In the brain, highly expressed in the ventral striatum and brain stem. Also expressed in fetal liver and kidney. Isoform PSMA' is the most abundant form in normal prostate. Isoform PSMA-1 is the most abundant form in primary prostate tumors. Isoform PSMA-2 is also found in normal prostate as well as in brain and liver. Isoform PSMA-9 is specifically expressed in prostate cancer. {ECO:0000269|PubMed:14716746, ECO:0000269|PubMed:16555021, ECO:0000269|PubMed:17150306, ECO:0000269|PubMed:9375657}. | Protease | Amyotrophic lateral sclerosis
Prostate cancer Stroke | Has both folate hydrolase and N-acetylated-alpha-linked- acidic dipeptidase (NAALADase) activity. Has a preference for tri- alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N- aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoform PSM-4 and isoform PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression. Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC. | Glutamate carboxypeptidase 2 other/unknown: Capromab | 15.11 | ||
| dfaFPPS | Farnesyl pyrophosphate synthase | 1 | 212 | 99.69 | 99.73 | ND | 0.49 | 0.53 | 1.0 | Mammalian | Transferase | Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate. | Farnesyl pyrophosphate synthase inhibitor: Pamidronate | 15.11 | ||||
| dfaFPR1 | fMet-Leu-Phe receptor | 3 | 140 | 96.20 | 97.12 | ND | 0.35 | 0.80 | 0.6 | Mammalian | Neutrophils. | Family A G protein-coupled receptor | Gastric ulcer | High affinity receptor for N-formyl-methionyl peptides (fMLP), which are powerful neutrophil chemotactic factors (PubMed:2161213, PubMed:2176894, PubMed:10514456, PubMed:15153520). Binding of fMLP to the receptor stimulates intracellular calcium mobilization and superoxide anion release (PubMed:2161213, PubMed:1712023, PubMed:15153520). This response is mediated via a G-protein that activates a phosphatidylinositol- calcium second messenger system (PubMed:1712023, PubMed:10514456). {ECO:0000269|PubMed:10514456, ECO:0000269|PubMed:15153520, ECO:0000269|PubMed:2161213, ECO:0000269|PubMed:2176894, ECO:0000303|PubMed:10514456, ECO:0000303|PubMed:1712023, ECO:0000303|PubMed:2161213, ECO:0000303|PubMed:2176894}. | fMet-Leu-Phe receptor antagonist: Nedocromil | 16.04 | ||
| dfaFPR2 | N-formyl peptide receptor 2 | 4 | 94 | 99.47 | 99.39 | ND | 0.68 | 0.34 | 0.4 | Mammalian | Expressed abundantly in the lung and neutrophils. Also found in the spleen and testis. {ECO:0000269|PubMed:9151906}. | Family A G protein-coupled receptor | Alzheimer's disease | Low affinity receptor for N-formyl-methionyl peptides, which are powerful neutrophils chemotactic factors. Binding of FMLP to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The activation of LXA4R could result in an anti-inflammatory outcome counteracting the actions of proinflammatory signals such as LTB4 (leukotriene B4). | 16.04 | |||
| dfaFRK | Tyrosine-protein kinase FRK | 4 | 216 | 88.83 | 94.56 | ND | 0.16 | 0.51 | 1.5 | Mammalian | Predominantly expressed in epithelial derived cell lines and tissues, especially normal liver, kidney, breast and colon. {ECO:0000269|PubMed:7696183}. | Kinase | Non-receptor tyrosine-protein kinase that negatively regulates cell proliferation. Positively regulates PTEN protein stability through phosphorylation of PTEN on 'Tyr-336', which in turn prevents its ubiquitination and degradation, possibly by reducing its binding to NEDD4. May function as a tumor suppressor. {ECO:0000269|PubMed:19345329}. | Tyrosine-protein kinase FRK inhibitor: Regorafenib | 16.04 | |||
| dfaFSHR | Follicle-stimulating hormone receptor | 3 | 44 | 99.79 | 99.88 | ND | 0.69 | 0.72 | 0.6 | Mammalian | Sertoli cells and ovarian granulosa cells. | Family A G protein-coupled receptor | Ovarian dysgenesis 1 (ODG1) [MIM:233300]: An autosomal recessive disease characterized by primary amenorrhea, variable development of secondary sex characteristics, poorly developed streak ovaries, and high serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). {ECO:0000269|PubMed:10551778, ECO:0000269|PubMed:11889179, ECO:0000269|PubMed:12571157, ECO:0000269|PubMed:12915623, ECO:0000269|PubMed:7553856, ECO:0000269|PubMed:9769327, ECO:0000269|PubMed:9851774}. Note=The disease is caused by mutations affecting the gene represented in this entry. Ovarian hyperstimulation syndrome (OHSS) [MIM:608115]: Disorder which occurs either spontaneously or most often as an iatrogenic complication of ovarian stimulation treatments for in vitro fertilization. The clinical manifestations vary from abdominal distention and discomfort to potentially life- threatening, massive ovarian enlargement and capillary leak with fluid sequestration. Pathologic features of this syndrome include the presence of multiple serous and hemorrhagic follicular cysts lined by luteinized cells, a condition called hyperreactio luteinalis. {ECO:0000269|PubMed:12930927, ECO:0000269|PubMed:12930928, ECO:0000269|PubMed:15080154, ECO:0000269|PubMed:16278261, ECO:0000269|PubMed:17721928, ECO:0000269|PubMed:24058690, ECO:0000269|PubMed:25581598}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for follicle-stimulating hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Induces cAMP production through the activation of PI3K-AKT and SRC-ERK1/2 signaling pathways. {ECO:0000269|PubMed:24058690}. | Follicle-stimulating hormone receptor agonist: Follitropin beta, Urofollitropin Follicle-stimulating hormone receptor antagonist: Suramin Follicle-stimulating hormone receptor binder: Choriogonadotropin alfa, Menotropins | 16.04 | ||
| dfaFUCO | Tissue alpha-L-fucosidase | 1 | 100 | 97.37 | 96.10 | ND | 0.22 | 0.65 | 1.0 | Mammalian | Enzyme | Fucosidosis (FUCA1D) [MIM:230000]: An autosomal recessive lysosomal storage disease characterized by accumulation of fucose- containing glycolipids and glycoproteins in various tissues. Clinical signs include facial dysmorphism, dysostosis multiplex, moderate hepatomegaly, severe intellectual deficit, deafness, and according to age, angiokeratomas. {ECO:0000269|PubMed:7874128, ECO:0000269|PubMed:8504303, ECO:0000269|PubMed:9762612}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Alpha-L-fucosidase is responsible for hydrolyzing the alpha-1,6-linked fucose joined to the reducing-end N- acetylglucosamine of the carbohydrate moieties of glycoproteins. | 16.04 | ||||
| dfaFYN | Tyrosine-protein kinase Fyn | 5 | 440 | 84.45 | 84.50 | ND | 0.70 | 0.72 | 0.5 | Mammalian | Isoform 1 is highly expressed in the brain. Isoform 2 is expressed in cells of hemopoietic lineages, especially T-lymphocytes. {ECO:0000269|PubMed:10196263}. | Kinase | Philadelphia-positive leukemia | Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta- catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1. {ECO:0000269|PubMed:11005864, ECO:0000269|PubMed:11162638, ECO:0000269|PubMed:11536198, ECO:0000269|PubMed:12788081, ECO:0000269|PubMed:14707117, ECO:0000269|PubMed:14761972, ECO:0000269|PubMed:15536091, ECO:0000269|PubMed:15557120, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:16841086, ECO:0000269|PubMed:17194753, ECO:0000269|PubMed:18056706, ECO:0000269|PubMed:18258597, ECO:0000269|PubMed:19179337, ECO:0000269|PubMed:19652227, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:22080863, ECO:0000269|PubMed:7568038, ECO:0000269|PubMed:7822789}. | Tyrosine-protein kinase Fyn multitarget: Dasatinib | 15.11 | ||
| dfaG6PD | Glucose-6-phosphate 1-dehydrogenase | 5 | 99 | 99.44 | 95.20 | ND | 0.47 | 0.09 | 0.4 | Mammalian | Isoform Long is found in lymphoblasts, granulocytes and sperm. | Enzyme | Anemia, non-spherocytic hemolytic, due to G6PD deficiency (NSHA) [MIM:300908]: A disease characterized by G6PD deficiency, acute hemolytic anemia, fatigue, back pain, and jaundice. In most patients, the disease is triggered by an exogenous agent, such as some drugs, food, or infection. Increased unconjugated bilirubin, lactate dehydrogenase, and reticulocytosis are markers of the disorder. Although G6PD deficiency can be life-threatening, most patients are asymptomatic throughout their life. {ECO:0000269|PubMed:1611091, ECO:0000269|PubMed:26479991}. Note=The disease is caused by mutations affecting the gene represented in this entry. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of NSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity. | Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis. The main function of this enzyme is to provide reducing power (NADPH) and pentose phosphates for fatty acid and nucleic acid synthesis. {ECO:0000269|PubMed:15858258, ECO:0000269|PubMed:24769394}. | 16.04 | |||
| dfaGABR1 | Gamma-aminobutyric acid type B receptor subunit 1 | 1 | 69 | 99.14 | 99.11 | ND | 0.35 | 0.60 | 0.4 | Mammalian | Highly expressed in brain and weakly in heart, small intestine and uterus. Isoform 1A is mostly expressed in granular cell and molecular layer. Isoform 1B is mostly expressed in Purkinje cells. Isoform 1E is predominantly expressed in peripheral tissues as kidney, lung, trachea, colon, small intestine, stomach, bone marrow, thymus and mammary gland. {ECO:0000269|PubMed:9844003}. | Family C G protein-coupled receptor | Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Calcium is required for high affinity binding to GABA. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception. Activated by (-)-baclofen, cgp27492 and blocked by phaclofen. Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites. | Gamma-aminobutyric acid type B receptor subunit 1 agonist: Baclofen | 15.11 | |||
| dfaGABT | 4-aminobutyrate aminotransferase, mitochondrial | 3 | 50 | 97.43 | 97.71 | ND | 0.83 | 0.91 | 0.4 | Mammalian | Liver > pancreas > brain > kidney > heart > placenta. | Transferase | GABA transaminase deficiency (GABATD) [MIM:613163]: An enzymatic deficiency resulting in psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, and EEG abnormalities. {ECO:0000269|PubMed:10407778}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of gamma-aminobutyrate and L- beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively. Can also convert delta-aminovalerate and beta-alanine. | 4-aminobutyrate aminotransferase, mitochondrial inhibitor: L-Alanine, Phenelzine, Pyruvic acid, Valproic Acid, Vigabatrin | 16.04 | ||
| dfaGAK | Cyclin-G-associated kinase | 6 | 69 | 97.62 | 93.45 | ND | 0.84 | 0.97 | 0.5 | Mammalian | Ubiquitous. Highest in testis. | Kinase | Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin- coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1. {ECO:0000269|PubMed:10625686}. | 16.04 | ||||
| dfaGALK1 | Galactokinase | 5 | 109 | 99.63 | 95.74 | ND | 0.39 | 0.66 | 0.4 | Mammalian | Enzyme | Galactosemia II (GALCT2) [MIM:230200]: Autosomal recessive deficiency characterized by congenital cataracts during infancy and presenile cataracts in the adult population. The cataracts are secondary to accumulation of galactitol in the lenses. {ECO:0000269|PubMed:10521295, ECO:0000269|PubMed:10790206, ECO:0000269|PubMed:11139256, ECO:0000269|PubMed:11231902, ECO:0000269|PubMed:15024738}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Major enzyme for galactose metabolism. | 16.04 | ||||
| dfaGALR2 | Galanin receptor type 2 | 2 | 41 | 99.98 | 99.70 | ND | 0.24 | 0.37 | 0.4 | Mammalian | Expressed abundantly within the central nervous system in both hypothalamus and hippocampus. In peripheral tissues, the strongest expression was observed in heart, kidney, liver, and small intestine. | Family A G protein-coupled receptor | Alzheimer's disease
Central nervous system diseases Cerebral hemorrhage Diabetes mellitus Diarrhea Eating disorders Obesity | Receptor for the hormone galanin and GALP. Receptor for the hormone spexin-1 (PubMed:24517231). The activity of this receptor is mediated by G proteins that activate the phospholipase C/protein kinase C pathway (via G(q)) and that inhibit adenylyl cyclase (via G(i)). {ECO:0000269|PubMed:24517231, ECO:0000269|PubMed:25691535, ECO:0000269|PubMed:9480833, ECO:0000269|PubMed:9685625, ECO:0000269|PubMed:9832121, ECO:0000269|PubMed:9880084}. | 16.04 | |||
| dfaGASR | Gastrin/cholecystokinin type B receptor | 3 | 1164 | 98.75 | 98.98 | ND | 0.77 | 0.01 | 0.7 | Nature11159 | Mammalian | Isoform 1 is expressed in brain, pancreas, stomach, the colon cancer cell line LoVo and the T-lymphoblastoma Jurkat, but not in heart, placenta, liver, lung, skeletal muscle, kidney or the stomach cancer cell line AGS. Expressed at high levels in the small cell lung cancer cell line NCI-H510, at lower levels in NCI-H345, NCI-H69 and GLC-28 cell lines, not expressed in GLC-19 cell line. Within the stomach, expressed at high levels in the mucosa of the gastric fundus and at low levels in the antrum and duodenum. Isoform 2 is present in pancreatic cancer cells and colorectal cancer cells, but not in normal pancreas or colonic mucosa. Isoform 3 is expressed in brain, pancreas, stomach, the stomach cancer cell line AGS and the colon cancer cell line LoVo. {ECO:0000269|PubMed:10913157, ECO:0000269|PubMed:12429993, ECO:0000269|PubMed:7848914, ECO:0000269|PubMed:7887934, ECO:0000269|PubMed:8185170, ECO:0000269|PubMed:8349705}. | Family A G protein-coupled receptor | Acid-related diseases
Anxiety disorder, unspecified Cocaine dependence Gastrin sensitive tumours Gastrointestinal adenocarcinomas Gastrointestinal motility disorders Malignant gliomas Medullary thyroid cancer Neuroendocrine tumors Small cell lung cancer Stromal ovarian tumors | Receptor for gastrin and cholecystokinin. The CKK-B receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 is constitutively activated and may regulate cancer cell proliferation via a gastrin-independent mechanism. | Gastrin/cholecystokinin type B receptor agonist: Pentagastrin | 16.04 | |
| dfaGBA2 | Non-lysosomal glucosylceramidase | 1 | 44 | 99.60 | 99.84 | ND | 0.73 | 0.84 | 0.6 | Mammalian | Widely expressed. Highly expressed in brain, heart, skeletal muscle, kidney and placenta and expressed at lower level in liver. {ECO:0000269|PubMed:11489889}. | Enzyme | Spastic paraplegia 46, autosomal recessive (SPG46) [MIM:614409]: A neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging. {ECO:0000269|PubMed:23332916, ECO:0000269|PubMed:23332917}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-lysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide (GlcCer) to free glucose and ceramide. Involved in sphingomyelin generation and prevention of glycolipid accumulation. May also catalyze the hydrolysis of bile acid 3-O-glucosides, however, the relevance of such activity is unclear in vivo. Plays a role in central nevous system development. Required for proper formation of motor neuron axons. {ECO:0000269|PubMed:17105727, ECO:0000269|PubMed:23332916}. | 16.04 | |||
| dfaGBRA1 | Gamma-aminobutyric acid receptor subunit alpha-1 | 5 | 162 | 95.73 | 92.56 | ND | 0.03 | 0.69 | 0.8 | Nature11159 | Mammalian | Agitation Amnesia Apnoea Ataxia Cholestasis Confusional state Dependence Dermatitis exfoliative Dysarthria Erythema multiforme Folate deficiency Gangrene Hiccups Hypoprothrombinaemia Hypotension Incontinence Irritability Jaundice Laryngospasm Libido disorder Necrosis Nystagmus Respiratory depression Respiratory disorder Salivary gland disorder Somnolence Speech disorder Thrombophlebitis Urinary retention | Ligand-gated ion channel | Epilepsy, childhood absence 4 (ECA4) [MIM:611136]: A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood. {ECO:0000269|PubMed:16718694}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Epilepsy, idiopathic generalized 13 (EIG13) [MIM:611136]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:21714819}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Juvenile myoclonic epilepsy 5 (EJM5) [MIM:611136]: A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. {ECO:0000269|PubMed:11992121}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Epileptic encephalopathy, early infantile, 19 (EIEE19) [MIM:615744]: A severe neurologic disorder characterized by onset of seizures in the first months of life and usually associated with EEG abnormalities. Affected infants have convulsive seizures (hemiclonic or generalized) that are often prolonged and triggered by fever. Other seizure types include focal, myoclonic, absence seizures, and drop attacks. Development is normal in the first year of life with later slowing and intellectual disability. {ECO:0000269|PubMed:24623842}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand- gated chloride channel (By similarity). {ECO:0000250}. | Gamma-aminobutyric acid receptor subunit alpha-1 : Olanzapine Gamma-aminobutyric acid receptor subunit alpha-1 agonist: Ergoloid mesylate, Ethanol, Etomidate, Glutethimide, Isoflurane, Meprobamate, Methoxyflurane, Methyprylon, Progabide, Sevoflurane, Thiamylal, Topiramate Gamma-aminobutyric acid receptor subunit alpha-1 antagonist: Amoxapine, Flumazenil, Methohexital Gamma-aminobutyric acid receptor subunit alpha-1 negative modulator: Ginkgo biloba Gamma-aminobutyric acid receptor subunit alpha-1 other/unknown: Halothane Gamma-aminobutyric acid receptor subunit alpha-1 positive allosteric modulator: Alprazolam, Butabarbital, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Desflurane, Diazepam, Enflurane, Estazolam, Ethchlorvynol, Halazepam, Lorazepam, Prazepam, Propofol, Quazepam Gamma-aminobutyric acid receptor subunit alpha-1 positive modulator: Acamprosate Gamma-aminobutyric acid receptor subunit alpha-1 potentiator: Adinazolam, Amobarbital, Aprobarbital, Bromazepam, Butalbital, Butethal, Cinolazepam, Clotiazepam, Eszopiclone, Fludiazepam, Flurazepam, Heptabarbital, Hexobarbital, Ketazolam, Methylphenobarbital, Midazolam, Nitrazepam, Oxazepam, Pentobarbital, Phenobarbital, Primidone, Quinidine barbiturate, Secobarbital, Talbutal, Temazepam, Thiopental, Triazolam, Zaleplon, Zolpidem, Zopiclone | 16.04 | |
| dfaGBRA2 | Gamma-aminobutyric acid receptor subunit alpha-2 | 3 | 106 | 99.38 | 95.92 | ND | 0.34 | 0.56 | 0.4 | Mammalian | Agitation Amnesia Apnoea Ataxia Bone marrow disorder Cholestasis Confusional state Dependence Dermatitis exfoliative Dysarthria Erythema multiforme Folate deficiency Gangrene Hypoprothrombinaemia Hypotension Incontinence Irritability Jaundice Laryngospasm Libido disorder Nystagmus Respiratory depression Respiratory disorder Salivary gland disorder Somnolence Urinary retention Vertigo | Ligand-gated ion channel | Anxiety disorder, unspecified
Disorders of initiating and maintaining sleep [insomnias] | GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. | Gamma-aminobutyric acid receptor subunit alpha-2 : Ethanol Gamma-aminobutyric acid receptor subunit alpha-2 agonist: Eszopiclone, Meprobamate, Zolpidem Gamma-aminobutyric acid receptor subunit alpha-2 potentiator: Adinazolam, Amobarbital, Aprobarbital, Bromazepam, Butalbital, Butethal, Cinolazepam, Clotiazepam, Diazepam, Estazolam, Fludiazepam, Flunitrazepam, Flurazepam, Halazepam, Heptabarbital, Hexobarbital, Methylphenobarbital, Midazolam, Nitrazepam, Oxazepam, Pentobarbital, Prazepam, Primidone, Quazepam, Quinidine barbiturate, Secobarbital, Talbutal, Temazepam, Thiopental, Triazolam, Zopiclone | 16.04 | ||
| dfaGBRA3 | Gamma-aminobutyric acid receptor subunit alpha-3 | 6 | 71 | 99.67 | 100.00 | ND | 0.79 | 0.78 | 0.2 | Mammalian | Agitation Amnesia Apnoea Ataxia Bone marrow disorder Cholestasis Confusional state Dependence Dermatitis exfoliative Dysarthria Erythema multiforme Folate deficiency Gangrene Hypoprothrombinaemia Hypotension Incontinence Irritability Jaundice Laryngospasm Libido disorder Nystagmus Respiratory depression Respiratory disorder Salivary gland disorder Somnolence Speech disorder Urinary retention | Ligand-gated ion channel | Anxiety disorder, unspecified
Disorders of initiating and maintaining sleep [insomnias] | GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. | Gamma-aminobutyric acid receptor subunit alpha-3 : Ethanol Gamma-aminobutyric acid receptor subunit alpha-3 agonist: Eszopiclone, Meprobamate, Zolpidem Gamma-aminobutyric acid receptor subunit alpha-3 potentiator: Adinazolam, Amobarbital, Aprobarbital, Bromazepam, Butalbital, Butethal, Cinolazepam, Clotiazepam, Diazepam, Estazolam, Fludiazepam, Flunitrazepam, Flurazepam, Halazepam, Heptabarbital, Hexobarbital, Methylphenobarbital, Midazolam, Nitrazepam, Oxazepam, Pentobarbital, Prazepam, Primidone, Quazepam, Secobarbital, Talbutal, Temazepam, Thiopental, Triazolam, Zopiclone | 16.04 | ||
| dfaGBRA5 | Gamma-aminobutyric acid receptor subunit alpha-5 | 4 | 102 | 92.71 | 93.67 | ND | 0.71 | 0.67 | 0.4 | Mammalian | Agitation Amnesia Apnoea Ataxia Bone marrow disorder Cholestasis Confusional state Dependence Dermatitis exfoliative Dysarthria Erythema multiforme Folate deficiency Gangrene Hypoprothrombinaemia Hypotension Incontinence Irritability Jaundice Laryngospasm Libido disorder Nystagmus Respiratory depression Respiratory disorder Salivary gland disorder Somnolence Speech disorder Urinary retention | Ligand-gated ion channel | Alzheimer's Disease
Central nervous system diseases Cognitive deficits Delirium Dementia | GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. | Gamma-aminobutyric acid receptor subunit alpha-5 : Ethanol Gamma-aminobutyric acid receptor subunit alpha-5 agonist: Eszopiclone, Meprobamate Gamma-aminobutyric acid receptor subunit alpha-5 antagonist: Flumazenil Gamma-aminobutyric acid receptor subunit alpha-5 potentiator: Adinazolam, Amobarbital, Aprobarbital, Bromazepam, Butalbital, Butethal, Cinolazepam, Clotiazepam, Diazepam, Estazolam, Fludiazepam, Flunitrazepam, Flurazepam, Halazepam, Heptabarbital, Hexobarbital, Methylphenobarbital, Midazolam, Nitrazepam, Oxazepam, Pentobarbital, Prazepam, Primidone, Quazepam, Secobarbital, Talbutal, Temazepam, Thiopental, Triazolam, Zopiclone | 16.04 | ||
| dfaGCKR | Glucokinase regulatory protein | 2 | 50 | 99.92 | 99.99 | ND | 0.73 | 0.64 | 0.4 | Mammalian | Found in liver and pancreas. Not detected in muscle, brain, heart, thymus, intestine, uterus, adipose tissue, kidney, adrenal, lung or spleen. {ECO:0000269|PubMed:19643913, ECO:0000269|PubMed:9570959}. | Inhibits glucokinase (GCK) by forming an inactive complex with this enzyme. The affinity of GCKR for GCK is modulated by fructose metabolites: GCKR with bound fructose 6- phosphate has increased affinity for GCK, while GCKR with bound fructose 1-phosphate has strongly decreased affinity for GCK and does not inhibit GCK activity. {ECO:0000269|PubMed:23621087, ECO:0000269|PubMed:23733961}. | 15.11 | |||||
| dfaGCR | Glucocorticoid receptor | 5 | 1819 | 94.82 | 88.50 | ND | 0.65 | 0.61 | 0.6 | Nature11159 VirtualToxLab | Mammalian | Widely expressed. In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart. {ECO:0000269|PubMed:10902803}. | Acne Adrenal disorder Adrenal insufficiency Adrenal suppression Amenorrhoea Bone disorder Calcium metabolism disorder Cataract Cushingoid Depression Dysphonia Embolism arterial Endocrine disorder Epidural lipomatosis Epistaxis Euphoric mood Fluid retention Foot and mouth disease Fracture Fungal infection Glaucoma Growth retardation Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Impaired healing Increased appetite Intracranial pressure increased Menstrual disorder Muscular weakness Nitrogen balance negative Oedema Oral candidiasis Osteonecrosis Osteoporosis Pancreatic disorder Pancreatitis acute Peptic ulcer Phosphorus metabolism disorder Sepsis Skin atrophy Skin striae Superinfection Telangiectasia | Nuclear receptor | Glucocorticoid resistance, generalized (GCCR) [MIM:615962]: An autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of Cushing syndrome typical signs. Clinical features include hypoglycemia, hypertension, metabolic alkalosis, chronic fatigue and profound anxiety. {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946}. Note=The disease is caused by mutations affecting the gene represented in this entry. Glucocorticoid resistance (GCRES) [MIM:138040]: Hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant. {ECO:0000269|PubMed:11589680, ECO:0000269|PubMed:12050230, ECO:0000269|PubMed:7683692}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic genes expression. {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946, ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:21664385}. | Glucocorticoid receptor agonist: Flunisolide | 15.11 |
| dfaGGPPS | Geranylgeranyl pyrophosphate synthase | 1 | 72 | 91.90 | 94.59 | ND | 0.71 | 0.55 | 0.5 | Mammalian | Abundantly expressed in testis. Found in other tissues to a lower extent. | Enzyme | Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins. | Geranylgeranyl pyrophosphate synthase inhibitor: Zoledronate | 16.04 | |||
| dfaGHRL | Appetite-regulating hormone | 1 | 41 | 99.99 | 99.98 | ND | 0.58 | 0.73 | 0.5 | Mammalian | Highest level in stomach. All forms are found in serum as well. Other tissues compensate for the loss of ghrelin synthesis in the stomach following gastrectomy. {ECO:0000269|PubMed:12414809}. | Anorexia nervosa
Cachexia Noninsulin-dependent diabetes mellitus Obesity | Ghrelin is the ligand for growth hormone secretagogue receptor type 1 (GHSR). Induces the release of growth hormone from the pituitary. Has an appetite-stimulating effect, induces adiposity and stimulates gastric acid secretion. Involved in growth regulation. Obestatin may be the ligand for GPR39. May have an appetite-reducing effect resulting in decreased food intake. May reduce gastric emptying activity and jejunal motility (By similarity). {ECO:0000250}. | 16.04 | ||||
| dfaGHSR | Growth hormone secretagogue receptor type 1 | 4 | 923 | 96.75 | 95.95 | ND | 0.48 | 0.58 | 0.6 | Nature11159 | Mammalian | Pituitary and hypothalamus. | Family A G protein-coupled receptor | Growth hormone deficiency, isolated partial (GHDP) [MIM:615925]: A disorder characterized by partial growth hormone deficiency resulting in growth delay and short stature, sometimes associated with recurrent episodes of abdominal pain, vomiting, ketosis and hypoglycemia. {ECO:0000269|PubMed:16511605, ECO:0000269|PubMed:19789204}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine). {ECO:0000269|PubMed:10604470, ECO:0000269|PubMed:11322507}. | 16.04 | ||
| dfaGIPR | Gastric inhibitory polypeptide receptor | 1 | 98 | 99.98 | 99.88 | ND | 0.40 | 0.44 | 0.4 | Mammalian | Family B G protein-coupled receptor | This is a receptor for GIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. | 16.04 | |||||
| dfaGLCM | Glucosylceramidase | 6 | 510 | 86.60 | 80.90 | ND | 0.50 | 0.53 | 0.6 | Mammalian | Enzyme | Gaucher disease (GD) [MIM:230800]: A lysosomal storage disease due to deficient activity of beta-glucocerebrosidase and characterized by accumulation of glucosylceramide in the reticulo- endothelial system. Different clinical forms are recognized depending on the presence (neuronopathic forms) or absence of central nervous system involvement, severity and age of onset. {ECO:0000269|PubMed:10352942, ECO:0000269|PubMed:10360404, ECO:0000269|PubMed:10447266, ECO:0000269|PubMed:10744424, ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, ECO:0000269|PubMed:11992489, ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:15292921, ECO:0000269|PubMed:1972019, ECO:0000269|PubMed:1974409, ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:7627192, ECO:0000269|PubMed:7916532, ECO:0000269|PubMed:8076951, ECO:0000269|PubMed:8112750, ECO:0000269|PubMed:8294033, ECO:0000269|PubMed:8432537, ECO:0000269|PubMed:8790604, ECO:0000269|PubMed:8829654, ECO:0000269|PubMed:8829663, ECO:0000269|PubMed:8937765, ECO:0000269|PubMed:9061570, ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9182788, ECO:0000269|PubMed:9217217, ECO:0000269|PubMed:9279145, ECO:0000269|PubMed:9516376, ECO:0000269|PubMed:9554454, ECO:0000269|PubMed:9554746, ECO:0000269|PubMed:9650766, ECO:0000269|PubMed:9683600}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease 1 (GD1) [MIM:230800]: A form of Gaucher disease characterized by hepatosplenomegaly with consequent anemia and thrombopenia, and bone involvement. The central nervous system is not involved. {ECO:0000269|PubMed:10206680, ECO:0000269|PubMed:10340647, ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:8889591, ECO:0000269|Ref.14}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease 2 (GD2) [MIM:230900]: The most severe form of Gaucher disease. It manifests soon after birth, with death generally occurring before patients reach two years of age. {ECO:0000269|PubMed:9637431, ECO:0000269|PubMed:9851895}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease 3 (GD3) [MIM:231000]: A subacute form of neuronopathic Gaucher disease. It has later onset and slower progression compared to the acute form of neuronopathic Gaucher disease 2. {ECO:0000269|PubMed:8780099}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease 3C (GD3C) [MIM:231005]: A variant of subacute neuronopathic Gaucher disease 3 associated with cardiovascular calcifications. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease perinatal lethal (GDPL) [MIM:608013]: Distinct form of Gaucher disease type 2, characterized by fetal onset. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. Parkinson disease (PARK) [MIM:168600]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. {ECO:0000269|PubMed:12847165, ECO:0000269|PubMed:16148263, ECO:0000269|PubMed:19286695}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. | 16.04 | |||||
| dfaGLR | Glucagon receptor | 4 | 617 | 97.81 | 99.42 | ND | 0.66 | 0.67 | 0.5 | Mammalian | Family B G protein-coupled receptor | Hyperglycemia
Insulin-dependent diabetes mellitus Lipid metabolic disorders Noninsulin-dependent diabetes mellitus Obesity | G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. Regulates the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis. Plays an important role in mediating the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase. Besides, plays a role in signaling via a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:19657311, ECO:0000269|PubMed:22908259, ECO:0000269|PubMed:23863937, ECO:0000269|PubMed:7507321, ECO:0000269|PubMed:9287038}. | Glucagon receptor agonist: Glucagon recombinant | 16.04 | |||
| dfaGLRA1 | Glycine receptor subunit alpha-1 | 3 | 78 | 87.60 | 83.85 | ND | 0.67 | 0.77 | 0.6 | Mammalian | Respiratory depression | Ligand-gated ion channel | Hyperekplexia 1 (HKPX1) [MIM:149400]: A neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to unexpected acoustic or tactile stimuli. {ECO:0000269|PubMed:10514101, ECO:0000269|PubMed:7611730, ECO:0000269|PubMed:7881416, ECO:0000269|PubMed:7981700, ECO:0000269|PubMed:8298642, ECO:0000269|PubMed:8571969, ECO:0000269|PubMed:8733061, ECO:0000269|PubMed:9067762, ECO:0000269|PubMed:9920650, ECO:0000269|Ref.10}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing). | Glycine receptor subunit alpha-1 : Glycine Glycine receptor subunit alpha-1 agonist: Desflurane, Enflurane, Ethanol, Isoflurane, Methoxyflurane, Sevoflurane Glycine receptor subunit alpha-1 allosteric modulator: Halothane Glycine receptor subunit alpha-1 antagonist: Ginkgo biloba, Lindane | 15.11 | ||
| dfaGNRHR | Gonadotropin-releasing hormone receptor | 4 | 1039 | 98.62 | 98.92 | ND | 0.58 | 0.68 | 0.7 | Mammalian | Pituitary, ovary, testis, breast and prostate but not in liver and spleen. | Flushing | Family A G protein-coupled receptor | Hypogonadotropic hypogonadism 7 with or without anosmia (HH7) [MIM:146110]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:10022417, ECO:0000269|PubMed:10084584, ECO:0000269|PubMed:10523035, ECO:0000269|PubMed:11318785, ECO:0000269|PubMed:11397842, ECO:0000269|PubMed:11397871, ECO:0000269|PubMed:12679486, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900, ECO:0000269|PubMed:9371856, ECO:0000269|PubMed:9425890}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in GNRHR as well as in other HH-associated genes including FGFR1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}. | Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle- stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol- calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling. | Gonadotropin-releasing hormone receptor : Buserelin Gonadotropin-releasing hormone receptor agonist: Gonadorelin, Goserelin, Leuprolide, Nafarelin, Triptorelin Gonadotropin-releasing hormone receptor antagonist: Abarelix, Cetrorelix, Degarelix, Ganirelix Gonadotropin-releasing hormone receptor negative modulator: Danazol | 16.04 | |
| dfaGP119 | Glucose-dependent insulinotropic receptor | 4 | 542 | 98.94 | 98.06 | ND | 0.43 | 0.52 | 0.5 | Mammalian | Predominantly expressed in the pancreas, especially in the islets. {ECO:0000269|PubMed:15607732}. | Family A G protein-coupled receptor | Diabetes Mellitus Type 2 | Receptor for the endogenous fatty-acid ethanolamide oleoylethanolamide (OEA) and lysophosphatidylcholine (LPC). Functions as a glucose-dependent insulinotropic receptor. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Seems to act through a G(s) mediated pathway. {ECO:0000269|PubMed:16517404}. | 16.04 | |||
| dfaGP142 | Probable G-protein coupled receptor 142 | 2 | 85 | 99.94 | 100.00 | ND | 0.52 | 0.62 | 0.5 | Mammalian | Exclusively expressed in the central nervous system, most abundantly in the ventrolateral region of caudate putamen, the habenular nucleus, the zona incerta, and the medial mammillary nucleus. {ECO:0000269|PubMed:15845401}. | Family A G protein-coupled receptor | Orphan receptor. | 16.04 | ||||
| dfaGPBAR | G-protein coupled bile acid receptor 1 | 8 | 373 | 95.91 | 94.38 | ND | 0.70 | 0.71 | 0.6 | Mammalian | Ubiquitously expressed. Expressed at higher level in spleen and placenta. Expressed at lower level in other tissues. In digestive tissues, it is expressed in stomach, duodenum, ileocecum, ileum, jejunum, ascending colon, transverse colon, descending colon, cecum and liver, but not in esophagus and rectum. {ECO:0000269|PubMed:12044878, ECO:0000269|PubMed:12419312, ECO:0000269|PubMed:12524422}. | Family A G protein-coupled receptor | Type 2 Diabetes | Receptor for bile acid. Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids. {ECO:0000269|PubMed:12419312, ECO:0000269|PubMed:12524422}. | 16.04 | |||
| dfaGPR35 | G-protein coupled receptor 35 | 7 | 228 | 88.45 | 82.61 | ND | 0.83 | 0.87 | 0.4 | Mammalian | Predominantly expressed in immune and gastrointestinal tissues. {ECO:0000269|PubMed:16754668}. | Family A G protein-coupled receptor | Acts as a receptor for kynurenic acid, an intermediate in the tryptophan metabolic pathway. The activity of this receptor is mediated by G-proteins that elicit calcium mobilization and inositol phosphate production through G(qi/o) proteins. {ECO:0000269|PubMed:16754668}. | 16.04 | ||||
| dfaGPR55 | G-protein coupled receptor 55 | 4 | 445 | 80.62 | 81.75 | ND | 0.37 | 0.53 | 0.4 | Mammalian | Expressed in the caudate nucleus and putamen, but not detected in the hippocampus, thalamus, pons cerebellum, frontal cortex of the brain or in the liver. Expressed in osteoclasts and osteoblasts. {ECO:0000269|PubMed:19805329, ECO:0000269|PubMed:9931487}. | Family A G protein-coupled receptor | May be involved in hyperalgesia associated with inflammatory and neuropathic pain (By similarity). Receptor for L- alpha-lysophosphatidylinositol (LPI). LPI induces Ca(2+) release from intracellular stores via the heterotrimeric G protein GNA13 and RHOA. Putative cannabinoid receptor. May play a role in bone physiology by regulating osteoclast number and function. {ECO:0000250, ECO:0000269|PubMed:19805329}. | 16.04 | ||||
| dfaGRB2 | Growth factor receptor-bound protein 2 | 1 | 183 | 99.85 | 99.76 | ND | 0.51 | 0.67 | 0.8 | Mammalian | Other cytosolic protein | Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death. | Growth factor receptor-bound protein 2 binder: Pegademase bovine | 15.11 | ||||
| dfaGRIA1 | Glutamate receptor 1 | 2 | 96 | 99.07 | 91.15 | ND | 0.68 | 0.78 | 0.7 | Mammalian | Widely expressed in brain. | Ligand-gated ion channel | Schizophrenia | Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:20805473, ECO:0000269|PubMed:21172611}. | Glutamate receptor 1 : Ethanol Glutamate receptor 1 antagonist: Desflurane, Enflurane, Isoflurane, Methoxyflurane, Perampanel, Sevoflurane | 16.04 | ||
| dfaGRIA2 | Glutamate receptor 2 | 5 | 256 | 95.98 | 95.24 | ND | 0.57 | 0.65 | 0.6 | Mammalian | Ligand-gated ion channel | Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:20614889}. | Glutamate receptor 2 : Ethanol Glutamate receptor 2 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Quinidine barbiturate, Secobarbital, Talbutal, Thiopental | 15.11 | ||||
| dfaGRIA4 | Glutamate receptor 4 | 6 | 121 | 99.64 | 99.27 | ND | 0.50 | 0.72 | 0.8 | Mammalian | Detected in cerebellum (at protein level). | Ligand-gated ion channel | Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate (By similarity). {ECO:0000250, ECO:0000269|PubMed:12603841, ECO:0000269|PubMed:19102704, ECO:0000269|PubMed:20107073}. | 15.11 | ||||
| dfaGRIK1 | Glutamate receptor ionotropic, kainate 1 | 3 | 257 | 95.00 | 94.16 | ND | 0.51 | 0.65 | 0.7 | Mammalian | Most abundant in the cerebellum and the suprachiasmatic nuclei (SCN) of the hypothalamus. | Ligand-gated ion channel | Analgesics
Epilepsy Pain | Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus. | Glutamate receptor ionotropic, kainate 1 antagonist: Topiramate | 15.11 | ||
| dfaGRIK2 | Glutamate receptor ionotropic, kainate 2 | 2 | 169 | 98.64 | 95.82 | ND | 0.62 | 0.73 | 0.8 | Mammalian | Expression is higher in cerebellum than in cerebral cortex. | Ligand-gated ion channel | Mental retardation, autosomal recessive 6 (MRT6) [MIM:611092]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. In contrast to syndromic or specific mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic mental retardation. MRT6 patients display mild to severe mental retardation and psychomotor development delay in early childhood. Patients do not have neurologic problems, congenital malformations, or facial dysmorphism. Body height, weight, and head circumference are normal. {ECO:0000269|PubMed:17847003}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus. Modulates cell surface expression of NETO2 (By similarity). {ECO:0000250}. | Glutamate receptor ionotropic, kainate 2 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Talbutal, Thiopental | 16.04 | ||
| dfaGRIK3 | Glutamate receptor ionotropic, kainate 3 | 2 | 66 | 99.31 | 99.54 | ND | 0.62 | 0.77 | 0.6 | Mammalian | Expressed in the deep cortical layers, dentate gyrus, reticular thalamic nucleus, mammillary bodies, pons, and cerebellum of the adult. | Ligand-gated ion channel | Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA. {ECO:0000269|PubMed:21907808}. | 15.11 | ||||
| dfaGRK4 | G protein-coupled receptor kinase 4 | 4 | 60 | 86.69 | 90.50 | ND | 0.46 | 0.93 | 0.5 | Mammalian | Isoform 1, isoform 2, isoform 3, and isoform 4 are expressed in testis. Isoform 4 is expressed in myometrium. {ECO:0000269|PubMed:16636192, ECO:0000269|PubMed:8626439}. | Kinase | Specifically phosphorylates the activated forms of G protein-coupled receptors. GRK4-alpha can phosphorylate rhodopsin and its activity is inhibited by calmodulin; the other three isoforms do not phosphorylate rhodopsin and do not interact with calmodulin. GRK4-alpha and GRK4-gamma phosphorylate DRD3. Phosphorylates ADRB2. {ECO:0000269|PubMed:19520868, ECO:0000269|PubMed:8626439}. | 15.11 | ||||
| dfaGRK5 | G protein-coupled receptor kinase 5 | 7 | 136 | 86.47 | 83.47 | ND | 0.22 | 0.48 | 0.3 | Mammalian | Highest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney. {ECO:0000269|PubMed:7685906}. | Kinase | Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein- coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70- interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2- mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G- protein-coupled receptor, LRP6 during Wnt signaling (in vitro). {ECO:0000269|PubMed:19661922, ECO:0000269|PubMed:19801552, ECO:0000269|PubMed:20038610, ECO:0000269|PubMed:20124405, ECO:0000269|PubMed:21728385}. | 15.11 | ||||
| dfaGRM1 | Metabotropic glutamate receptor 1 | 8 | 701 | 96.96 | 89.83 | ND | 0.76 | 0.72 | 0.6 | Mammalian | Detected in brain. | Family C G protein-coupled receptor | Spinocerebellar ataxia, autosomal recessive, 13 (SCAR13) [MIM:614831]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR13 is characterized by delayed psychomotor development beginning in infancy. Affected individuals show mild to profound mental retardation with poor or absent speech as well as gait and stance ataxia and hyperreflexia. {ECO:0000269|PubMed:22901947}. Note=The disease is caused by mutations affecting the gene represented in this entry. | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum. {ECO:0000269|PubMed:24603153, ECO:0000269|PubMed:7476890}. | 15.11 | |||
| dfaGRM2 | Metabotropic glutamate receptor 2 | 6 | 812 | 95.54 | 89.79 | ND | 0.70 | 0.67 | 0.6 | Mammalian | Detected in brain cortex (at protein level). Widely expressed in different regions of the adult brain as well as in fetal brain. {ECO:0000269|PubMed:18297054}. | Family C G protein-coupled receptor | Alzheimer's disease
Analgesics Anxiety disorder, unspecified Epilepsy Pain, unspecified Traumatic brain injury | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization. {ECO:0000269|PubMed:18297054, ECO:0000269|PubMed:22300836, ECO:0000269|PubMed:23129762, ECO:0000269|PubMed:7620613}. | 15.11 | |||
| dfaGRM3 | Metabotropic glutamate receptor 3 | 6 | 192 | 98.79 | 99.65 | ND | 0.67 | 0.71 | 0.6 | Mammalian | Detected in brain cortex, thalamus, subthalamic nucleus, substantia nigra, hypothalamus, hippocampus, corpus callosum, caudate nucleus and amygdala. {ECO:0000269|PubMed:8840013}. | Family C G protein-coupled receptor | Alzheimer's disease
Analgesics Epilepsy Pain Psychosis Schizophrenia and Schizoaffective Disorders Traumatic brain injury | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:8840013}. | 15.11 | |||
| dfaGRM4 | Metabotropic glutamate receptor 4 | 6 | 305 | 97.83 | 92.25 | ND | 0.64 | 0.63 | 0.4 | Mammalian | Strongly expressed in the cerebellum. Expressed at low levels in hippocampus, hypothalamus and thalamus. No expression detected in liver. {ECO:0000269|PubMed:7617140, ECO:0000269|PubMed:8738157}. | Family C G protein-coupled receptor | Parkinson's disease | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:7617140, ECO:0000269|PubMed:8738157, ECO:0000269|PubMed:9473604}. | 16.04 | |||
| dfaGRM5 | Metabotropic glutamate receptor 5 | 3 | 2236 | 95.27 | 86.97 | ND | 0.51 | 0.54 | 0.7 | Mammalian | Family C G protein-coupled receptor | Analgesics
Anxiety Disorders Convulsions Depression Drug dependence Gastroesophageal Reflux Disease (GERD) Inflammatory pain Migraine and Cluster Headaches Neuronal injury Parkinson's disease | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. Plays an important role in the regulation of synaptic plasticity and the modulation of the neural network activity. {ECO:0000269|PubMed:7908515, ECO:0000269|Ref.7}. | Metabotropic glutamate receptor 5 antagonist: Acamprosate Metabotropic glutamate receptor 5 inhibitor: Rufinamide | 15.11 | |||
| dfaGRM7 | Metabotropic glutamate receptor 7 | 2 | 58 | 99.71 | 97.28 | ND | 0.98 | 0.75 | 0.2 | Mammalian | Expressed in many areas of the brain, especially in the cerebral cortex, hippocampus, and cerebellum. Expression of GRM7 isoforms in non-neuronal tissues appears to be restricted to isoform 3 and isoform 4. {ECO:0000269|PubMed:12052533, ECO:0000269|PubMed:8840028}. | Family C G protein-coupled receptor | Convulsions | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:9473604}. | 15.11 | |||
| dfaGRM8 | Metabotropic glutamate receptor 8 | 2 | 82 | 99.12 | 99.92 | ND | 0.67 | 0.41 | 0.6 | Mammalian | Family C G protein-coupled receptor | Analgesics
Epilepsy Pain | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:9473604}. | 16.04 | ||||
| dfaGRP78 | 78 kDa glucose-regulated protein | 2 | 72 | 100.00 | 99.95 | ND | 0.83 | 0.90 | 0.4 | Mammalian | Note=Autoantigen in rheumatoid arthritis. {ECO:0000269|PubMed:11160188}. | Probably plays a role in facilitating the assembly of multimeric protein complexes inside the endoplasmic reticulum. Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10, probably to facilitate the release of DNAJC10 from its substrate. {ECO:0000269|PubMed:2294010, ECO:0000269|PubMed:23769672, ECO:0000269|PubMed:23990668}. | 78 kDa glucose-regulated protein binding: Acetylsalicylic acid 78 kDa glucose-regulated protein chaperone: Antihemophilic Factor (Recombinant) | 16.04 | ||||
| dfaGSHR | Glutathione reductase, mitochondrial | 12 | 118 | 87.39 | 91.60 | ND | 0.88 | 0.83 | 0.2 | Mammalian | Oxidoreductase | Maintains high levels of reduced glutathione in the cytosol. | Glutathione reductase, mitochondrial : Flavin adenine dinucleotide, Glutathione Glutathione reductase, mitochondrial inhibitor: Carmustine | 15.11 | ||||
| dfaGSK3A | Glycogen synthase kinase-3 alpha | 5 | 664 | 93.43 | 91.62 | ND | 0.61 | 0.37 | 0.6 | Mammalian | Kinase | Not Available | Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. {ECO:0000269|PubMed:12761548, ECO:0000269|PubMed:17229088}. | 16.04 | ||||
| dfaGSK3B | Glycogen synthase kinase-3 beta | 7 | 2337 | 93.45 | 90.22 | ND | 0.61 | 0.66 | 0.6 | Mammalian | Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Colocalizes with EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain. {ECO:0000269|PubMed:21029237}. | Kinase | Alzheimer's disease
Bipolar affective disorder Brain injury Immunodeficiency Ischemia Noninsulin-dependent diabetes mellitus | Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation. Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). {ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20932480, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:8397507, ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}. | Glycogen synthase kinase-3 beta inhibitor: Lithium | 15.11 | ||
| dfaGSTP1 | Glutathione S-transferase P | 2 | 83 | 99.85 | 98.92 | ND | 0.54 | 0.70 | 0.6 | Mammalian | Enzyme | Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration. {ECO:0000269|PubMed:21668448}. | Glutathione S-transferase P : Carbocisteine, Glutathione Glutathione S-transferase P inhibitor: Clomipramine, Vitamin E Glutathione S-transferase P substrate: Busulfan, Carboplatin, Chlorambucil, Cisplatin, Etoposide, Oxaliplatin | 15.11 | ||||
| dfaHCAR2 | Hydroxycarboxylic acid receptor 2 | 7 | 466 | 95.90 | 97.62 | ND | 0.56 | 0.62 | 0.6 | Mammalian | Expression largely restricted to adipose tissue and spleen. Expressed on mature neutrophils but not on immature neutrophils or eosinophils. {ECO:0000269|PubMed:12522134, ECO:0000269|PubMed:17932499}. | Family A G protein-coupled receptor | Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5- methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide. {ECO:0000269|PubMed:17932499}. | Hydroxycarboxylic acid receptor 2 agonist: Niacin | 16.04 | |||
| dfaHCAR3 | Hydroxycarboxylic acid receptor 3 | 3 | 43 | 95.57 | 99.08 | ND | 0.37 | 0.66 | 0.6 | Mammalian | Expression largely restricted to adipose tissue and spleen. {ECO:0000269|PubMed:12522134}. | Family A G protein-coupled receptor | Receptor for 3-OH-octanoid acid mediates a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. Acts as a low affinity receptor for nicotinic acid. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. {ECO:0000269|PubMed:12522134, ECO:0000269|PubMed:19561068}. | Hydroxycarboxylic acid receptor 3 agonist: Niacin | 16.04 | |||
| dfaHCK | Tyrosine-protein kinase HCK | 5 | 326 | 98.36 | 99.12 | ND | 0.59 | 0.63 | 0.6 | Mammalian | Detected in monocytes and neutrophils (at protein level). Expressed predominantly in cells of the myeloid and B-lymphoid lineages. Highly expressed in granulocytes. Detected in tonsil. {ECO:0000269|PubMed:3453117, ECO:0000269|PubMed:8064233, ECO:0000269|PubMed:8995234}. | Kinase | Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity. Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation. | Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS. {ECO:0000269|PubMed:10092522, ECO:0000269|PubMed:10779760, ECO:0000269|PubMed:10973280, ECO:0000269|PubMed:11741929, ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:12411494, ECO:0000269|PubMed:15010462, ECO:0000269|PubMed:15952790, ECO:0000269|PubMed:15998323, ECO:0000269|PubMed:17310994, ECO:0000269|PubMed:17535448, ECO:0000269|PubMed:19114024, ECO:0000269|PubMed:19903482, ECO:0000269|PubMed:20452982, ECO:0000269|PubMed:21338576, ECO:0000269|PubMed:7535819, ECO:0000269|PubMed:8132624, ECO:0000269|PubMed:9406996, ECO:0000269|PubMed:9407116}. | Tyrosine-protein kinase HCK inhibitor: Bosutinib | 15.11 | ||
| dfaHDA10 | Histone deacetylase 10 | 4 | 136 | 99.47 | 99.10 | ND | 0.64 | 0.88 | 0.7 | Mammalian | Ubiquitous. High expression in liver, spleen, pancreas and kidney. | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. | Histone deacetylase 10 inhibitor: Panobinostat | 16.04 | |||
| dfaHDA11 | Histone deacetylase 11 | 4 | 109 | 97.88 | 96.73 | ND | 0.70 | 0.95 | 0.7 | Mammalian | Weakly expressed in most tissues. Strongly expressed in brain, heart, skeletal muscle, kidney and testis. | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. {ECO:0000269|PubMed:11948178}. | 16.04 | ||||
| dfaHDAC1 | Histone deacetylase 1 | 5 | 1668 | 94.95 | 93.84 | ND | 0.62 | 0.64 | 0.6 | Mammalian | Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain. | Eraser | Cancer, unspecific
Proliferative diseases Prostate cancer (hormone refractory) | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST- mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation. {ECO:0000269|PubMed:12837748, ECO:0000269|PubMed:16478997, ECO:0000269|PubMed:17000776, ECO:0000269|PubMed:17704056, ECO:0000269|PubMed:17996965, ECO:0000269|PubMed:19081374, ECO:0000269|PubMed:19343227}. | Histone deacetylase 1 inhibitor: Panobinostat, Vorinostat | 16.04 | ||
| dfaHDAC2 | Histone deacetylase 2 | 4 | 461 | 96.94 | 95.92 | ND | 0.59 | 0.67 | 0.7 | Mammalian | Widely expressed; lower levels in brain and lung. | Eraser | Colon cancer | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation. Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A. {ECO:0000269|PubMed:19343227, ECO:0000269|PubMed:21965678}. | Histone deacetylase 2 : Valproic Acid Histone deacetylase 2 activator: Aminophylline, Oxtriphylline, Theophylline Histone deacetylase 2 inhibitor: Panobinostat, Vorinostat Histone deacetylase 2 other: Lovastatin | 15.11 | ||
| dfaHDAC3 | Histone deacetylase 3 | 4 | 371 | 97.03 | 94.09 | ND | 0.68 | 0.76 | 0.7 | Mammalian | Widely expressed. | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys- 27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803). {ECO:0000269|PubMed:21444723, ECO:0000269|PubMed:23911289, ECO:0000269|PubMed:25190803}. | Histone deacetylase 3 inhibitor: Panobinostat, Vorinostat | 16.04 | |||
| dfaHDAC4 | Histone deacetylase 4 | 7 | 363 | 94.69 | 96.49 | ND | 0.75 | 0.89 | 0.6 | Mammalian | Ubiquitous. | Eraser | Brachydactyly-mental retardation syndrome (BDMR) [MIM:600430]: A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism. {ECO:0000269|PubMed:20691407, ECO:0000269|PubMed:23188045, ECO:0000269|PubMed:24715439}. Note=The gene represented in this entry is involved in disease pathogenesis. HDAC4 point mutations and chromosomal microdeletions encompassing this gene have been found in BDMR patients (PubMed:20691407, PubMed:24715439, PubMed:23188045). However, HDAC4 haploinsufficiency is not fully penetrant and multiple genes may contribute to manifestation of the full phenotypic spectrum (PubMed:24715439, PubMed:23188045). {ECO:0000269|PubMed:20691407, ECO:0000269|PubMed:23188045, ECO:0000269|PubMed:24715439}. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. {ECO:0000269|PubMed:10523670, ECO:0000269|PubMed:24413532}. | Histone deacetylase 4 inhibitor: Panobinostat | 15.11 | ||
| dfaHDAC5 | Histone deacetylase 5 | 6 | 162 | 90.99 | 93.51 | ND | 0.90 | 0.86 | 0.4 | Mammalian | Ubiquitous. | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. {ECO:0000269|PubMed:24413532}. | Histone deacetylase 5 inhibitor: Panobinostat | 16.04 | |||
| dfaHDAC6 | Histone deacetylase 6 | 4 | 878 | 94.72 | 89.26 | ND | 0.73 | 0.78 | 0.6 | Mammalian | Eraser | Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia (CDP-PBHM) [MIM:300863]: A disease characterized by chondrodysplasia, severe platyspondyly, hydrocephaly, and facial features with microphthalmia. Bone abnormalities include a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges. Affected females show a milder phenotype with small stature, sometimes associated with body asymmetry and mild mental retardation. {ECO:0000269|PubMed:20181727}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. {ECO:0000250, ECO:0000269|PubMed:12024216, ECO:0000269|PubMed:17846173, ECO:0000269|PubMed:24413532}. In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy. | Histone deacetylase 6 inhibitor: Panobinostat, Vorinostat | 16.04 | |||
| dfaHDAC7 | Histone deacetylase 7 | 5 | 168 | 97.49 | 96.41 | ND | 0.69 | 0.80 | 0.6 | Mammalian | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565). {ECO:0000250|UniProtKB:Q8C2B3, ECO:0000269|PubMed:12239305, ECO:0000269|PubMed:17360565}. | Histone deacetylase 7 inhibitor: Panobinostat | 15.11 | ||||
| dfaHDAC8 | Histone deacetylase 8 | 4 | 669 | 91.03 | 90.42 | ND | 0.80 | 0.77 | 0.4 | Mammalian | Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney. {ECO:0000269|PubMed:10926844, ECO:0000269|PubMed:14701748, ECO:0000269|PubMed:15772115, ECO:0000269|PubMed:16538051}. | Eraser | Cornelia de Lange syndrome 5 (CDLS5) [MIM:300882]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:22885700}. Note=The disease is caused by mutations affecting the gene represented in this entry. Wilson-Turner X-linked mental retardation syndrome (WTS) [MIM:309585]: A neurologic disorder characterized by severe intellectual disability, dysmorphic facial features, hypogonadism, short stature, and truncal obesity. Affected females have a milder phenotype than affected males. {ECO:0000269|PubMed:22889856}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. {ECO:0000269|PubMed:10748112, ECO:0000269|PubMed:10922473, ECO:0000269|PubMed:10926844, ECO:0000269|PubMed:14701748, ECO:0000269|PubMed:22885700}. | Histone deacetylase 8 : Vorinostat Histone deacetylase 8 inhibitor: Panobinostat | 15.11 | ||
| dfaHDAC9 | Histone deacetylase 9 | 5 | 124 | 94.50 | 96.24 | ND | 0.90 | 0.91 | 0.5 | Mammalian | Broadly expressed, with highest levels in brain, heart, muscle and testis. Isoform 3 is present in human bladder carcinoma cells (at protein level). {ECO:0000269|PubMed:10655483, ECO:0000269|PubMed:11535832, ECO:0000269|PubMed:12590135, ECO:0000269|PubMed:12706107}. | Eraser | Note=A chromosomal aberration involving HDAC9 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with TGFB2 resulting in lack of HDAC9 protein. {ECO:0000269|PubMed:12706107}. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Represses MEF2-dependent transcription. Isoform 3 lacks active site residues and therefore is catalytically inactive. Represses MEF2-dependent transcription by recruiting HDAC1 and/or HDAC3. Seems to inhibit skeletal myogenesis and to be involved in heart development. Protects neurons from apoptosis, both by inhibiting JUN phosphorylation by MAPK10 and by repressing JUN transcription via HDAC1 recruitment to JUN promoter. | Histone deacetylase 9 inhibitor: Panobinostat, Valproic Acid | 16.04 | ||
| dfaHIPK2 | Homeodomain-interacting protein kinase 2 | 5 | 286 | 93.41 | 88.81 | ND | 0.41 | 0.75 | 1.2 | Mammalian | Highly expressed in heart, muscle and kidney. Weakly expressed in a ubiquitous way. Down-regulated in several thyroid and breast tumors. {ECO:0000269|PubMed:11267674, ECO:0000269|PubMed:11798164}. | Kinase | Serine/threonine-protein kinase involved in transcription regulation, p53/TP53-mediated cellular apoptosis and regulation of the cell cycle. Acts as a corepressor of several transcription factors, including SMAD1 and POU4F1/Brn3a and probably NK homeodomain transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1 and ZBTB4. Inhibits cell growth and promotes apoptosis through the activation of p53/TP53 both at the transcription level and at the protein level (by phosphorylation and indirect acetylation). The phosphorylation of p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates transcriptional activation of TP73. In response to TGFB, cooperates with DAXX to activate JNK. Negative regulator through phosphorylation and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an intermediate kinase between MAP3K7/TAK1 and NLK to promote the proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and promotes its E3 SUMO- protein ligase activity. Activates CREB1 and ATF1 transcription factors by phosphorylation in response to genotoxic stress. In response to DNA damage, stabilizes PML by phosphorylation. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53- dependent transactivation. Promotes angiogenesis, and is involved in erythroid differentiation, especially during fetal liver erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300 transcription regulation activity. Triggers ZBTB4 protein degradation in response to DNA damage. Modulates HMGA1 DNA-binding affinity. In response to high glucose, triggers phosphorylation- mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis. {ECO:0000269|PubMed:11740489, ECO:0000269|PubMed:11925430, ECO:0000269|PubMed:12851404, ECO:0000269|PubMed:12874272, ECO:0000269|PubMed:14678985, ECO:0000269|PubMed:17018294, ECO:0000269|PubMed:17960875, ECO:0000269|PubMed:18695000, ECO:0000269|PubMed:18809579, ECO:0000269|PubMed:19015637, ECO:0000269|PubMed:19046997, ECO:0000269|PubMed:19448668, ECO:0000269|PubMed:20307497, ECO:0000269|PubMed:20573984, ECO:0000269|PubMed:20637728, ECO:0000269|PubMed:20980392, ECO:0000269|PubMed:21192925, ECO:0000269|PubMed:22825850}. | 16.04 | ||||
| dfaHIPK4 | Homeodomain-interacting protein kinase 4 | 2 | 272 | 90.86 | 94.17 | ND | 0.54 | 0.66 | 0.5 | Mammalian | Kinase | Protein kinase that phosphorylates human TP53 at Ser-9, and thus induces TP53 repression of BIRC5 promoter (By similarity). May act as a corepressor of transcription factors (Potential). {ECO:0000250, ECO:0000305}. | 16.04 | |||||
| dfaHMDH | 3-hydroxy-3-methylglutaryl-coenzyme A reductase | 2 | 738 | 98.75 | 98.60 | ND | 0.56 | 0.69 | 0.7 | Mammalian | Myalgia | Oxidoreductase | Atherosclerosis
Cardiovascular disease, unspecified Cervical cancer Coronary heart disease Dyslipidemia Head and neck squamous cell carcinomas Hypercholesterolemia Hypertriglyceridemia Myocardial infarction | Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins. | 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor: Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin | 15.11 | ||
| dfaHMOX1 | Heme oxygenase 1 | 5 | 106 | 98.36 | 99.26 | ND | 0.58 | 0.62 | 0.5 | Mammalian | Expressed at higher levels in renal cancer tissue than in normal tissue (at protein level). {ECO:0000269|PubMed:20855888}. | Enzyme | Heme oxygenase 1 deficiency (HMOX1D) [MIM:614034]: A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly. {ECO:0000269|PubMed:9884342}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed. Exhibits cytoprotective effects since excess of free heme sensitizes cells to undergo apoptosis. | Heme oxygenase 1 inducer: Vitamin E | 15.11 | ||
| dfaHMOX2 | Heme oxygenase 2 | 2 | 89 | 99.65 | 99.80 | ND | 0.42 | 0.53 | 0.3 | Mammalian | Enzyme | Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed. Heme oxygenase 2 could be implicated in the production of carbon monoxide in brain where it could act as a neurotransmitter. | 16.04 | |||||
| dfaHPGDS | Hematopoietic prostaglandin D synthase | 2 | 57 | 91.12 | 89.82 | ND | 0.72 | 0.78 | 0.6 | Mammalian | Expressed in a number of megakaryocytic cell lines but not in platelets. Highly expressed in adipose tissue, macrophages and placenta. Also expressed at lower levels in lung, heart, lymph nodes, appendix, bone marrow and fetal liver. {ECO:0000269|PubMed:10824118, ECO:0000269|PubMed:11672424, ECO:0000269|PubMed:9353279, ECO:0000269|PubMed:9425264}. | Enzyme | Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide. {ECO:0000269|PubMed:10824118, ECO:0000269|PubMed:11672424, ECO:0000269|PubMed:12627223, ECO:0000269|PubMed:15113825, ECO:0000269|PubMed:16547010, ECO:0000269|PubMed:19939518, ECO:0000269|PubMed:9353279, ECO:0000269|PubMed:9425264}. | Hematopoietic prostaglandin D synthase : Glutathione, Tranilast | 15.11 | |||
| dfaHPPD | 4-hydroxyphenylpyruvate dioxygenase | 2 | 51 | 97.83 | 96.58 | ND | 0.71 | 0.80 | 0.4 | Mammalian | Oxidoreductase | Tyrosinemia 3 (TYRSN3) [MIM:276710]: An inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, seizures and mild mental retardation. {ECO:0000269|PubMed:10942115, ECO:0000269|PubMed:11073718}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hawkinsinuria (HAWK) [MIM:140350]: An inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin, in the urine. {ECO:0000269|PubMed:11073718}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Key enzyme in the degradation of tyrosine. | 4-hydroxyphenylpyruvate dioxygenase inhibitor: Nitisinone | 16.04 | |||
| dfaHPRT | Hypoxanthine-guanine phosphoribosyltransferase | 2 | 87 | 99.58 | 99.51 | ND | 0.35 | 0.27 | 0.4 | Mammalian | Enzyme | Lesch-Nyhan syndrome (LNS) [MIM:300322]: Characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self- mutilation. {ECO:0000269|PubMed:15571223, ECO:0000269|PubMed:17027311, ECO:0000269|PubMed:2071157, ECO:0000269|PubMed:2246854, ECO:0000269|PubMed:2347587, ECO:0000269|PubMed:2358296, ECO:0000269|PubMed:24940672, ECO:0000269|PubMed:2910902, ECO:0000269|PubMed:3265398, ECO:0000269|PubMed:3384338, ECO:0000269|PubMed:6853716, ECO:0000269|PubMed:7627191, ECO:0000269|PubMed:9452051}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gout HPRT-related (GOUT-HPRT) [MIM:300323]: Characterized by partial enzyme activity and hyperuricemia. {ECO:0000269|PubMed:15571223, ECO:0000269|PubMed:17027311, ECO:0000269|PubMed:20544509, ECO:0000269|PubMed:24940672, ECO:0000269|PubMed:2909537, ECO:0000269|PubMed:3198771, ECO:0000269|PubMed:3358423, ECO:0000269|PubMed:6572373, ECO:0000269|PubMed:6706936, ECO:0000269|PubMed:6853490, ECO:0000269|PubMed:7987318}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5- phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway. | Hypoxanthine-guanine phosphoribosyltransferase inhibitor: Azathioprine, Mercaptopurine Hypoxanthine-guanine phosphoribosyltransferase substrate: Tioguanine | 15.11 | |||
| dfaHPSE | Heparanase | 1 | 133 | 99.82 | 99.90 | ND | 0.42 | 0.52 | 0.3 | Mammalian | Highly expressed in placenta and spleen and weakly expressed in lymph node, thymus, peripheral blood leukocytes, bone marrow, endothelial cells, fetal liver and tumor tissues. Also expressed in hair follicles, specifically in both Henle's and Huxley's layers of inner the root sheath (IRS) at anagen phase. {ECO:0000269|PubMed:10395326, ECO:0000269|PubMed:10405343, ECO:0000269|PubMed:10764835, ECO:0000269|PubMed:18557927, ECO:0000269|PubMed:20309870}. | Enzyme | Hepatocellular Cancer Following Curative Resection
Lung Cancer Prostate cancer | Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up- regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis. {ECO:0000269|PubMed:12213822, ECO:0000269|PubMed:12773484, ECO:0000269|PubMed:15044433, ECO:0000269|PubMed:16452201, ECO:0000269|PubMed:18557927, ECO:0000269|PubMed:18798279, ECO:0000269|PubMed:19244131, ECO:0000269|PubMed:20097882, ECO:0000269|PubMed:20181948, ECO:0000269|PubMed:20309870, ECO:0000269|PubMed:20561914, ECO:0000269|PubMed:21131364}. | Heparanase substrate: Dalteparin, Heparin | 16.04 | ||
| dfaHRH1 | Histamine H1 receptor | 4 | 1486 | 91.33 | 88.13 | ND | 0.70 | 0.62 | 0.6 | Nature11159 | Mammalian | Agranulocytosis Akathisia Anticholinergic syndrome Ataxia Bladder disorder Bone marrow disorder Central nervous system stimulation Chest discomfort Conduction disorder Constipation Convulsion Cycloplegia Dermatitis allergic Diabetic eye disease Dry mouth Dystonia Dysuria Euphoric mood Extrapyramidal disorder Galactorrhoea Haemolytic anaemia Hypercholesterolaemia Hyperthermia Hyporeflexia Increased appetite Increased viscosity of bronchial secretion Insomnia Muscular weakness Myopathy Nervousness Parkinsonism Photosensitivity reaction Sedation Skin sensitisation Somnolence Tachycardia Tardive dyskinesia Tinnitus Tremor Urinary retention Urinary tract disorder Vision blurred Weight increased | Family A G protein-coupled receptor | Acute lymphoblastic leukaemia (therapy-refractory)
Allergic diseases Allergic rhinitis, unspecified Anxiety disorder, unspecified Chronic rhinitis Chronic urticaria Epidermal hyperplasia Epilepsy Hypotension Intimal hyperplasia Ischemia Motion sickness Nausea and vomiting Seasonal allergic rhinitis Systemic arterial vasodilation | In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system. | Histamine H1 receptor agonist: Betahistine, Histamine Phosphate, Paliperidone, Tolazoline Histamine H1 receptor antagonist: Aceprometazine, Alcaftadine, Alimemazine, Amitriptyline, Amoxapine, Antazoline, Aripiprazole, Asenapine, Astemizole, Azatadine, Azelastine, Benzatropine, Bepotastine, Bromodiphenhydramine, Brompheniramine, Buclizine, Butriptyline, Carbinoxamine, Cariprazine, Cetirizine, Chlorcyclizine, Chloropyramine, Chlorphenamine, Chlorpromazine, Chlorprothixene, Cinnarizine, Clemastine, Clofedanol, Clozapine, Cyclizine, Cyproheptadine, Desipramine, Desloratadine, Dexbrompheniramine, Dimenhydrinate, Dimetindene, Diphenhydramine, Diphenylpyraline, Doxepin, Doxylamine, Emedastine, Epinastine, Escitalopram, Fexofenadine, Flunarizine, Hydroxyzine, Iloperidone, Imipramine, Isothipendyl, Ketotifen, Levocabastine, Levocetirizine, Loratadine, Maprotiline, Meclizine, Mepyramine, Mequitazine, Methdilazine, Methotrimeprazine, Mianserin, Mirtazapine, Nortriptyline, Olanzapine, Olopatadine, Orphenadrine, Phenindamine, Pheniramine, Promazine, Promethazine, Propiomazine, Quetiapine, Risperidone, Trazodone, Trimipramine, Tripelennamine, Triprolidine, Ziprasidone, Zuclopenthixol Histamine H1 receptor binder: Citalopram, Loxapine Histamine H1 receptor inhibitor: | 15.11 | |
| dfaHRH2 | Histamine H2 receptor | 5 | 479 | 84.11 | 84.19 | ND | 0.53 | 0.66 | 0.6 | Nature11159 | Mammalian | Anticholinergic syndrome Cycloplegia | Family A G protein-coupled receptor | Epidermal hyperplasia
Lasting tachycardia Peptic ulcer Systemic arterial vasodilation Zollinger-Ellison syndrome | The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and differentiation. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and, through a separate G protein-dependent mechanism, the phosphoinositide/protein kinase (PKC) signaling pathway (By similarity). {ECO:0000250}. | Histamine H2 receptor agonist: Betazole, Histamine Phosphate, Tolazoline Histamine H2 receptor antagonist: Asenapine, Cimetidine, Doxepin, Epinastine, Famotidine, Methantheline, Nizatidine, Olanzapine, Ranitidine, Roxatidine acetate Histamine H2 receptor binder: Loxapine Histamine H2 receptor blocker: Amitriptyline | 16.04 | |
| dfaHRH3 | Histamine H3 receptor | 5 | 3120 | 93.33 | 88.79 | ND | 0.53 | 0.59 | 0.7 | Nature11159 | Mammalian | Expressed predominantly in the CNS, with the greatest expression in the thalamus and caudate nucleus. The various isoforms are mainly coexpressed in brain, but their relative expression level varies in a region-specific manner. Isoform 3 and isoform 7 are highly expressed in the thalamus, caudate nucleus and cerebellum while isoform 5 and isoform 6 show a poor expression. Isoform 5 and isoform 6 show a high expression in the amygdala, substantia nigra, cerebral cortex and hypothalamus. Isoform 7 is not found in hypothalamus or substantia nigra. | Family A G protein-coupled receptor | Acid-related diseases
Allergic rhinitis, unspecified Alzheimer's disease Attention-deficit hyperactivity disorder Central nervous system diseases Inflammatory diseases Schizophrenia | The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization. | Histamine H3 receptor agonist: Histamine Phosphate Histamine H3 receptor antagonist: Betahistine, Mirtazapine | 16.04 | |
| dfaHRH4 | Histamine H4 receptor | 5 | 834 | 96.16 | 96.79 | ND | 0.60 | 0.62 | 0.6 | Mammalian | Expressed primarily in the bone marrow and eosinophils. Shows preferential distribution in cells of immunological relevance such as T-cells, dendritic cells, monocytes, mast cells, neutrophils. Also expressed in a wide variety of peripheral tissues, including the heart, kidney, liver, lung, pancreas, skeletal muscle, prostate, small intestine, spleen, testis, colon, fetal liver and lymph node. {ECO:0000269|PubMed:12503632}. | Anticholinergic syndrome | Family A G protein-coupled receptor | Allergic diseases
Allergy, unspecified Asthma | The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist). {ECO:0000269|PubMed:12503632}. | Histamine H4 receptor agonist: Histamine Phosphate Histamine H4 receptor antagonist: Clozapine, Olanzapine Histamine H4 receptor binder: Amitriptyline, Amoxapine, Chlorpromazine, Doxepin, Loxapine, Mianserin | 16.04 | |
| dfaHS90B | Heat shock protein HSP 90-beta | 4 | 379 | 96.46 | 92.06 | ND | 0.79 | 0.81 | 0.5 | Mammalian | Other cytosolic protein | Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. {ECO:0000269|PubMed:16478993, ECO:0000269|PubMed:19696785}. | 15.11 | |||||
| dfaHXK4 | Glucokinase | 5 | 564 | 98.36 | 98.88 | ND | 0.43 | 0.56 | 0.5 | Mammalian | Isoform 1 is expressed in pancreas. Isoform 2 and isoform 3 is expressed in liver. | Enzyme | Maturity-onset diabetes of the young 2 (MODY2) [MIM:125851]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:10588527, ECO:0000269|PubMed:10694920, ECO:0000269|PubMed:11106831, ECO:0000269|PubMed:11372010, ECO:0000269|PubMed:1303265, ECO:0000269|PubMed:1464666, ECO:0000269|PubMed:1502186, ECO:0000269|PubMed:8168652, ECO:0000269|PubMed:8325892, ECO:0000269|PubMed:8495817, ECO:0000269|PubMed:9049484, ECO:0000269|PubMed:9662401}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperinsulinemic hypoglycemia 3 (HHF3) [MIM:602485]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269|PubMed:9435328}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage. | 15.11 | |||
| dfaHYEP | Epoxide hydrolase 1 | 3 | 82 | 98.62 | 96.93 | ND | 0.49 | 0.83 | 0.5 | Mammalian | Found in liver. {ECO:0000269|PubMed:12878321}. | Protease | Note=In some populations, the high activity haplotype tyr113/his139 is overrepresented among women suffering from pregnancy-induced hypertension (pre-eclampsia) when compared with healthy controls. {ECO:0000269|PubMed:12173035}. Familial hypercholanemia (FHCA) [MIM:607748]: A disorder characterized by elevated serum bile acid concentrations, itching, and fat malabsorption. {ECO:0000269|PubMed:12878321}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water. | 16.04 | |||
| dfaHYES | Bifunctional epoxide hydrolase 2 | 3 | 1186 | 97.89 | 98.31 | ND | 0.54 | 0.67 | 0.7 | Mammalian | Protease | Cardiovascular disease, unspecified
Hypertension Renal diseases | Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo- 9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro- 9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy- octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate. {ECO:0000269|PubMed:12574508, ECO:0000269|PubMed:12574510}. | 15.11 | ||||
| dfaI23O1 | Indoleamine 2,3-dioxygenase 1 | 4 | 263 | 90.82 | 85.09 | ND | 0.75 | 0.70 | 0.4 | Mammalian | Expressed in mature dendritic cells located in lymphoid organs (including lymph nodes, spleen, tonsils, Peyers's patches, the gut lamina propria, and the thymic medulla), in some epithelial cells of the female genital tract, as well as in endothelial cells of term placenta and in lung parenchyma (PubMed:25691885). Weakly or not expressed in most normal tissues, but mostly inducible in most tissues (PubMed:25691885). Expressed in more than 50% of tumors, either by tumoral, stromal, or endothelial cells (expression in tumor is associated with a worse clinical outcome) (PubMed:18418598). Not overexpressed in tumor- draining lymph nodes (PubMed:26155395, PubMed:25691885). {ECO:0000269|PubMed:18418598, ECO:0000269|PubMed:25691885, ECO:0000269|PubMed:26155395}. | Enzyme | Depression | Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway (PubMed:17671174). Involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses (PubMed:25691885). Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells (PubMed:25691885). Acts as a suppressor of anti-tumor immunity (PubMed:23103127, PubMed:25157255, PubMed:14502282, PubMed:25691885). Limits the growth of intracellular pathogens by depriving tryptophan (PubMed:25691885). Protects the fetus from maternal immune rejection (PubMed:25691885). {ECO:0000269|PubMed:14502282, ECO:0000269|PubMed:17671174, ECO:0000303|PubMed:23103127, ECO:0000303|PubMed:25157255, ECO:0000303|PubMed:25691885}. | Indoleamine 2,3-dioxygenase 1 substrate: L-Tryptophan, Melatonin | 16.04 | ||
| dfaICMT | Transmembrane protein 106A | 2 | 187 | 96.35 | 97.15 | ND | 0.65 | 0.75 | 0.5 | Mammalian | 16.04 | |||||||
| dfaIF4E | Eukaryotic translation initiation factor 4E | 1 | 123 | 90.76 | 91.19 | ND | 0.38 | 0.48 | 0.5 | Mammalian | Other nuclear protein | Autism 19 (AUTS19) [MIM:615091]: A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate mental retardation. {ECO:0000269|PubMed:19556253}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A heterozygous single-nucleotide insertion has been found in families affected by autism. The variant results in increased promoter activity and is involved in disease pathogenesis through EIF4E deregulation (PubMed:19556253). {ECO:0000269|PubMed:19556253}. Note=A chromosomal aberration involving EIF4E has been found in a patient with classic autism. Translocation t(45)(q23q31.3). The breakpoint on chromosome 4 is located 56 kb downstream of EIF4E (PubMed:19556253). {ECO:0000269|PubMed:19556253}. | Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap. {ECO:0000269|PubMed:16271312, ECO:0000269|PubMed:22578813}. | 15.11 | ||||
| dfaIF4H | Eukaryotic translation initiation factor 4H | 8 | 86 | 99.87 | 99.44 | ND | 0.81 | 0.86 | 0.2 | Mammalian | The short isoform is the predominant isoform and is expressed alone in liver and skeletal muscle. Both isoforms are expressed in fibroblast, spleen, testis and bone marrow. Levels are high in lung and pancreas and low in heart, frontal cortex and kidney. {ECO:0000269|PubMed:11003705, ECO:0000269|PubMed:8812460}. | Note=EIF4H is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of EIF4H may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease. {ECO:0000269|PubMed:8812460}. | Stimulates the RNA helicase activity of EIF4A in the translation initiation complex. Binds weakly mRNA. {ECO:0000269|PubMed:10585411, ECO:0000269|PubMed:11418588}. | 16.04 | ||||
| dfaIGF1R | Insulin-like growth factor 1 receptor | 4 | 1176 | 95.21 | 91.51 | ND | 0.80 | 0.80 | 0.6 | Mammalian | Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney. {ECO:0000269|PubMed:12019176, ECO:0000269|PubMed:8247543, ECO:0000269|PubMed:9202395, ECO:0000269|PubMed:9355755}. | Kinase | Insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]: A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels. {ECO:0000269|PubMed:14657428, ECO:0000269|PubMed:15928254}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K- driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R. When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. | Insulin-like growth factor 1 receptor : Insulin Lispro, Insulin Regular, Insulin, porcine Insulin-like growth factor 1 receptor agonist: Insulin Glargine, Mecasermin | 15.11 | ||
| dfaIKBA | NF-kappa-B inhibitor alpha | 1 | 41 | 99.85 | 99.79 | ND | 0.75 | 0.43 | 0.3 | Mammalian | Other cytosolic protein | Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency autosomal dominant (ADEDAID) [MIM:612132]: A form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. This form of ectodermal dysplasia is associated with decreased production of pro-inflammatory cytokines and certain interferons, rendering patients susceptible to infection. {ECO:0000269|PubMed:14523047, ECO:0000269|PubMed:18412279}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL dimers in the cytoplasm through masking of their nuclear localization signals. On cellular stimulation by immune and proinflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription. {ECO:0000269|PubMed:7479976}. | 16.04 | ||||
| dfaIKKA | Inhibitor of nuclear factor kappa-B kinase subunit alpha | 3 | 390 | 91.63 | 95.33 | ND | 0.61 | 0.68 | 0.6 | Mammalian | Widely expressed. | Kinase | Cocoon syndrome (COCOS) [MIM:613630]: A lethal syndrome characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin. {ECO:0000269|PubMed:20961246}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine kinase that plays an essential role in the NF- kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa- B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260). {ECO:0000269|PubMed:12789342, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:17434128, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20501937, ECO:0000269|PubMed:21765415}. | Inhibitor of nuclear factor kappa-B kinase subunit alpha inhibitor: Acetylcysteine, Aminosalicylic Acid, Mesalazine, Sulfasalazine | 16.04 | ||
| dfaIKKB | Inhibitor of nuclear factor kappa-B kinase subunit beta | 7 | 897 | 95.30 | 95.95 | ND | 0.67 | 0.77 | 0.6 | Mammalian | Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood. | Kinase | Immunodeficiency 15 (IMD15) [MIM:615592]: An autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T- cells, and impaired differentiation and activation of immune cells. {ECO:0000269|PubMed:24369075}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine kinase that plays an essential role in the NF- kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF- dependent inactivation of this pro-apoptotic transcription factor. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation. {ECO:0000269|PubMed:11297557, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:17213322, ECO:0000269|PubMed:19716809, ECO:0000269|PubMed:20410276, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20797629, ECO:0000269|PubMed:21138416}. | Inhibitor of nuclear factor kappa-B kinase subunit beta : Acetylsalicylic acid Inhibitor of nuclear factor kappa-B kinase subunit beta inducer: Arsenic trioxide Inhibitor of nuclear factor kappa-B kinase subunit beta inhibitor: Acetylcysteine, Auranofin, Mesalazine, Sulfasalazine | 15.11 | ||
| dfaIKKE | Inhibitor of nuclear factor kappa-B kinase subunit epsilon | 1 | 240 | 88.27 | 93.97 | ND | 0.61 | 0.58 | 0.6 | Mammalian | Highly expressed in spleen followed by thymus, peripheral blood leukocytes, pancreas, placenta. Weakly expressed in lung, kidney, prostate, ovary and colon. | Kinase | Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG- I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1. {ECO:0000269|PubMed:17568778, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:19153231, ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:22532683, ECO:0000269|PubMed:23453969, ECO:0000269|PubMed:23478265}. | 16.04 | ||||
| dfaIMDH1 | Inosine-5'-monophosphate dehydrogenase 1 {ECO:0000255|HAMAP-Rule:MF_03156} | 3 | 110 | 99.70 | 99.53 | ND | 0.64 | 0.43 | 0.7 | Mammalian | IMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor. | Oxidoreductase | Retinitis pigmentosa 10 (RP10) [MIM:180105]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:11875049, ECO:0000269|PubMed:11875050, ECO:0000269|PubMed:16384941}. Note=The disease is caused by mutations affecting the gene represented in this entry. Leber congenital amaurosis 11 (LCA11) [MIM:613837]: A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. {ECO:0000269|PubMed:16384941}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate- limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors. | Inosine-5'-monophosphate dehydrogenase 1 {ECO:0000255|HAMAP-Rule:MF_03156} Inhibitor: Mercaptopurine Inosine-5'-monophosphate dehydrogenase 1 {ECO:0000255|HAMAP-Rule:MF_03156} inhibitor: Mycophenolate mofetil, Mycophenolic acid, Ribavirin | 16.04 | ||
| dfaIMDH2 | Inosine-5'-monophosphate dehydrogenase 2 {ECO:0000255|HAMAP-Rule:MF_03156} | 3 | 617 | 97.37 | 88.90 | ND | 0.64 | 0.49 | 0.5 | Mammalian | IMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor. | Oxidoreductase | Leukemia, unspecified | Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate- limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors. | Inosine-5'-monophosphate dehydrogenase 2 {ECO:0000255|HAMAP-Rule:MF_03156} inhibitor: Mycophenolate mofetil, Mycophenolic acid | 15.11 | ||
| dfaINSR | Insulin receptor | 4 | 884 | 94.93 | 93.65 | ND | 0.68 | 0.72 | 0.6 | Mammalian | Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas. {ECO:0000269|PubMed:10207053, ECO:0000269|PubMed:2369896, ECO:0000269|PubMed:9202395, ECO:0000269|PubMed:9355755}. | Kinase | Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10443650, ECO:0000269|PubMed:12023989, ECO:0000269|PubMed:17201797, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:8314008}. Note=The disease is caused by mutations affecting the gene represented in this entry. Leprechaunism (LEPRCH) [MIM:246200]: Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive. {ECO:0000269|PubMed:12538626, ECO:0000269|PubMed:12970295, ECO:0000269|PubMed:1607067, ECO:0000269|PubMed:1730625, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2479553, ECO:0000269|PubMed:2834824, ECO:0000269|PubMed:7538143, ECO:0000269|PubMed:7815442, ECO:0000269|PubMed:8188715, ECO:0000269|PubMed:8326490, ECO:0000269|PubMed:8419945, ECO:0000269|PubMed:8636294, ECO:0000269|PubMed:9249867, ECO:0000269|PubMed:9703342}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:1470163, ECO:0000269|PubMed:1607076, ECO:0000269|PubMed:7657032}. Note=The gene represented in this entry may be involved in disease pathogenesis. Familial hyperinsulinemic hypoglycemia 5 (HHF5) [MIM:609968]: Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. {ECO:0000269|PubMed:15161766}. Note=The disease is caused by mutations affecting the gene represented in this entry. Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]: Characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. {ECO:0000269|PubMed:10733238, ECO:0000269|PubMed:11260230, ECO:0000269|PubMed:12107746, ECO:0000269|PubMed:12970295, ECO:0000269|PubMed:1563582, ECO:0000269|PubMed:1963473, ECO:0000269|PubMed:2002058, ECO:0000269|PubMed:2168397, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2544998, ECO:0000269|PubMed:3283938, ECO:0000269|PubMed:8243830, ECO:0000269|PubMed:8288049, ECO:0000269|PubMed:8314008, ECO:0000269|PubMed:8388389, ECO:0000269|PubMed:9175790}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src- homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti- apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K- AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. {ECO:0000269|PubMed:12138094, ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16831875, ECO:0000269|PubMed:8257688, ECO:0000269|PubMed:8276809, ECO:0000269|PubMed:8452530, ECO:0000269|PubMed:9428692}. | Insulin receptor : Mecasermin Insulin receptor agonist: Insulin Aspart, Insulin Detemir, Insulin Glargine, Insulin Glulisine, Insulin Lispro, Insulin Regular, Insulin, isophane Insulin receptor binder: Insulin, porcine | 15.11 | ||
| dfaINSRR | Insulin receptor-related protein | 4 | 66 | 99.77 | 92.81 | ND | 0.36 | 0.94 | 0.4 | Mammalian | Kinase | Receptor with tyrosine-protein kinase activity. Functions as a pH sensing receptor which is activated by increased extracellular pH. Activates an intracellular signaling pathway that involves IRS1 and AKT1/PKB. {ECO:0000269|PubMed:21641549}. | 16.04 | |||||
| dfaIRAK1 | Interleukin-1 receptor-associated kinase 1 | 4 | 243 | 80.40 | 87.99 | ND | 0.51 | 0.73 | 0.4 | Mammalian | Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2. {ECO:0000269|PubMed:11397809}. | Kinase | Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor- signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3. {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12860405, ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:15465816, ECO:0000269|PubMed:15767370, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509}. | 16.04 | ||||
| dfaIRAK3 | Interleukin-1 receptor-associated kinase 3 | 3 | 65 | 86.29 | 92.55 | ND | 0.32 | 0.89 | 0.5 | Mammalian | Expressed predominantly in peripheral blood lymphocytes. {ECO:0000269|PubMed:10383454}. | Kinase | Asthma-related traits 5 (ASRT5) [MIM:611064]: Asthma- related traits include clinical symptoms of asthma, such as coughing, wheezing, dyspnea, bronchial hyperresponsiveness as assessed by methacholine challenge test, serum IgE levels, atopy and atopic dermatitis. {ECO:0000269|PubMed:17503328}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Inhibits dissociation of IRAK1 and IRAK4 from the Toll- like receptor signaling complex by either inhibiting the phosphorylation of IRAK1 and IRAK4 or stabilizing the receptor complex. {ECO:0000250|UniProtKB:Q8K4B2, ECO:0000269|PubMed:10383454}. | 16.04 | |||
| dfaIRAK4 | Interleukin-1 receptor-associated kinase 4 | 5 | 375 | 92.87 | 91.94 | ND | 0.60 | 0.71 | 0.5 | Mammalian | Kinase | Recurrent isolated invasive pneumococcal disease 1 (IPD1) [MIM:610799]: Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. {ECO:0000269|PubMed:16950813}. Note=The disease is caused by mutations affecting the gene represented in this entry. IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. {ECO:0000269|PubMed:12637671, ECO:0000269|PubMed:12925671, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:19663824, ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino- mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA- IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. {ECO:0000269|PubMed:11960013, ECO:0000269|PubMed:12538665, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:17217339, ECO:0000269|PubMed:17337443, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509, ECO:0000269|PubMed:24316379}. | 15.11 | ||||
| dfaITA2B | Integrin alpha-IIb | 2 | 41 | 99.97 | 97.23 | ND | 0.75 | 0.50 | 0.3 | Mammalian | Isoform 1 and isoform 2 were identified in platelets and megakaryocytes, but not in reticulocytes or in Jurkat and U-937 white blood cell line. Isoform 3 is expressed by leukemia, prostate adenocarcinoma and melanoma cells but not by platelets or normal prostate or breast epithelial cells. | Membrane receptor | Glanzmann thrombasthenia (GT) [MIM:273800]: A common inherited disease of platelet aggregation. It is characterized by mucocutaneous bleeding of mild-to-moderate severity. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb-IIIa complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the GPIIb-IIIa complex at reduced levels, have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. {ECO:0000269|PubMed:10607701, ECO:0000269|PubMed:11798398, ECO:0000269|PubMed:12083483, ECO:0000269|PubMed:12181054, ECO:0000269|PubMed:12424194, ECO:0000269|PubMed:12506038, ECO:0000269|PubMed:15099289, ECO:0000269|PubMed:15219201, ECO:0000269|PubMed:17018384, ECO:0000269|PubMed:20020534, ECO:0000269|PubMed:7508443, ECO:0000269|PubMed:7706461, ECO:0000269|PubMed:8282784, ECO:0000269|PubMed:8704171, ECO:0000269|PubMed:9215749, ECO:0000269|PubMed:9473221, ECO:0000269|PubMed:9722314, ECO:0000269|PubMed:9734640, ECO:0000269|PubMed:9763559, ECO:0000269|PubMed:9920835}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bleeding disorder, platelet-type 16 (BDPLT16) [MIM:187800]: An autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities. {ECO:0000269|PubMed:21454453, ECO:0000269|PubMed:9834222}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha- IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface. | Integrin alpha-IIb antagonist: Abciximab, Tirofiban | 15.11 | ||
| dfaITA4 | Integrin alpha-4 | 2 | 147 | 96.64 | 98.34 | ND | 0.57 | 0.83 | 0.7 | Mammalian | Membrane receptor | Not Available | Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are also receptors for VCAM1. Integrin alpha- 4/beta-1 recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha- 4/beta-7 is also a receptor for MADCAM1. It recognizes the sequence L-D-T in MADCAM1. On activated endothelial cells integrin VLA-4 triggers homotypic aggregation for most VLA-4-positive leukocyte cell lines. It may also participate in cytolytic T-cell interactions with target cells. {ECO:0000269|PubMed:19064666}. | Integrin alpha-4 antibody: Natalizumab, Vedolizumab Integrin alpha-4 inhibitor: Tinzaparin | 16.04 | |||
| dfaITAL | Integrin alpha-L | 4 | 139 | 99.78 | 98.72 | ND | 0.58 | 0.73 | 0.6 | Mammalian | Leukocytes. | Adhesion | Integrin alpha-L/beta-2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. It is involved in a variety of immune phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell mediated killing, and antibody dependent killing by granulocytes and monocytes. | Integrin alpha-L : Anti-thymocyte Globulin (Rabbit) Integrin alpha-L antibody: Efalizumab Integrin alpha-L other/unknown: Lovastatin | 15.11 | |||
| dfaITAV | Integrin alpha-V | 3 | 44 | 99.60 | 99.80 | ND | 0.81 | 0.82 | 0.6 | Mammalian | Membrane receptor | Brain tumors | The alpha-V (ITGAV) integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. (Microbial infection) Integrin ITGAV:ITGB5 acts as a receptor for adenovirus type C (PubMed:20615244). Integrin ITGAV:ITGB5 and ITGAV:ITGB3 act as receptors for coxsackievirus A9 and B1 (PubMed:9426447, PubMed:15194773, PubMed:7519807). Integrin ITGAV:ITGB3 acts as a receptor for herpes virus 8/HHV-8 (PubMed:18045938). Integrin ITGAV:ITGB6 acts as a receptor for herpes simplex 1/HHV-1 (PubMed:24367260). Integrin ITGAV:ITGB3 acts as a receptor for Human parechovirus 1 (PubMed:11160695). Integrin ITGAV:ITGB3 acts as a receptor for West nile virus (PubMed:23658209). In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions (PubMed:10397733). {ECO:0000269|PubMed:10397733, ECO:0000269|PubMed:11160695, ECO:0000269|PubMed:15194773, ECO:0000269|PubMed:18045938, ECO:0000269|PubMed:20615244, ECO:0000269|PubMed:23658209, ECO:0000269|PubMed:24367260, ECO:0000269|PubMed:7519807, ECO:0000269|PubMed:9426447}. | 16.04 | ||||
| dfaITK | Tyrosine-protein kinase ITK/TSK | 6 | 683 | 95.97 | 97.47 | ND | 0.64 | 0.68 | 0.6 | Mammalian | T-cell lines and natural killer cell lines. | Kinase | Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011]: A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma. {ECO:0000269|PubMed:19425169}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. {ECO:0000269|PubMed:12186560, ECO:0000269|PubMed:12682224, ECO:0000269|PubMed:21725281}. | Tyrosine-protein kinase ITK/TSK inhibitor: Pazopanib | 15.11 | ||
| dfaJAK1 | Tyrosine-protein kinase JAK1 | 5 | 482 | 96.15 | 94.85 | ND | 0.83 | 0.80 | 0.5 | Mammalian | Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue. {ECO:0000269|PubMed:7896447}. | Kinase | Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. {ECO:0000269|PubMed:11909529}. | Tyrosine-protein kinase JAK1 inhibitor: Ruxolitinib, Tofacitinib | 15.11 | |||
| dfaJAK2 | Tyrosine-protein kinase JAK2 | 6 | 1284 | 92.80 | 90.23 | ND | 0.64 | 0.71 | 0.7 | Mammalian | Ubiquitously expressed throughout most tissues. {ECO:0000269|PubMed:16424865}. | Kinase | Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Budd-Chiari syndrome (BDCHS) [MIM:600880]: A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. {ECO:0000269|PubMed:16707754}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Polycythemia vera (PV) [MIM:263300]: A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly. {ECO:0000269|PubMed:15781101, ECO:0000269|PubMed:15793561, ECO:0000269|PubMed:15858187, ECO:0000269|PubMed:16603627}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thrombocythemia 3 (THCYT3) [MIM:614521]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. {ECO:0000269|PubMed:16325696, ECO:0000269|PubMed:22397670}. Note=The disease may be caused by mutations affecting the gene represented in this entry. Myelofibrosis (MYELOF) [MIM:254450]: A disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry. Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:16247455}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin. {ECO:0000269|PubMed:12023369, ECO:0000269|PubMed:19783980, ECO:0000269|PubMed:20098430, ECO:0000269|PubMed:21423214}. | Tyrosine-protein kinase JAK2 inhibitor: Ruxolitinib, Tofacitinib | 15.11 | ||
| dfaJAK3 | Tyrosine-protein kinase JAK3 | 6 | 877 | 94.58 | 93.63 | ND | 0.57 | 0.69 | 0.6 | Mammalian | In NK cells and an NK-like cell line but not in resting T-cells or in other tissues. The S-form is more commonly seen in hematopoietic lines, whereas the B-form is detected in cells both of hematopoietic and epithelial origins. {ECO:0000269|PubMed:7535338}. | Kinase | Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:600802]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:10982185, ECO:0000269|PubMed:14615376, ECO:0000269|PubMed:7659163, ECO:0000269|PubMed:9354668, ECO:0000269|PubMed:9753072}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion. {ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:20440074, ECO:0000269|PubMed:7662955, ECO:0000269|PubMed:8022485}. | Tyrosine-protein kinase JAK3 inhibitor: Tofacitinib | 15.11 | ||
| dfaJUN | Transcription factor AP-1 | 6 | 83 | 89.19 | 81.99 | ND | 0.73 | 0.80 | 0.4 | Mammalian | Transcription factor | Allergic airway inflammation
Breast cancer Cancer (multidrug resistant) Cancer, unspecific Melanoma Rheumatoid arthritis Vascular disease | Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'. Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. Involved in activated KRAS-mediated transcriptional activation of USP28 in colorectal cancer (CRC) cells (PubMed:24623306). Binds to the USP28 promoter in colorectal cancer (CRC) cells (PubMed:24623306). {ECO:0000269|PubMed:10995748, ECO:0000269|PubMed:17210646, ECO:0000269|PubMed:24623306}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine | 16.04 | |||
| dfaKAPCA | cAMP-dependent protein kinase catalytic subunit alpha | 5 | 497 | 89.71 | 89.70 | ND | 0.46 | 0.50 | 0.6 | Mammalian | Isoform 1 is ubiquitous. Isoform 2 is sperm- specific and is enriched in pachytene spermatocytes but is not detected in round spermatids. {ECO:0000269|PubMed:10906071, ECO:0000269|PubMed:21812984}. | Kinase | Primary pigmented nodular adrenocortical disease 4 (PPNAD4) [MIM:615830]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:24571724, ECO:0000269|PubMed:24700472, ECO:0000269|PubMed:24747643, ECO:0000269|PubMed:24855271}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose- mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B- alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha- difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. {ECO:0000269|PubMed:15642694, ECO:0000269|PubMed:15905176, ECO:0000269|PubMed:16387847, ECO:0000269|PubMed:17333334, ECO:0000269|PubMed:17565987, ECO:0000269|PubMed:17693412, ECO:0000269|PubMed:18836454, ECO:0000269|PubMed:19949837, ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:21423175, ECO:0000269|PubMed:21514275, ECO:0000269|PubMed:21812984}. | 15.11 | |||
| dfaKC1A | Casein kinase I isoform alpha | 5 | 407 | 89.71 | 89.49 | ND | 0.67 | 0.62 | 0.4 | Mammalian | Kinase | Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates CTNNB1 at 'Ser-45'. May phosphorylate PER1 and PER2. May play a role in segregating chromosomes during mitosis (PubMed:11955436, PubMed:1409656, PubMed:18305108). May play a role in keratin cytoskeleton disassembly and thereby, it may regulate epithelial cell migration (PubMed:23902688). {ECO:0000269|PubMed:11955436, ECO:0000269|PubMed:1409656, ECO:0000269|PubMed:18305108, ECO:0000269|PubMed:23902688}. | 16.04 | |||||
| dfaKC1AL | Casein kinase I isoform alpha-like | 3 | 63 | 99.94 | 85.59 | ND | 0.46 | 0.97 | 0.3 | Mammalian | Kinase | Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling (By similarity). {ECO:0000250}. | 16.04 | |||||
| dfaKC1D | Casein kinase I isoform delta | 6 | 463 | 91.32 | 90.70 | ND | 0.74 | 0.80 | 0.5 | Mammalian | Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. However, kinase activity is not uniform, with highest kinase activity in splenocytes. In blood, highly expressed in hemopoietic cells and mature granulocytes. Also found in monocytes and lymphocytes. {ECO:0000269|PubMed:15070676, ECO:0000269|PubMed:16027726}. | Kinase | Advanced sleep phase syndrome, familial, 2 (FASPS2) [MIM:615224]: A disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. {ECO:0000269|PubMed:15800623, ECO:0000269|PubMed:23636092}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In balance with PP1, determines the circadian period length through the regulation of the speed and rhythmicity of PER1 and PER2 phospohorylation. Controls PER1 and PER2 nuclear transport and degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate. {ECO:0000269|PubMed:10606744, ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16027726, ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:19043076, ECO:0000269|PubMed:19339517, ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20637175, ECO:0000269|PubMed:20696890, ECO:0000269|PubMed:20699359, ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092}. | 15.11 | |||
| dfaKC1E | Casein kinase I isoform epsilon | 6 | 104 | 91.77 | 86.87 | ND | 0.95 | 0.93 | 0.2 | Mammalian | Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. Expressed in monocytes and lymphocytes but not in granulocytes. | Kinase | Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates DVL1. Central component of the circadian clock. In balance with PP1, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phospohorylation. Controls PER1 and PER2 nuclear transport and degradation. Inhibits cytokine- induced granuloytic differentiation. {ECO:0000269|PubMed:12556519, ECO:0000269|PubMed:15070676, ECO:0000269|PubMed:15917222, ECO:0000269|PubMed:16790549}. | 15.11 | ||||
| dfaKC1G1 | Casein kinase I isoform gamma-1 | 6 | 231 | 84.53 | 84.43 | ND | 0.68 | 0.71 | 0.4 | Mammalian | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Regulates fast synaptic transmission mediated by glutamate (By similarity). Phosphorylates CLSPN. {ECO:0000250, ECO:0000269|PubMed:21680713}. | 15.11 | |||||
| dfaKC1G2 | Casein kinase I isoform gamma-2 | 6 | 270 | 88.36 | 90.66 | ND | 0.65 | 0.80 | 0.4 | Mammalian | Testis. | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates COL4A3BP/CERT, MTA1 and SMAD3. Involved in brain development and vesicular trafficking and neurotransmitter releasing from small synaptic vesicles. Regulates fast synaptic transmission mediated by glutamate. SMAD3 phosphorylation promotes its ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Hyperphosphorylation of the serine-repeat motif of COL4A3BP/CERT leads to its inactivation by dissociation from the Golgi complex, thus down-regulating ER-to-Golgi transport of ceramide and sphingomyelin synthesis. Triggers PER1 proteasomal degradation probably through phosphorylation. {ECO:0000269|PubMed:15077195, ECO:0000269|PubMed:15342122, ECO:0000269|PubMed:15917222, ECO:0000269|PubMed:18794808, ECO:0000269|PubMed:19005213}. | 15.11 | ||||
| dfaKC1G3 | Casein kinase I isoform gamma-3 | 6 | 193 | 86.39 | 91.55 | ND | 0.65 | 0.71 | 0.4 | Mammalian | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Regulates fast synaptic transmission mediated by glutamate (By similarity). {ECO:0000250}. | 15.11 | |||||
| dfaKCC1A | Calcium/calmodulin-dependent protein kinase type 1 | 5 | 124 | 85.67 | 86.19 | ND | 0.48 | 0.82 | 0.5 | Mammalian | Widely expressed. Expressed in cells of the zona glomerulosa of the adrenal cortex. {ECO:0000269|PubMed:12193581, ECO:0000269|PubMed:17056143}. | Kinase | Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca(2+) elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser- 694', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser-92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser- 498' in the regulation of muscle cell differentiation. Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-276' and 'Ser-295'. Involved in the regulation of basal and estrogen- stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation (By similarity). Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K(+) and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I. {ECO:0000250, ECO:0000269|PubMed:11114197, ECO:0000269|PubMed:12193581, ECO:0000269|PubMed:14507913, ECO:0000269|PubMed:14754892, ECO:0000269|PubMed:17056143, ECO:0000269|PubMed:17442826, ECO:0000269|PubMed:18184567, ECO:0000269|PubMed:20181577}. | 16.04 | ||||
| dfaKCC1D | Calcium/calmodulin-dependent protein kinase type 1D | 8 | 140 | 87.96 | 83.79 | ND | 0.37 | 0.91 | 0.5 | Mammalian | Widely expressed. Highly and mostly expressed in polymorphonuclear leukocytes (neutrophilic and eosinophilic granulocytes) while little or no expression is observed in monocytes and lymphocytes. {ECO:0000269|PubMed:11050006, ECO:0000269|PubMed:12935886, ECO:0000269|PubMed:15840691}. | Kinase | Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine- induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta. {ECO:0000269|PubMed:11050006, ECO:0000269|PubMed:15840691, ECO:0000269|PubMed:16324104, ECO:0000269|PubMed:17056143}. | 15.11 | ||||
| dfaKCC1G | Calcium/calmodulin-dependent protein kinase type 1G | 3 | 65 | 95.23 | 98.54 | ND | 0.46 | 0.75 | 0.8 | Mammalian | Mainly expressed in brain with small amounts in skeletal muscles, kidney, spleen and liver. Strongly expressed in forebrain neocortex, striatum and limbic system. {ECO:0000269|PubMed:12637513}. | Kinase | Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade. In vitro phosphorylates transcription factor CREB1 (By similarity). {ECO:0000250}. | 15.11 | ||||
| dfaKCC2A | Calcium/calmodulin-dependent protein kinase type II subunit alpha | 5 | 141 | 81.38 | 83.14 | ND | 0.74 | 0.88 | 0.3 | Mammalian | Kinase | CaM-kinase II (CAMK2) is a prominent kinase in the central nervous system that may function in long-term potentiation and neurotransmitter release. Member of the NMDAR signaling complex in excitatory synapses it may regulate NMDAR-dependent potentiation of the AMPAR and synaptic plasticity (By similarity). {ECO:0000250}. | 16.04 | |||||
| dfaKCC2B | Calcium/calmodulin-dependent protein kinase type II subunit beta | 2 | 222 | 84.24 | 89.72 | ND | 0.46 | 0.56 | 0.4 | Mammalian | Widely expressed. Expressed in adult and fetal brain. Expression is slightly lower in fetal brain. Expressed in skeletal muscle. {ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic reticulum Ca(2+) transport in skeletal muscle. In neurons, plays an essential structural role in the reorganization of the actin cytoskeleton during plasticity by binding and bundling actin filaments in a kinase-independent manner. This structural function is required for correct targeting of CaMK2A, which acts downstream of NMDAR to promote dendritic spine and synapse formation and maintain synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. In developing hippocampal neurons, promotes arborization of the dendritic tree and in mature neurons, promotes dendritic remodeling. Participates in the modulation of skeletal muscle function in response to exercise. In slow-twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of triadin, a ryanodine receptor-coupling factor, and phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2. {ECO:0000269|PubMed:16690701}. | 16.04 | ||||
| dfaKCC2D | Calcium/calmodulin-dependent protein kinase type II subunit delta | 2 | 338 | 89.12 | 94.12 | ND | 0.36 | 0.38 | 0.7 | Mammalian | Expressed in cardiac muscle and skeletal muscle. Isoform Delta 3, isoform Delta 2, isoform Delta 8 and isoform Delta 9 are expressed in cardiac muscle. Isoform Delta 11 is expressed in skeletal muscle. {ECO:0000269|PubMed:10189359, ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser- 2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program. Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis. May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor- coupling factor. {ECO:0000269|PubMed:16690701, ECO:0000269|PubMed:17179159}. | 15.11 | ||||
| dfaKCC2G | Calcium/calmodulin-dependent protein kinase type II subunit gamma | 1 | 233 | 88.28 | 90.97 | ND | 0.73 | 0.79 | 0.5 | Mammalian | Expressed in skeletal muscle. {ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in sarcoplsamic reticulum Ca(2+) transport in skeletal muscle and may function in dendritic spine and synapse formation and neuronal plasticity. In slow- twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of the ryanodine receptor-coupling factor triadin. In neurons, may participate in the promotion of dendritic spine and synapse formation and maintenance of synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. {ECO:0000269|PubMed:16690701}. | Calcium/calmodulin-dependent protein kinase type II subunit gamma inhibitor: Bosutinib | 15.11 | |||
| dfaKCJ11 | ATP-sensitive inward rectifier potassium channel 11 | 1 | 49 | 98.41 | 99.97 | ND | 0.00 | 0.34 | 0.6 | Mammalian | Voltage-gated ion channel | Familial hyperinsulinemic hypoglycemia 2 (HHF2) [MIM:601820]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269|PubMed:10204114, ECO:0000269|PubMed:12364426, ECO:0000269|PubMed:15562009, ECO:0000269|PubMed:15579781, ECO:0000269|PubMed:15807877, ECO:0000269|PubMed:15998776, ECO:0000269|PubMed:16332676, ECO:0000269|PubMed:16357843, ECO:0000269|PubMed:18596924, ECO:0000269|PubMed:19357197, ECO:0000269|PubMed:7847376, ECO:0000269|PubMed:8923010}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes mellitus, permanent neonatal (PNDM) [MIM:606176]: A rare form of diabetes distinct from childhood- onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy. {ECO:0000269|PubMed:15115830, ECO:0000269|PubMed:15292329, ECO:0000269|PubMed:15448106, ECO:0000269|PubMed:15448107, ECO:0000269|PubMed:15580558, ECO:0000269|PubMed:16609879, ECO:0000269|PubMed:16731833, ECO:0000269|PubMed:17213273, ECO:0000269|PubMed:17652641, ECO:0000269|PubMed:20022885}. Note=The disease is caused by mutations affecting the gene represented in this entry. Transient neonatal diabetes mellitus 3 (TNDM3) [MIM:610582]: Neonatal diabetes mellitus, defined as insulin- requiring hyperglycemia within the first month of life, is a rare entity. In about half of the neonates, diabetes is transient and resolves at a median age of 3 months, whereas the rest have a permanent form of diabetes. In a significant number of patients with transient neonatal diabetes mellitus, diabetes type 2 appears later in life. The onset and severity of TNDM3 is variable with childhood-onset diabetes, gestational diabetes or adult-onset diabetes described. {ECO:0000269|PubMed:15718250, ECO:0000269|PubMed:15784703}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Defects in KCNJ11 may contribute to non-insulin- dependent diabetes mellitus (NIDDM), also known as diabetes mellitus type 2. Maturity-onset diabetes of the young 13 (MODY13) [MIM:616329]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:22701567}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium (By similarity). Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation. {ECO:0000250, ECO:0000269|PubMed:17855752, ECO:0000269|PubMed:9831708}. | ATP-sensitive inward rectifier potassium channel 11 inducer: Diazoxide, Levosimendan ATP-sensitive inward rectifier potassium channel 11 inhibitor: Glimepiride, Ibutilide, Thiamylal, Verapamil ATP-sensitive inward rectifier potassium channel 11 modulator: Glyburide | 16.04 | |||
| dfaKCMA1 | Calcium-activated potassium channel subunit alpha-1 | 2 | 85 | 97.64 | 87.57 | ND | 0.08 | 0.51 | 1.2 | Mammalian | Widely expressed. Except in myocytes, it is almost ubiquitously expressed. {ECO:0000269|PubMed:11880513}. | Voltage-gated ion channel | Generalized epilepsy and paroxysmal dyskinesia (GEPD) [MIM:609446]: Epilepsy is one of the most common and debilitating neurological disorders. Paroxysmal dyskinesias are neurological disorders characterized by sudden, unpredictable, disabling attacks of involuntary movement often requiring life-long treatment. The coexistence of epilepsy and paroxysmal dyskinesia in the same individual or family is an increasingly recognized phenomenon. Patients manifest absence seizures, generalized tonic- clonic seizures, paroxysmal nonkinesigenic dyskinesia, involuntary dystonic or choreiform movements. Onset is usually in childhood and patients may have seizures only, dyskinesia only, or both. {ECO:0000269|PubMed:15937479}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX). | Calcium-activated potassium channel subunit alpha-1 : Chlorzoxazone Calcium-activated potassium channel subunit alpha-1 binder: Procaine Calcium-activated potassium channel subunit alpha-1 inducer: Bendroflumethiazide Calcium-activated potassium channel subunit alpha-1 inhibitor: Cromoglicic acid, Halothane, Miconazole Calcium-activated potassium channel subunit alpha-1 other: Diazoxide Calcium-activated potassium channel subunit alpha-1 other/unknown: Hydrochlorothiazide, Hydroflumethiazide | 16.04 | ||
| dfaKCNA3 | Potassium voltage-gated channel subfamily A member 3 | 7 | 330 | 91.38 | 93.94 | ND | 0.36 | 0.43 | 0.5 | Mammalian | Voltage-gated ion channel | Autoimmune diseases
Immunosuppression Multiple Sclerosis T cell-mediated autoimmune diseases | Mediates the voltage-dependent potassium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a potassium-selective channel through which potassium ions may pass in accordance with their electrochemical gradient. | Potassium voltage-gated channel subfamily A member 3 antagonist: Dalfampridine | 16.04 | |||
| dfaKCNA5 | Potassium voltage-gated channel subfamily A member 5 | 8 | 478 | 92.44 | 92.92 | ND | 0.65 | 0.57 | 0.4 | Mammalian | Pancreatic islets and insulinoma. | Voltage-gated ion channel | Atrial fibrillation, familial, 7 (ATFB7) [MIM:612240]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:16772329}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:8505626, PubMed:12130714). May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform 2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation (PubMed:11524461). {ECO:0000269|PubMed:11524461, ECO:0000269|PubMed:12130714, ECO:0000269|PubMed:8505626}. | Potassium voltage-gated channel subfamily A member 5 antagonist: Dalfampridine | 16.04 | ||
| dfaKCNJ1 | ATP-sensitive inward rectifier potassium channel 1 | 1 | 68 | 97.85 | 99.93 | ND | 0.42 | 0.32 | 0.3 | Mammalian | In the kidney and pancreatic islets. Lower levels in skeletal muscle, pancreas, spleen, brain, heart and liver. {ECO:0000269|PubMed:7635463}. | Voltage-gated ion channel | Bartter syndrome 2 (BS2) [MIM:241200]: An autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. Bartter syndrome type 2 is a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia. {ECO:0000269|PubMed:8841184, ECO:0000269|PubMed:9002665, ECO:0000269|PubMed:9727001}. Note=The disease is caused by mutations affecting the gene represented in this entry. | In the kidney, probably plays a major role in potassium homeostasis. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This channel is activated by internal ATP and can be blocked by external barium. | ATP-sensitive inward rectifier potassium channel 1 inducer: Minoxidil ATP-sensitive inward rectifier potassium channel 1 inhibitor: Bethanidine, Glimepiride, Glyburide, Tolazamide, Tolbutamide ATP-sensitive inward rectifier potassium channel 1 other/unknown: Glycodiazine | 16.04 | ||
| dfaKCNN3 | Small conductance calcium-activated potassium channel protein 3 | 3 | 114 | 99.32 | 98.13 | ND | 0.85 | 0.68 | 0.5 | Mammalian | Voltage-gated ion channel | Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. The channel is blocked by apamin. | Small conductance calcium-activated potassium channel protein 3 inhibitor: Miconazole | 16.04 | ||||
| dfaKCNN4 | Intermediate conductance calcium-activated potassium channel protein 4 | 2 | 50 | 98.96 | 98.47 | ND | 0.97 | 0.94 | 0.2 | Mammalian | Widely expressed in non-excitable tissues. | Voltage-gated ion channel | Dehydrated hereditary stomatocytosis 2 (DHS2) [MIM:616689]: An autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. Affected individuals typically manifest mild to moderate compensated hemolytic anemia, with an increased erythrocyte mean corpuscular hemoglobin concentration and a decreased osmotic fragility, both of which reflect cellular dehydration. Their red cells exhibit a panel of various shape abnormalities such as elliptocytes, hemighosts, schizocytes, and very rare stomatocytic cells. Complications such as splenomegaly and cholelithiasis, resulting from increased red cell trapping in the spleen and elevated bilirubin levels, respectively, may occur. {ECO:0000269|PubMed:26148990, ECO:0000269|PubMed:26178367, ECO:0000269|PubMed:26198474}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Forms a voltage-independent potassium channel that is activated by intracellular calcium (PubMed:26148990). Activation is followed by membrane hyperpolarization which promotes calcium influx. Required for maximal calcium influx and proliferation during the reactivation of naive T-cells. The channel is blocked by clotrimazole and charybdotoxin but is insensitive to apamin (PubMed:17157250, PubMed:18796614). {ECO:0000269|PubMed:17157250, ECO:0000269|PubMed:18796614, ECO:0000269|PubMed:26148990}. | Intermediate conductance calcium-activated potassium channel protein 4 inhibitor: Clotrimazole, Enflurane, Halothane, Miconazole, Quinine | 16.04 | ||
| dfaKCNQ1 | Potassium voltage-gated channel subfamily KQT member 1 {ECO:0000305} | 4 | 94 | 98.15 | 90.35 | ND | 0.51 | 0.67 | 0.7 | Mammalian | Abundantly expressed in heart, pancreas, prostate, kidney, small intestine and peripheral blood leukocytes. Less abundant in placenta, lung, spleen, colon, thymus, testis and ovaries. | Voltage-gated ion channel | Long QT syndrome 1 (LQT1) [MIM:192500]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:10024302, ECO:0000269|PubMed:10220144, ECO:0000269|PubMed:10220146, ECO:0000269|PubMed:10367071, ECO:0000269|PubMed:10409658, ECO:0000269|PubMed:10482963, ECO:0000269|PubMed:10728423, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:11799244, ECO:0000269|PubMed:12442276, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:16414944, ECO:0000269|PubMed:16922724, ECO:0000269|PubMed:18165683, ECO:0000269|PubMed:18400097, ECO:0000269|PubMed:19540844, ECO:0000269|PubMed:19716085, ECO:0000269|PubMed:21241800, ECO:0000269|PubMed:24184248, ECO:0000269|PubMed:24269949, ECO:0000269|PubMed:24713462, ECO:0000269|PubMed:25037568, ECO:0000269|PubMed:25139741, ECO:0000269|PubMed:25705178, ECO:0000269|PubMed:8528244, ECO:0000269|PubMed:8818942, ECO:0000269|PubMed:8872472, ECO:0000269|PubMed:9024139, ECO:0000269|PubMed:9272155, ECO:0000269|PubMed:9302275, ECO:0000269|PubMed:9312006, ECO:0000269|PubMed:9323054, ECO:0000269|PubMed:9386136, ECO:0000269|PubMed:9482580, ECO:0000269|PubMed:9570196, ECO:0000269|PubMed:9641694, ECO:0000269|PubMed:9693036, ECO:0000269|PubMed:9702906, ECO:0000269|PubMed:9799083, ECO:0000269|PubMed:9927399, ECO:0000269|Ref.31}. Note=The disease is caused by mutations affecting the gene represented in this entry. Jervell and Lange-Nielsen syndrome 1 (JLNS1) [MIM:220400]: An autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death. {ECO:0000269|PubMed:10090886, ECO:0000269|PubMed:10728423, ECO:0000269|PubMed:18400097, ECO:0000269|PubMed:18441444, ECO:0000269|PubMed:25705178, ECO:0000269|PubMed:9781056}. Note=The disease is caused by mutations affecting the gene represented in this entry. Atrial fibrillation, familial, 3 (ATFB3) [MIM:607554]: An autosomal dominant form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:12522251}. Note=The disease is caused by mutations affecting the gene represented in this entry. Short QT syndrome 2 (SQT2) [MIM:609621]: A heart disorder characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. It causes syncope and sudden death. {ECO:0000269|PubMed:15159330}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:18711366, ECO:0000269|PubMed:18711367, ECO:0000269|PubMed:24390345}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Potassium channel that plays an important role in a number of tissues, including heart, inner ear, stomach and colon (By similarity) (PubMed:10646604). Associates with KCNE beta subunits that modulates current kinetics (By similarity) (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505, PubMed:19687231). Induces a voltage-dependent by rapidly activating and slowly deactivating potassium-selective outward current (By similarity) (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505). Promotes also a delayed voltage activated potassium current showing outward rectification characteristic (By similarity). During beta- adrenergic receptor stimulation participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks) (By similarity) (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current (PubMed:10713961). When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions (PubMed:10646604). This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents (By similarity). During conditions of increased substrate load, maintains the driving force for proximal tubular and intestinal sodium ions absorption, gastric acid secretion, and cAMP-induced jejunal chloride ions secretion (By similarity). Allows the provision of potassium ions to the luminal membrane of the secretory canaliculus in the resting state as well as during stimulated acid secretion (By similarity). When associated with KCNE2, forms an heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505). When associated with KCNE4, inhibits voltage-gated potassium channel activity (PubMed:19687231). When associated with KCNE5, this complex only conducts current upon strong and continued depolarization (PubMed:12324418). Also forms an heterotetramer with KCNQ5; has a voltage-gated potassium channel activity (PubMed:24855057). Binds with phosphatidylinositol 4,5- bisphosphate (PubMed:25037568). {ECO:0000250|UniProtKB:P97414, ECO:0000250|UniProtKB:Q9Z0N7, ECO:0000269|PubMed:10646604, ECO:0000269|PubMed:10713961, ECO:0000269|PubMed:11101505, ECO:0000269|PubMed:12324418, ECO:0000269|PubMed:19687231, ECO:0000269|PubMed:24855057, ECO:0000269|PubMed:25037568, ECO:0000269|PubMed:8900283, ECO:0000269|PubMed:9108097, ECO:0000269|PubMed:9312006}. Isoform 2: Non-functional alone but modulatory when coexpressed with the full-length isoform 1. {ECO:0000269|PubMed:9305853}. | Potassium voltage-gated channel subfamily KQT member 1 {ECO:0000305} inhibitor: Bepridil, Indapamide | 16.04 | ||
| dfaKCNQ2 | Potassium voltage-gated channel subfamily KQT member 2 | 5 | 174 | 90.98 | 89.30 | ND | 0.06 | 0.50 | 0.9 | Mammalian | In adult and fetal brain. Highly expressed in areas containing neuronal cell bodies, low in spinal chord and corpus callosum. Isoform 2 is preferentially expressed in differentiated neurons. Isoform 6 is prominent in fetal brain, undifferentiated neuroblastoma cells and brain tumors. {ECO:0000269|PubMed:10781098}. | Voltage-gated ion channel | Seizures, benign familial neonatal 1 (BFNS1) [MIM:121200]: A disorder characterized by clusters of seizures occurring in the first days of life. Most patients have spontaneous remission by 12 months of age and show normal psychomotor development. Some rare cases manifest an atypical severe phenotype associated with epileptic encephalopathy and psychomotor retardation. The disorder is distinguished from benign familial infantile seizures by an earlier age at onset. In some patients, neonatal convulsions are followed later in life by myokymia, a benign condition characterized by spontaneous involuntary contractions of skeletal muscles fiber groups that can be observed as vermiform movement of the overlying skin. Electromyography typically shows continuous motor unit activity with spontaneous oligo- and multiplet-discharges of high intraburst frequency (myokymic discharges). Some patients may have isolated myokymia. {ECO:0000269|PubMed:11175290, ECO:0000269|PubMed:11572947, ECO:0000269|PubMed:14534157, ECO:0000269|PubMed:15249611, ECO:0000269|PubMed:9425895}. Note=The disease is caused by mutations affecting the gene represented in this entry. Epileptic encephalopathy, early infantile, 7 (EIEE7) [MIM:613720]: An autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. {ECO:0000269|PubMed:12742592, ECO:0000269|PubMed:15249611}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Probably important in the regulation of neuronal excitability. Associates with KCNQ3 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. KCNQ2/KCNQ3 current is blocked by linopirdine and XE991, and activated by the anticonvulsant retigabine. Muscarinic agonist oxotremorine-M strongly suppress KCNQ2/KCNQ3 current in cells in which cloned KCNQ2/KCNQ3 channels were coexpressed with M1 muscarinic receptors. | Potassium voltage-gated channel subfamily KQT member 2 inhibitor: Amitriptyline Potassium voltage-gated channel subfamily KQT member 2 other: Diclofenac, Meclofenamic acid | 16.04 | ||
| dfaKDM1A | Lysine-specific histone demethylase 1A | 7 | 145 | 95.85 | 97.60 | ND | 0.77 | 0.72 | 0.4 | Mammalian | Ubiquitously expressed. {ECO:0000269|PubMed:16079795}. | Eraser | Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr- 6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Effector of SNAI1-mediated transcription repression of E- cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7. {ECO:0000269|PubMed:12032298, ECO:0000269|PubMed:15620353, ECO:0000269|PubMed:16079795, ECO:0000269|PubMed:17805299, ECO:0000269|PubMed:20228790, ECO:0000269|PubMed:20562920}. | 15.11 | ||||
| dfaKGP1 | cGMP-dependent protein kinase 1 | 2 | 188 | 92.09 | 95.67 | ND | 0.60 | 0.57 | 0.5 | Mammalian | Primarily expressed in lung and placenta. {ECO:0000269|PubMed:9192852}. | Kinase | Aortic aneurysm, familial thoracic 8 (AAT8) [MIM:615436]: A disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance. {ECO:0000269|PubMed:23910461}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine protein kinase that acts as key mediator of the nitric oxide (NO)/cGMP signaling pathway. GMP binding activates PRKG1, which phosphorylates serines and threonines on many cellular proteins. Numerous protein targets for PRKG1 phosphorylation are implicated in modulating cellular calcium, but the contribution of each of these targets may vary substantially among cell types. Proteins that are phosphorylated by PRKG1 regulate platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes involved in several aspects of the CNS like axon guidance, hippocampal and cerebellar learning, circadian rhythm and nociception. Smooth muscle relaxation is mediated through lowering of intracellular free calcium, by desensitization of contractile proteins to calcium, and by decrease in the contractile state of smooth muscle or in platelet activation. Regulates intracellular calcium levels via several pathways: phosphorylates MRVI1/IRAG and inhibits IP3- induced Ca(2+) release from intracellular stores, phosphorylation of KCNMA1 (BKCa) channels decreases intracellular Ca(2+) levels, which leads to increased opening of this channel. PRKG1 phosphorylates the canonical transient receptor potential channel (TRPC) family which inactivates the associated inward calcium current. Another mode of action of NO/cGMP/PKGI signaling involves PKGI-mediated inactivation of the Ras homolog gene family member A (RhoA). Phosphorylation of RHOA by PRKG1 blocks the action of this protein in myriad processes: regulation of RHOA translocation; decreasing contraction; controlling vesicle trafficking, reduction of myosin light chain phosphorylation resulting in vasorelaxation. Activation of PRKG1 by NO signaling alters also gene expression in a number of tissues. In smooth muscle cells, increased cGMP and PRKG1 activity influence expression of smooth muscle-specific contractile proteins, levels of proteins in the NO/cGMP signaling pathway, down-regulation of the matrix proteins osteopontin and thrombospondin-1 to limit smooth muscle cell migration and phenotype. Regulates vasodilator-stimulated phosphoprotein (VASP) functions in platelets and smooth muscle. {ECO:0000269|PubMed:10567269, ECO:0000269|PubMed:11162591, ECO:0000269|PubMed:11723116, ECO:0000269|PubMed:12082086, ECO:0000269|PubMed:14608379, ECO:0000269|PubMed:15194681, ECO:0000269|PubMed:16990611, ECO:0000269|PubMed:8182057}. | 16.04 | |||
| dfaKGP2 | cGMP-dependent protein kinase 2 | 2 | 131 | 96.77 | 94.32 | ND | 0.47 | 0.68 | 0.6 | Mammalian | Highly concentrated in brain, lung and intestinal mucosa. | Kinase | 16.04 | |||||
| dfaKHK | Ketohexokinase {ECO:0000312|HGNC:HGNC:6315} | 2 | 85 | 99.90 | 99.93 | ND | 0.48 | 0.46 | 0.5 | Mammalian | Most abundant in liver, kidney, gut, spleen and pancreas. Low levels also found in adrenal, muscle, brain and eye. {ECO:0000269|PubMed:9799106}. | Enzyme | Fructosuria (FRUCT) [MIM:229800]: Benign defect of intermediary metabolism. {ECO:0000269|PubMed:12941785, ECO:0000269|PubMed:7833921}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate. {ECO:0000269|PubMed:12941785}. | 15.11 | |||
| dfaKIF11 | Kinesin-like protein KIF11 | 4 | 758 | 96.50 | 95.34 | ND | 0.55 | 0.64 | 0.6 | Mammalian | Other cytosolic protein | Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:152950]: An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes. {ECO:0000269|PubMed:22284827}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays. {ECO:0000269|PubMed:19001501}. | 15.11 | ||||
| dfaKISSR | KiSS-1 receptor | 1 | 52 | 99.91 | 100.00 | ND | 0.51 | 0.65 | 0.8 | Mammalian | Most highly expressed in the pancreas, placenta and spinal cord, with lower-level of expression in peripheral blood leukocytes, kidney, lung, fetal liver, stomach, small intestine, testes, spleen, thymus, adrenal glands and lymph nodes. In the adult brain, expressed in the superior frontal gyrus, putamen, caudate nucleus, cingulate gyrus, nucleus accumbens, hippocampus, pons and amygdala, as well as the hypothalamus and pituitary. Expression levels are higher in early (7-9 weeks) than term placentas. Expression levels were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells. Expressed at higher levels in first trimester trophoblasts than at term of gestation. Also found in the extravillous trophoblast suggesting endocrine/paracrine activation mechanism. {ECO:0000269|PubMed:11385580, ECO:0000269|PubMed:11387329, ECO:0000269|PubMed:11414709, ECO:0000269|PubMed:11457843, ECO:0000269|PubMed:12414911, ECO:0000269|PubMed:15020672}. | Family A G protein-coupled receptor | Hypogonadotropic hypogonadism 8 with or without anosmia (HH8) [MIM:614837]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:12944565, ECO:0000269|PubMed:14573733, ECO:0000269|PubMed:15598687, ECO:0000269|PubMed:17164310, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in KISS1R as well as in other HH- associated genes including FGFR1 and IL17RD (PubMed:23643382). {ECO:0000269|PubMed:23643382}. Precocious puberty, central 1 (CPPB1) [MIM:176400]: A condition defined as the development of secondary sexual characteristics in boys and girls at a chronological age that is 2.5 standard deviations below the mean age at onset of puberty in the population. Central precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis. {ECO:0000269|PubMed:18272894}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for metastin (kisspeptin-54 or kp-54), a C- terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein that suppresses metastases in malignant melanomas and in some breast carcinomas without affecting tumorigenicity. The metastasis suppressor properties may be mediated in part by cell cycle arrest and induction of apoptosis in malignant cells. The receptor is essential for normal gonadotropin-released hormone physiology and for puberty. The hypothalamic KiSS1/KISS1R system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood. The receptor is also probably involved in the regulation and fine- tuning of trophoblast invasion generated by the trophoblast itself. Analysis of the transduction pathways activated by the receptor identifies coupling to phospholipase C and intracellular calcium release through pertussis toxin-insensitive G(q) proteins. {ECO:0000269|PubMed:15020672}. | 16.04 | |||
| dfaKIT | Mast/stem cell growth factor receptor Kit | 5 | 807 | 96.26 | 96.40 | ND | 0.58 | 0.66 | 0.6 | Mammalian | Isoform 1 and isoform 2 are detected in spermatogonia and Leydig cells. Isoform 3 is detected in round spermatids, elongating spermatids and spermatozoa (at protein level). Widely expressed. Detected in the hematopoietic system, the gastrointestinal system, in melanocytes and in germ cells. {ECO:0000269|PubMed:20601678, ECO:0000269|PubMed:2448137}. | Kinase | Piebald trait (PBT) [MIM:172800]: Autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. {ECO:0000269|PubMed:11074500, ECO:0000269|PubMed:1370874, ECO:0000269|PubMed:1376329, ECO:0000269|PubMed:1717985, ECO:0000269|PubMed:7687267, ECO:0000269|PubMed:8680409, ECO:0000269|PubMed:9450866, ECO:0000269|PubMed:9699740}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gastrointestinal stromal tumor (GIST) [MIM:606764]: Common mesenchymal neoplasms arising in the gastrointestinal tract, most often in the stomach. They are histologically, immunohistochemically, and genetically different from typical leiomyomas, leiomyosarcomas, and schwannomas. Most GISTs are composed of a fairly uniform population of spindle-shaped cells. Some tumors are dominated by epithelioid cells or contain a mixture of spindle and epithelioid morphologies. Primary GISTs in the gastrointestinal tract commonly metastasize in the omentum and mesenteries, often as multiple nodules. However, primary tumors may also occur outside of the gastrointestinal tract, in other intra-abdominal locations, especially in the omentum and mesentery. {ECO:0000269|PubMed:11505412, ECO:0000269|PubMed:15824741, ECO:0000269|PubMed:9438854, ECO:0000269|PubMed:9697690}. Note=The gene represented in this entry is involved in disease pathogenesis. Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. Note=The gene represented in this entry may be involved in disease pathogenesis. Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. Note=The gene represented in this entry is involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase. | Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1. {ECO:0000269|PubMed:10397721, ECO:0000269|PubMed:12444928, ECO:0000269|PubMed:12511554, ECO:0000269|PubMed:12878163, ECO:0000269|PubMed:17904548, ECO:0000269|PubMed:19265199, ECO:0000269|PubMed:21135090, ECO:0000269|PubMed:21640708, ECO:0000269|PubMed:7520444, ECO:0000269|PubMed:9528781}. | Mast/stem cell growth factor receptor Kit Inhibitor: Lenvatinib Mast/stem cell growth factor receptor Kit antagonist: Dasatinib, Imatinib, Nilotinib, Sorafenib, Sunitinib Mast/stem cell growth factor receptor Kit inhibitor: Pazopanib, Ponatinib, Regorafenib Mast/stem cell growth factor receptor Kit multitarget: | 15.11 | ||
| dfaKITH | Thymidine kinase, cytosolic | 3 | 90 | 99.69 | 99.46 | ND | 0.47 | 0.58 | 0.5 | Mammalian | Enzyme | Thymidine kinase, cytosolic substrate: Trifluridine, Zidovudine | 16.04 | |||||
| dfaKKCC1 | Calcium/calmodulin-dependent protein kinase kinase 1 | 5 | 66 | 97.63 | 95.97 | ND | 0.66 | 0.82 | 0.3 | Mammalian | Kinase | Calcium/calmodulin-dependent protein kinase that belongs to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1, CAMK1D, CAMK1G and CAMK4. Involved in regulating cell apoptosis. Promotes cell survival by phosphorylating AKT1/PKB that inhibits pro-apoptotic BAD/Bcl2-antagonist of cell death. {ECO:0000269|PubMed:12935886}. | 16.04 | |||||
| dfaKKCC2 | Calcium/calmodulin-dependent protein kinase kinase 2 | 7 | 77 | 91.71 | 85.91 | ND | 0.71 | 0.85 | 0.6 | Mammalian | Ubiquitously expressed with higher levels in the brain. Intermediate levels are detected in spleen, prostate, thyroid and leukocytes. The lowest level is in lung. {ECO:0000269|PubMed:9662074}. | Kinase | Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Isoform 1, isoform 2 and isoform 3 phosphorylate CAMK1 and CAMK4. Isoform 3 phosphorylates CAMK1D. Isoform 4, isoform 5 and isoform 6 lacking part of the calmodulin- binding domain are inactive. Efficiently phosphorylates 5'-AMP- activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals (By similarity). Seems to be involved in hippocampal activation of CREB1 (By similarity). May play a role in neurite growth. Isoform 3 may promote neurite elongation, while isoform 1 may promoter neurite branching. {ECO:0000250, ECO:0000269|PubMed:11395482, ECO:0000269|PubMed:12935886, ECO:0000269|PubMed:21957496, ECO:0000269|PubMed:9662074}. | 15.11 | ||||
| dfaKLK | Kallikrein-10 | 1 | 58 | 99.81 | 99.79 | ND | 0.57 | 0.27 | 0.3 | Mammalian | Expressed in breast, ovary and prostate. | Has a tumor-suppressor role for NES1 in breast and prostate cancer. | 16.04 | |||||
| dfaKLK1 | Kallikrein-1 | 3 | 77 | 99.16 | 99.79 | ND | 0.85 | 0.87 | 0.4 | Mammalian | Isoform 2 is expressed in pancreas, salivary glands, kidney, colon, prostate gland, testis, spleen and the colon adenocarcinoma cell line T84. {ECO:0000269|PubMed:7749372}. | Protease | Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin. | 16.04 | ||||
| dfaKLKB1 | Plasma kallikrein | 3 | 112 | 95.20 | 88.99 | ND | 0.85 | 0.96 | 0.5 | Mammalian | Protease | Prekallikrein deficiency (PKK deficiency) [MIM:612423]: This disorder is a blood coagulation defect. {ECO:0000269|PubMed:14652634, ECO:0000269|PubMed:17598838}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. | Plasma kallikrein inhibitor: Ecallantide | 16.04 | |||
| dfaKMO | Kynurenine 3-monooxygenase {ECO:0000255|HAMAP-Rule:MF_03018} | 2 | 54 | 99.56 | 92.20 | ND | 0.19 | 0.82 | 0.3 | Mammalian | Highest levels in placenta and liver. Detectable in kidney. {ECO:0000269|PubMed:9237672}. | Enzyme | Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid, a neurotoxic NMDA receptor antagonist and potential endogenous inhibitor of NMDA receptor signaling in axonal targeting, synaptogenesis and apoptosis during brain development. Quinolinic acid may also affect NMDA receptor signaling in pancreatic beta cells, osteoblasts, myocardial cells, and the gastrointestinal tract. | 16.04 | ||||
| dfaKPCA | Protein kinase C alpha type | 4 | 945 | 93.35 | 92.34 | ND | 0.62 | 0.69 | 0.8 | Mammalian | Kinase | Leukemia, unspecified
Prostate cancer | Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation, migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activating signaling cascade involving MAPK1/3 (ERK1/2) and RAP1GAP. Involved in cell proliferation and cell growth arrest by positive and negative regulation of the cell cycle. Can promote cell growth by phosphorylating and activating RAF1, which mediates the activation of the MAPK/ERK signaling cascade, and/or by up-regulating CDKN1A, which facilitates active cyclin-dependent kinase (CDK) complex formation in glioma cells. In intestinal cells stimulated by the phorbol ester PMA, can trigger a cell cycle arrest program which is associated with the accumulation of the hyper-phosphorylated growth-suppressive form of RB1 and induction of the CDK inhibitors CDKN1A and CDKN1B. Exhibits anti-apoptotic function in glioma cells and protects them from apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, and in leukemia cells mediates anti-apoptotic action by phosphorylating BCL2. During macrophage differentiation induced by macrophage colony-stimulating factor (CSF1), is translocated to the nucleus and is associated with macrophage development. After wounding, translocates from focal contacts to lamellipodia and participates in the modulation of desmosomal adhesion. Plays a role in cell motility by phosphorylating CSPG4, which induces association of CSPG4 with extensive lamellipodia at the cell periphery and polarization of the cell accompanied by increases in cell motility. Is highly expressed in a number of cancer cells where it can act as a tumor promoter and is implicated in malignant phenotypes of several tumors such as gliomas and breast cancers. Negatively regulates myocardial contractility and positively regulates angiogenesis, platelet aggregation and thrombus formation in arteries. Mediates hypertrophic growth of neonatal cardiomyocytes, in part through a MAPK1/3 (ERK1/2)- dependent signaling pathway, and upon PMA treatment, is required to induce cardiomyocyte hypertrophy up to heart failure and death, by increasing protein synthesis, protein-DNA ratio and cell surface area. Regulates cardiomyocyte function by phosphorylating cardiac troponin T (TNNT2/CTNT), which induces significant reduction in actomyosin ATPase activity, myofilament calcium sensitivity and myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation of kinase activation and vascular tube formation. Involved in the stabilization of VEGFA mRNA at post-transcriptional level and mediates VEGFA-induced cell proliferation. In the regulation of calcium-induced platelet aggregation, mediates signals from the CD36/GP4 receptor for granule release, and activates the integrin heterodimer ITGA2B- ITGB3 through the RAP1GAP pathway for adhesion. During response to lipopolysaccharides (LPS), may regulate selective LPS-induced macrophage functions involved in host defense and inflammation. But in some inflammatory responses, may negatively regulate NF- kappa-B-induced genes, through IL1A-dependent induction of NF- kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O- tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which modulates EIF4G1 binding to MKNK1 and may be involved in the regulation of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of KIT activity. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. {ECO:0000269|PubMed:10848585, ECO:0000269|PubMed:11909826, ECO:0000269|PubMed:12724315, ECO:0000269|PubMed:12832403, ECO:0000269|PubMed:15016832, ECO:0000269|PubMed:15504744, ECO:0000269|PubMed:15526160, ECO:0000269|PubMed:18056764, ECO:0000269|PubMed:19176525, ECO:0000269|PubMed:21576361, ECO:0000269|PubMed:23990668, ECO:0000269|PubMed:9738012, ECO:0000269|PubMed:9830023, ECO:0000269|PubMed:9873035, ECO:0000269|PubMed:9927633}. | Protein kinase C alpha type : Phosphatidylserine, Tamoxifen, Vitamin E Protein kinase C alpha type ligand: Ingenol Mebutate | 15.11 | |||
| dfaKPCB | Protein kinase C beta type | 3 | 351 | 97.29 | 96.28 | ND | 0.68 | 0.74 | 0.6 | Mammalian | Kinase | B-lineage malignancies
Diabetes mellitus Diabetic retinopathy Macular edema | Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosome, oxidative stress-induced apoptosis, androgen receptor-dependent transcription regulation, insulin signaling and endothelial cells proliferation. Plays a key role in B-cell activation by regulating BCR-induced NF-kappa-B activation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11/CARMA1 at 'Ser-559', 'Ser-644' and 'Ser-652'. Phosphorylation induces CARD11/CARMA1 association with lipid rafts and recruitment of the BCL10-MALT1 complex as well as MAP3K7/TAK1, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. Plays a direct role in the negative feedback regulation of the BCR signaling, by down-modulating BTK function via direct phosphorylation of BTK at 'Ser-180', which results in the alteration of BTK plasma membrane localization and in turn inhibition of BTK activity. Involved in apoptosis following oxidative damage: in case of oxidative conditions, specifically phosphorylates 'Ser-36' of isoform p66Shc of SHC1, leading to mitochondrial accumulation of p66Shc, where p66Shc acts as a reactive oxygen species producer. Acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag for epigenetic transcriptional activation that prevents demethylation of histone H3 'Lys-4' (H3K4me) by LSD1/KDM1A. In insulin signaling, may function downstream of IRS1 in muscle cells and mediate insulin-dependent DNA synthesis through the RAF1- MAPK/ERK signaling cascade. May participate in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. Under high glucose in pancreatic beta-cells, is probably involved in the inhibition of the insulin gene transcription, via regulation of MYC expression. In endothelial cells, activation of PRKCB induces increased phosphorylation of RB1, increased VEGFA-induced cell proliferation, and inhibits PI3K/AKT-dependent nitric oxide synthase (NOS3/eNOS) regulation by insulin, which causes endothelial dysfunction. Also involved in triglyceride homeostasis (By similarity). Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. {ECO:0000250, ECO:0000269|PubMed:11598012, ECO:0000269|PubMed:19176525, ECO:0000269|PubMed:20228790}. | 15.11 | ||||
| dfaKPCD | Protein kinase C delta type | 4 | 785 | 89.77 | 87.21 | ND | 0.62 | 0.00 | 0.7 | Mammalian | Kinase | Autoimmune lymphoproliferative syndrome 3 (ALPS3) [MIM:615559]: A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. CVID9 patients have B-cell deficiency and severe autoimmunity. {ECO:0000269|PubMed:23319571}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor- initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Negatively regulates B cell proliferation and also has an important function in self- antigen induced B cell tolerance induction. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53. In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)- induced inhibition of cell cycle progression at G1/S phase by up- regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1. Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro- survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl- phenylalanine (fMLP)-treated cells, is required for NCF1 (p47- phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways. May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation. Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release. Phosphorylates MUC1 in the C- terminal and regulates the interaction between MUC1 and beta- catenin. The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (By similarity). {ECO:0000250, ECO:0000269|PubMed:11748588, ECO:0000269|PubMed:11877440, ECO:0000269|PubMed:15774464, ECO:0000269|PubMed:16940418, ECO:0000269|PubMed:19587372, ECO:0000269|PubMed:19801500}. | Protein kinase C delta type ligand: Ingenol Mebutate | 15.11 | |||
| dfaKPCD1 | Serine/threonine-protein kinase D1 | 3 | 154 | 98.90 | 98.70 | ND | 0.80 | 0.84 | 0.6 | Mammalian | Kinase | Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and trafficking, cell survival through NF-kappa-B activation, cell migration, cell differentiation by mediating HDAC7 nuclear export, cell proliferation via MAPK1/3 (ERK1/2) signaling, and plays a role in cardiac hypertrophy, VEGFA-induced angiogenesis, genotoxic-induced apoptosis and flagellin-stimulated inflammatory response. Phosphorylates the epidermal growth factor receptor (EGFR) on dual threonine residues, which leads to the suppression of epidermal growth factor (EGF)-induced MAPK8/JNK1 activation and subsequent JUN phosphorylation. Phosphorylates RIN1, inducing RIN1 binding to 14-3-3 proteins YWHAB, YWHAE and YWHAZ and increased competition with RAF1 for binding to GTP-bound form of Ras proteins (NRAS, HRAS and KRAS). Acts downstream of the heterotrimeric G-protein beta/gamma-subunit complex to maintain the structural integrity of the Golgi membranes, and is required for protein transport along the secretory pathway. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane. May act by activating the lipid kinase phosphatidylinositol 4-kinase beta (PI4KB) at the TGN for the local synthesis of phosphorylated inositol lipids, which induces a sequential production of DAG, phosphatidic acid (PA) and lyso-PA (LPA) that are necessary for membrane fission and generation of specific transport carriers to the cell surface. Under oxidative stress, is phosphorylated at Tyr-463 via SRC-ABL1 and contributes to cell survival by activating IKK complex and subsequent nuclear translocation and activation of NFKB1. Involved in cell migration by regulating integrin alpha-5/beta-3 recycling and promoting its recruitment in newly forming focal adhesion. In osteoblast differentiation, mediates the bone morphogenic protein 2 (BMP2)- induced nuclear export of HDAC7, which results in the inhibition of HDAC7 transcriptional repression of RUNX2. In neurons, plays an important role in neuronal polarity by regulating the biogenesis of TGN-derived dendritic vesicles, and is involved in the maintenance of dendritic arborization and Golgi structure in hippocampal cells. May potentiate mitogenesis induced by the neuropeptide bombesin or vasopressin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. Plays an important role in the proliferative response induced by low calcium in keratinocytes, through sustained activation of MAPK1/3 (ERK1/2) pathway. Downstream of novel PKC signaling, plays a role in cardiac hypertrophy by phosphorylating HDAC5, which in turn triggers XPO1/CRM1-dependent nuclear export of HDAC5, MEF2A transcriptional activation and induction of downstream target genes that promote myocyte hypertrophy and pathological cardiac remodeling. Mediates cardiac troponin I (TNNI3) phosphorylation at the PKA sites, which results in reduced myofilament calcium sensitivity, and accelerated crossbridge cycling kinetics. The PRKD1-HDAC5 pathway is also involved in angiogenesis by mediating VEGFA-induced specific subset of gene expression, cell migration, and tube formation. In response to VEGFA, is necessary and required for HDAC7 phosphorylation which induces HDAC7 nuclear export and endothelial cell proliferation and migration. During apoptosis induced by cytarabine and other genotoxic agents, PRKD1 is cleaved by caspase-3 at Asp-378, resulting in activation of its kinase function and increased sensitivity of cells to the cytotoxic effects of genotoxic agents. In epithelial cells, is required for transducing flagellin-stimulated inflammatory responses by binding and phosphorylating TLR5, which contributes to MAPK14/p38 activation and production of inflammatory cytokines. May play a role in inflammatory response by mediating activation of NF-kappa- B. May be involved in pain transmission by directly modulating TRPV1 receptor. Plays a role in activated KRAS-mediated stabilization of ZNF304 in colorectal cancer (CRC) cells (PubMed:24623306). {ECO:0000269|PubMed:10523301, ECO:0000269|PubMed:10764790, ECO:0000269|PubMed:12505989, ECO:0000269|PubMed:12637538, ECO:0000269|PubMed:15471852, ECO:0000269|PubMed:17442957, ECO:0000269|PubMed:18332134, ECO:0000269|PubMed:18509061, ECO:0000269|PubMed:19135240, ECO:0000269|PubMed:19211839, ECO:0000269|PubMed:24623306}. | 16.04 | |||||
| dfaKPCD2 | Serine/threonine-protein kinase D2 | 7 | 341 | 88.66 | 91.26 | ND | 0.37 | 0.56 | 0.5 | Mammalian | Widely expressed. | Kinase | Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of cell proliferation via MAPK1/3 (ERK1/2) signaling, oxidative stress- induced NF-kappa-B activation, inhibition of HDAC7 transcriptional repression, signaling downstream of T-cell antigen receptor (TCR) and cytokine production, and plays a role in Golgi membrane trafficking, angiogenesis, secretory granule release and cell adhesion. May potentiate mitogenesis induced by the neuropeptide bombesin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. In response to oxidative stress, is phosphorylated at Tyr-438 by ABL1, which leads to the activation of PRKD2 without increasing its catalytic activity, and mediates activation of NF-kappa-B. In response to the activation of the gastrin receptor CCKBR, is phosphorylated at Ser-244 by CSNK1D and CSNK1E, translocates to the nucleus, phosphorylates HDAC7, leading to nuclear export of HDAC7 and inhibition of HDAC7 transcriptional repression of NR4A1/NUR77. Upon TCR stimulation, is activated independently of ZAP70, translocates from the cytoplasm to the nucleus and is required for interleukin-2 (IL2) promoter up-regulation. During adaptive immune responses, is required in peripheral T-lymphocytes for the production of the effector cytokines IL2 and IFNG after TCR engagement and for optimal induction of antibody responses to antigens. In epithelial cells stimulated with lysophosphatidic acid (LPA), is activated through a PKC-dependent pathway and mediates LPA-stimulated interleukin-8 (IL8) secretion via a NF- kappa-B-dependent pathway. During TCR-induced T-cell activation, interacts with and is activated by the tyrosine kinase LCK, which results in the activation of the NFAT transcription factors. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane and in polarized cells is involved in the transport of proteins from the TGN to the basolateral membrane. Plays an important role in endothelial cell proliferation and migration prior to angiogenesis, partly through modulation of the expression of KDR/VEGFR2 and FGFR1, two key growth factor receptors involved in angiogenesis. In secretory pathway, is required for the release of chromogranin-A (CHGA)-containing secretory granules from the TGN. Downstream of PRKCA, plays important roles in angiotensin-2- induced monocyte adhesion to endothelial cells. Plays a regulatory role in angiogenesis and tumor growth by phosphorylating a downstream mediator CIB1 isoform 2, resulting in vascular endothelial growth factor A (VEGFA) secretion. {ECO:0000269|PubMed:14743217, ECO:0000269|PubMed:15604256, ECO:0000269|PubMed:16928771, ECO:0000269|PubMed:17077180, ECO:0000269|PubMed:17951978, ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:18262756, ECO:0000269|PubMed:19001381, ECO:0000269|PubMed:19192391, ECO:0000269|PubMed:23503467}. | 16.04 | ||||
| dfaKPCD3 | Serine/threonine-protein kinase D3 | 5 | 411 | 88.51 | 89.90 | ND | 0.65 | 0.70 | 0.5 | Mammalian | Ubiquitous. | Kinase | Converts transient diacylglycerol (DAG) signals into prolonged physiological effects, downstream of PKC. Involved in resistance to oxidative stress (By similarity). {ECO:0000250}. | 16.04 | ||||
| dfaKPCE | Protein kinase C epsilon type | 6 | 348 | 95.10 | 97.39 | ND | 0.57 | 0.54 | 0.8 | Mammalian | Kinase | Not Available | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays essential roles in the regulation of multiple cellular processes linked to cytoskeletal proteins, such as cell adhesion, motility, migration and cell cycle, functions in neuron growth and ion channel regulation, and is involved in immune response, cancer cell invasion and regulation of apoptosis. Mediates cell adhesion to the extracellular matrix via integrin-dependent signaling, by mediating angiotensin-2-induced activation of integrin beta-1 (ITGB1) in cardiac fibroblasts. Phosphorylates MARCKS, which phosphorylates and activates PTK2/FAK, leading to the spread of cardiomyocytes. Involved in the control of the directional transport of ITGB1 in mesenchymal cells by phosphorylating vimentin (VIM), an intermediate filament (IF) protein. In epithelial cells, associates with and phosphorylates keratin-8 (KRT8), which induces targeting of desmoplakin at desmosomes and regulates cell-cell contact. Phosphorylates IQGAP1, which binds to CDC42, mediating epithelial cell-cell detachment prior to migration. In HeLa cells, contributes to hepatocyte growth factor (HGF)-induced cell migration, and in human corneal epithelial cells, plays a critical role in wound healing after activation by HGF. During cytokinesis, forms a complex with YWHAB, which is crucial for daughter cell separation, and facilitates abscission by a mechanism which may implicate the regulation of RHOA. In cardiac myocytes, regulates myofilament function and excitation coupling at the Z-lines, where it is indirectly associated with F- actin via interaction with COPB1. During endothelin-induced cardiomyocyte hypertrophy, mediates activation of PTK2/FAK, which is critical for cardiomyocyte survival and regulation of sarcomere length. Plays a role in the pathogenesis of dilated cardiomyopathy via persistent phosphorylation of troponin I (TNNI3). Involved in nerve growth factor (NFG)-induced neurite outgrowth and neuron morphological change independently of its kinase activity, by inhibition of RHOA pathway, activation of CDC42 and cytoskeletal rearrangement. May be involved in presynaptic facilitation by mediating phorbol ester-induced synaptic potentiation. Phosphorylates gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2), which reduces the response of GABA receptors to ethanol and benzodiazepines and may mediate acute tolerance to the intoxicating effects of ethanol. Upon PMA treatment, phosphorylates the capsaicin- and heat-activated cation channel TRPV1, which is required for bradykinin-induced sensitization of the heat response in nociceptive neurons. Is able to form a complex with PDLIM5 and N-type calcium channel, and may enhance channel activities and potentiates fast synaptic transmission by phosphorylating the pore-forming alpha subunit CACNA1B (CaV2.2). In prostate cancer cells, interacts with and phosphorylates STAT3, which increases DNA-binding and transcriptional activity of STAT3 and seems to be essential for prostate cancer cell invasion. Downstream of TLR4, plays an important role in the lipopolysaccharide (LPS)-induced immune response by phosphorylating and activating TICAM2/TRAM, which in turn activates the transcription factor IRF3 and subsequent cytokines production. In differentiating erythroid progenitors, is regulated by EPO and controls the protection against the TNFSF10/TRAIL- mediated apoptosis, via BCL2. May be involved in the regulation of the insulin-induced phosphorylation and activation of AKT1. {ECO:0000269|PubMed:11884385, ECO:0000269|PubMed:1374067, ECO:0000269|PubMed:15355962, ECO:0000269|PubMed:16757566, ECO:0000269|PubMed:17603037, ECO:0000269|PubMed:17875639, ECO:0000269|PubMed:17875724}. | 16.04 | ||||
| dfaKPCG | Protein kinase C gamma type | 6 | 371 | 89.73 | 91.12 | ND | 0.44 | 0.61 | 0.8 | Mammalian | Expressed in Purkinje cells of the cerebellar cortex. {ECO:0000269|PubMed:12644968}. | Kinase | Spinocerebellar ataxia 14 (SCA14) [MIM:605361]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA14 is an autosomal dominant cerebellar ataxia (ADCA). {ECO:0000269|PubMed:12644968}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays diverse roles in neuronal cells and eye tissues, such as regulation of the neuronal receptors GRIA4/GLUR4 and GRIN1/NMDAR1, modulation of receptors and neuronal functions related to sensitivity to opiates, pain and alcohol, mediation of synaptic function and cell survival after ischemia, and inhibition of gap junction activity after oxidative stress. Binds and phosphorylates GRIA4/GLUR4 glutamate receptor and regulates its function by increasing plasma membrane-associated GRIA4 expression. In primary cerebellar neurons treated with the agonist 3,5-dihyidroxyphenylglycine, functions downstream of the metabotropic glutamate receptor GRM5/MGLUR5 and phosphorylates GRIN1/NMDAR1 receptor which plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. May be involved in the regulation of hippocampal long-term potentiation (LTP), but may be not necessary for the process of synaptic plasticity. May be involved in desensitization of mu-type opioid receptor-mediated G-protein activation in the spinal cord, and may be critical for the development and/or maintenance of morphine-induced reinforcing effects in the limbic forebrain. May modulate the functionality of mu-type-opioid receptors by participating in a signaling pathway which leads to the phosphorylation and degradation of opioid receptors. May also contributes to chronic morphine-induced changes in nociceptive processing. Plays a role in neuropathic pain mechanisms and contributes to the maintenance of the allodynia pain produced by peripheral inflammation. Plays an important role in initial sensitivity and tolerance to ethanol, by mediating the behavioral effects of ethanol as well as the effects of this drug on the GABA(A) receptors. During and after cerebral ischemia modulate neurotransmission and cell survival in synaptic membranes, and is involved in insulin-induced inhibition of necrosis, an important mechanism for minimizing ischemic injury. Required for the elimination of multiple climbing fibers during innervation of Purkinje cells in developing cerebellum. Is activated in lens epithelial cells upon hydrogen peroxide treatment, and phosphorylates connexin-43 (GJA1/CX43), resulting in disassembly of GJA1 gap junction plaques and inhibition of gap junction activity which could provide a protective effect against oxidative stress (By similarity). Phosphorylates p53/TP53 and promotes p53/TP53-dependent apoptosis in response to DNA damage. Involved in the phase resetting of the cerebral cortex circadian clock during temporally restricted feeding. Stabilizes the core clock component ARNTL/BMAL1 by interfering with its ubiquitination, thus suppressing its degradation, resulting in phase resetting of the cerebral cortex clock (By similarity). {ECO:0000250|UniProtKB:P63318, ECO:0000250|UniProtKB:P63319, ECO:0000269|PubMed:16377624}. | 16.04 | |||
| dfaKPCI | Protein kinase C iota type | 7 | 107 | 88.48 | 86.81 | ND | 0.84 | 0.61 | 0.4 | Mammalian | Predominantly expressed in lung and brain, but also expressed at lower levels in many tissues including pancreatic islets. Highly expressed in non-small cell lung cancers. {ECO:0000269|PubMed:15994303, ECO:0000269|PubMed:7607695, ECO:0000269|PubMed:8226978}. | Kinase | Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non- small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis. {ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10467349, ECO:0000269|PubMed:10906326, ECO:0000269|PubMed:11042363, ECO:0000269|PubMed:11724794, ECO:0000269|PubMed:12871960, ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15994303, ECO:0000269|PubMed:18270268, ECO:0000269|PubMed:19327373, ECO:0000269|PubMed:21189248, ECO:0000269|PubMed:21419810, ECO:0000269|PubMed:8226978, ECO:0000269|PubMed:9346882}. | 15.11 | ||||
| dfaKPCL | Protein kinase C eta type | 4 | 249 | 97.91 | 95.02 | ND | 0.50 | 0.66 | 1.0 | Mammalian | Most abundant in lung, less in heart and skin. {ECO:0000269|PubMed:1986216}. | Kinase | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:17206144}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in the regulation of cell differentiation in keratinocytes and pre-B cell receptor, mediates regulation of epithelial tight junction integrity and foam cell formation, and is required for glioblastoma proliferation and apoptosis prevention in MCF-7 cells. In keratinocytes, binds and activates the tyrosine kinase FYN, which in turn blocks epidermal growth factor receptor (EGFR) signaling and leads to keratinocyte growth arrest and differentiation. Associates with the cyclin CCNE1-CDK2-CDKN1B complex and inhibits CDK2 kinase activity, leading to RB1 dephosphorylation and thereby G1 arrest in keratinocytes. In association with RALA activates actin depolymerization, which is necessary for keratinocyte differentiation. In the pre-B cell receptor signaling, functions downstream of BLNK by up-regulating IRF4, which in turn activates L chain gene rearrangement. Regulates epithelial tight junctions (TJs) by phosphorylating occludin (OCLN) on threonine residues, which is necessary for the assembly and maintenance of TJs. In association with PLD2 and via TLR4 signaling, is involved in lipopolysaccharide (LPS)-induced RGS2 down-regulation and foam cell formation. Upon PMA stimulation, mediates glioblastoma cell proliferation by activating the mTOR pathway, the PI3K/AKT pathway and the ERK1- dependent phosphorylation of ELK1. Involved in the protection of glioblastoma cells from irradiation-induced apoptosis by preventing caspase-9 activation. In camptothecin-treated MCF-7 cells, regulates NF-kappa-B upstream signaling by activating IKBKB, and confers protection against DNA damage-induced apoptosis. Promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Phosphorylates ATF2 which promotes its nuclear retention and transcriptional activity and negatively regulates its mitochondrial localization. {ECO:0000269|PubMed:10806212, ECO:0000269|PubMed:11112424, ECO:0000269|PubMed:11772428, ECO:0000269|PubMed:15489897, ECO:0000269|PubMed:17146445, ECO:0000269|PubMed:18780722, ECO:0000269|PubMed:19114660, ECO:0000269|PubMed:20558593, ECO:0000269|PubMed:21820409, ECO:0000269|PubMed:22304920}. | 15.11 | |||
| dfaKPCT | Protein kinase C theta type | 3 | 576 | 90.97 | 92.04 | ND | 0.64 | 0.66 | 0.6 | Mammalian | Expressed in skeletal muscle, T-cells, megakaryoblastic cells and platelets. {ECO:0000269|PubMed:7686153}. | Kinase | Not Available | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non- redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non- canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. {ECO:0000269|PubMed:11342610, ECO:0000269|PubMed:14988727, ECO:0000269|PubMed:15364919, ECO:0000269|PubMed:16252004, ECO:0000269|PubMed:16356855, ECO:0000269|PubMed:16709830, ECO:0000269|PubMed:19549985, ECO:0000269|PubMed:8657160}. | 15.11 | |||
| dfaKPCZ | Protein kinase C zeta type | 5 | 168 | 87.46 | 91.53 | ND | 0.36 | 0.68 | 0.9 | Mammalian | Expressed in brain, and to a lesser extent in lung, kidney and testis. | Kinase | Not Available | Calcium- and diacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5-MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF-kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Necessary and sufficient for LTP maintenance in hippocampal CA1 pyramidal cells. In vein endothelial cells treated with the oxidant peroxynitrite, phosphorylates STK11 leading to nuclear export of STK11, subsequent inhibition of PI3K/Akt signaling, and increased apoptosis. Phosphorylates VAMP2 in vitro (PubMed:17313651). {ECO:0000269|PubMed:11035106, ECO:0000269|PubMed:12162751, ECO:0000269|PubMed:15084291, ECO:0000269|PubMed:15324659, ECO:0000269|PubMed:17313651, ECO:0000269|PubMed:18321849, ECO:0000269|PubMed:9447975}. | 16.04 | |||
| dfaKPYM | Pyruvate kinase PKM | 7 | 1131 | 85.24 | 83.60 | ND | 0.61 | 0.58 | 0.4 | Mammalian | Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. {ECO:0000269|PubMed:18191611}. | Enzyme | Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival. {ECO:0000269|PubMed:17308100, ECO:0000269|PubMed:18191611, ECO:0000269|PubMed:21620138}. | 15.11 | ||||
| dfaKS6A1 | Ribosomal protein S6 kinase alpha-1 | 7 | 129 | 94.58 | 93.82 | ND | 0.76 | 0.82 | 0.4 | Mammalian | Kinase | Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1, which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin- derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the pre-initiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro- apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Mediates induction of hepatocyte prolifration by TGFA through phosphorylation of CEBPB (By similarity). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. {ECO:0000250|UniProtKB:P18653, ECO:0000250|UniProtKB:Q63531, ECO:0000269|PubMed:10679322, ECO:0000269|PubMed:11684016, ECO:0000269|PubMed:12213813, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:15342917, ECO:0000269|PubMed:16213824, ECO:0000269|PubMed:16223362, ECO:0000269|PubMed:16763566, ECO:0000269|PubMed:17360704, ECO:0000269|PubMed:18722121, ECO:0000269|PubMed:9430688}. | 15.11 | |||||
| dfaKS6A3 | Ribosomal protein S6 kinase alpha-3 | 5 | 594 | 85.79 | 88.66 | ND | 0.58 | 0.56 | 0.5 | Mammalian | Expressed in many tissues, highest levels in skeletal muscle. | Kinase | Coffin-Lowry syndrome (CLS) [MIM:303600]: A X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders. {ECO:0000269|PubMed:10094187, ECO:0000269|PubMed:10528858, ECO:0000269|PubMed:14986828, ECO:0000269|PubMed:15214012, ECO:0000269|PubMed:8955270, ECO:0000269|PubMed:9837815}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mental retardation, X-linked 19 (MRX19) [MIM:300844]: A non-syndromic form of mild to moderate mental retardation. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation. {ECO:0000269|PubMed:10319851, ECO:0000269|PubMed:17100996}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR- independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro- apoptotic proteins BAD and DAPK1 and suppressing their pro- apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Phosphorylates DAPK1. {ECO:0000269|PubMed:10436156, ECO:0000269|PubMed:16213824, ECO:0000269|PubMed:16223362, ECO:0000269|PubMed:17360704, ECO:0000269|PubMed:18722121, ECO:0000269|PubMed:8250835, ECO:0000269|PubMed:9770464}. | 15.11 | |||
| dfaKS6A4 | Ribosomal protein S6 kinase alpha-4 | 5 | 85 | 92.83 | 94.28 | ND | 0.31 | 0.89 | 0.8 | Mammalian | Kinase | Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factor RELA, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide- stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors. {ECO:0000269|PubMed:11035004, ECO:0000269|PubMed:12773393, ECO:0000269|PubMed:9792677}. | 16.04 | |||||
| dfaKS6A5 | Ribosomal protein S6 kinase alpha-5 | 7 | 248 | 91.33 | 91.06 | ND | 0.47 | 0.73 | 0.8 | Mammalian | Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver. {ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9873047}. | Kinase | Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression. In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress. In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential. Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation. Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto- oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro- inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti- inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors. Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury. {ECO:0000269|PubMed:11909979, ECO:0000269|PubMed:12569367, ECO:0000269|PubMed:12628924, ECO:0000269|PubMed:12763138, ECO:0000269|PubMed:12773393, ECO:0000269|PubMed:15010469, ECO:0000269|PubMed:18511904, ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9873047}. | 16.04 | ||||
| dfaKS6A6 | Ribosomal protein S6 kinase alpha-6 | 9 | 65 | 89.19 | 87.53 | ND | 0.80 | 0.86 | 0.4 | Mammalian | Kinase | Constitutively active serine/threonine-protein kinase that exhibits growth-factor-independent kinase activity and that may participate in p53/TP53-dependent cell growth arrest signaling and play an inhibitory role during embryogenesis. {ECO:0000269|PubMed:15042092, ECO:0000269|PubMed:15632195}. | 16.04 | |||||
| dfaKS6B1 | Ribosomal protein S6 kinase beta-1 | 6 | 442 | 86.65 | 86.64 | ND | 0.49 | 0.61 | 0.6 | Mammalian | Widely expressed. {ECO:0000269|PubMed:9804755}. | Kinase | Cancer, unspecific
Solid tumors | Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the pre-initiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative feedback mechanism for the RPS6KB1 anti- apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1- 2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin. Phosphorylates and activates the pyrimidine biosynthesis enzyme CAD, downstream of MTOR. {ECO:0000269|PubMed:11500364, ECO:0000269|PubMed:12801526, ECO:0000269|PubMed:14673156, ECO:0000269|PubMed:15071500, ECO:0000269|PubMed:15341740, ECO:0000269|PubMed:16286006, ECO:0000269|PubMed:17052453, ECO:0000269|PubMed:17053147, ECO:0000269|PubMed:17936702, ECO:0000269|PubMed:18952604, ECO:0000269|PubMed:19085255, ECO:0000269|PubMed:19720745, ECO:0000269|PubMed:19935711, ECO:0000269|PubMed:19995915, ECO:0000269|PubMed:23429703}. | 15.11 | |||
| dfaKSYK | Tyrosine-protein kinase SYK | 1 | 582 | 92.11 | 87.61 | ND | 0.65 | 0.56 | 0.6 | Mammalian | Widely expressed in hematopoietic cells (at protein level). Within the B-cells compartment it is for instance expressed for pro-B-cells to plasma cells. {ECO:0000269|PubMed:8163536}. | Kinase | Allergic Reaction
Asthma Inflammatory diseases Lymphoma, Non-Hodgkin's Obstructive airway disease Rheumatoid arthritis Thrombocytopenia | Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine- phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T- cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. {ECO:0000269|PubMed:12387735, ECO:0000269|PubMed:12456653, ECO:0000269|PubMed:15388330, ECO:0000269|PubMed:19909739, ECO:0000269|PubMed:8657103, ECO:0000269|PubMed:9535867}. | 15.11 | |||
| dfaLATS1 | Serine/threonine-protein kinase LATS1 | 2 | 64 | 99.82 | 96.84 | ND | 0.96 | 0.93 | 0.1 | Mammalian | Expressed in all adult tissues examined except for lung and kidney. {ECO:0000269|PubMed:10518011}. | Kinase | Negative regulator of YAP1 in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Acts as a tumor suppressor which plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G1 tetraploidy checkpoint. Negatively regulates G2/M transition by down-regulating CDK1 kinase activity. Involved in the control of p53 expression. Affects cytokinesis by regulating actin polymerization through negative modulation of LIMK1. May also play a role in endocrine function. {ECO:0000269|PubMed:10518011, ECO:0000269|PubMed:10831611, ECO:0000269|PubMed:15122335, ECO:0000269|PubMed:15220930, ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:19927127}. | 16.04 | ||||
| dfaLCAP | Leucyl-cystinyl aminopeptidase | 3 | 68 | 97.10 | 99.58 | ND | 0.85 | 0.80 | 0.5 | Mammalian | Highly expressed in placenta, heart, kidney and small intestine. Detected at lower levels in neuronal cells in the brain, in skeletal muscle, spleen, liver, testes and colon. {ECO:0000269|PubMed:11389728, ECO:0000269|PubMed:8550619, ECO:0000269|PubMed:9177475}. | Protease | Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain. {ECO:0000269|PubMed:11389728, ECO:0000269|PubMed:11707427, ECO:0000269|PubMed:1731608}. | 16.04 | ||||
| dfaLCK | Tyrosine-protein kinase Lck | 6 | 1767 | 94.02 | 93.67 | ND | 0.59 | 0.68 | 0.7 | Mammalian | Expressed specifically in lymphoid cells. | Kinase | Note=A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB. Immunodeficiency 22 (IMD22) [MIM:615758]: A primary immunodeficiency characterized by T-cell dysfunction. Affected individuals present with lymphopenia, recurrent infections, severe diarrhea, and failure to thrive. {ECO:0000269|PubMed:22985903}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T- cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. {ECO:0000269|PubMed:16339550, ECO:0000269|PubMed:16709819, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20851766, ECO:0000269|PubMed:21269457, ECO:0000269|PubMed:22080863}. | Tyrosine-protein kinase Lck Inhibitor: Nintedanib Tyrosine-protein kinase Lck inhibitor: Ponatinib Tyrosine-protein kinase Lck multitarget: Dasatinib | 15.11 | ||
| dfaLDHA | L-lactate dehydrogenase A chain | 5 | 97 | 99.58 | 90.76 | ND | 0.53 | 0.79 | 0.6 | Mammalian | Enzyme | Glycogen storage disease 11 (GSD11) [MIM:612933]: A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue. {ECO:0000269|PubMed:2334430}. Note=The disease is caused by mutations affecting the gene represented in this entry. | 15.11 | |||||
| dfaLDHB | L-lactate dehydrogenase B chain | 6 | 48 | 99.16 | 99.52 | ND | 0.65 | 0.73 | 0.5 | Mammalian | Enzyme | Lactate dehydrogenase B deficiency (LDHBD) [MIM:614128]: A condition with no deleterious effects on health. LDHBD is of interest to laboratory medicine mainly because it can cause misdiagnosis in those disorders in which elevation of serum LDH is expected. {ECO:0000269|PubMed:10211631, ECO:0000269|PubMed:11509017, ECO:0000269|PubMed:1587525, ECO:0000269|PubMed:2334429, ECO:0000269|PubMed:8314553, ECO:0000269|PubMed:8462975, ECO:0000269|PubMed:8611651, ECO:0000269|PubMed:9929983, ECO:0000269|Ref.19}. Note=The disease is caused by mutations affecting the gene represented in this entry. | 16.04 | |||||
| dfaLGUL | Lactoylglutathione lyase | 3 | 63 | 92.85 | 90.22 | ND | 0.70 | 0.75 | 0.5 | Mammalian | Enzyme | Tumors | Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione. Involved in the regulation of TNF-induced transcriptional activity of NF- kappa-B. Required for normal osteoclastogenesis. {ECO:0000269|PubMed:19199007, ECO:0000269|PubMed:23122816, ECO:0000269|PubMed:9705294}. | Lactoylglutathione lyase : Glutathione Lactoylglutathione lyase inhibitor: Indomethacin | 15.11 | |||
| dfaLIMK1 | LIM domain kinase 1 | 7 | 437 | 87.27 | 82.90 | ND | 0.52 | 0.72 | 0.5 | Mammalian | Highest expression in both adult and fetal nervous system. Detected ubiquitously throughout the different regions of adult brain, with highest levels in the cerebral cortex. Expressed to a lesser extent in heart and skeletal muscle. | Kinase | Note=LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. | Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin- 2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes. Required for atypical chemokine receptor ACKR2-induced phosphorylation of cofilin (CFL1). {ECO:0000269|PubMed:10196227, ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:11832213, ECO:0000269|PubMed:12807904, ECO:0000269|PubMed:15660133, ECO:0000269|PubMed:16230460, ECO:0000269|PubMed:18028908, ECO:0000269|PubMed:23633677}. | LIM domain kinase 1 inhibitor: Dabrafenib | 15.11 | ||
| dfaLIMK2 | LIM domain kinase 2 | 2 | 120 | 89.47 | 92.75 | ND | 0.89 | 0.83 | 0.4 | Mammalian | Highest expression in the placenta; moderate level in liver, lung, kidney, and pancreas. LIMK2a is found to be more abundant then LIMK2b in liver, colon, stomach, and spleen, while in brain, kidney, and placenta LIMK2b is the dominant form. In adult lung, both LIMK2a and LIMK2b is nearly equally observed. {ECO:0000269|PubMed:8954941}. | Kinase | Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro. {ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:11018042}. | 15.11 | ||||
| dfaLIPL | Lipoprotein lipase | 2 | 56 | 99.63 | 85.95 | ND | 0.37 | 0.75 | 0.8 | Mammalian | Enzyme | Lipoprotein lipase deficiency (LPL deficiency) [MIM:238600]: Recessive disorder usually manifesting in childhood. On a normal diet, patients often present with abdominal pain, hepatosplenomegaly, lipemia retinalis, eruptive xanthomata, and massive hypertriglyceridemia, sometimes complicated with acute pancreatitis. {ECO:0000269|PubMed:10660334, ECO:0000269|PubMed:10787434, ECO:0000269|PubMed:11068186, ECO:0000269|PubMed:11099402, ECO:0000269|PubMed:11134145, ECO:0000269|PubMed:11441134, ECO:0000269|PubMed:12204001, ECO:0000269|PubMed:12641539, ECO:0000269|PubMed:12966036, ECO:0000269|PubMed:1400331, ECO:0000269|PubMed:1479292, ECO:0000269|PubMed:14984478, ECO:0000269|PubMed:15185149, ECO:0000269|PubMed:1521525, ECO:0000269|PubMed:15256764, ECO:0000269|PubMed:15877202, ECO:0000269|PubMed:1598907, ECO:0000269|PubMed:1619366, ECO:0000269|PubMed:1639392, ECO:0000269|PubMed:1674945, ECO:0000269|PubMed:1702428, ECO:0000269|PubMed:1730727, ECO:0000269|PubMed:1752947, ECO:0000269|PubMed:1907278, ECO:0000269|PubMed:1969408, ECO:0000269|PubMed:1975597, ECO:0000269|PubMed:2010533, ECO:0000269|PubMed:2038366, ECO:0000269|PubMed:2110364, ECO:0000269|PubMed:2121025, ECO:0000269|PubMed:7647785, ECO:0000269|PubMed:7806969, ECO:0000269|PubMed:7906986, ECO:0000269|PubMed:7912254, ECO:0000269|PubMed:7999071, ECO:0000269|PubMed:8077845, ECO:0000269|PubMed:8096693, ECO:0000269|PubMed:8135797, ECO:0000269|PubMed:8288243, ECO:0000269|PubMed:8301230, ECO:0000269|PubMed:8325986, ECO:0000269|PubMed:8486765, ECO:0000269|PubMed:8728326, ECO:0000269|PubMed:8778602, ECO:0000269|PubMed:8858123, ECO:0000269|PubMed:8872057, ECO:0000269|PubMed:8956048, ECO:0000269|PubMed:8956052, ECO:0000269|PubMed:9279761, ECO:0000269|PubMed:9298816, ECO:0000269|PubMed:9498099, ECO:0000269|PubMed:9662394, ECO:0000269|PubMed:9714430, ECO:0000269|PubMed:9719626}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The primary function of this lipase is the hydrolysis of triglycerides of circulating chylomicrons and very low density lipoproteins (VLDL). Binding to heparin sulfate proteogylcans at the cell surface is vital to the function. The apolipoprotein, APOC2, acts as a coactivator of LPL activity in the presence of lipids on the luminal surface of vascular endothelium (By similarity). {ECO:0000250}. | Lipoprotein lipase : AST-120 Lipoprotein lipase inhibitor: Tyloxapol | 16.04 | |||
| dfaLIPS | Hormone-sensitive lipase | 3 | 159 | 92.89 | 90.04 | ND | 0.48 | 0.58 | 0.8 | Mammalian | Enzyme | Lipodystrophy, familial partial, 6 (FPLD6) [MIM:615980]: A form of lipodystrophy characterized by abnormal subcutaneous fat distribution. Affected individuals have increased visceral fat, impaired lipolysis, dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. Some patients manifest muscular dystrophy. {ECO:0000269|PubMed:24848981}. Note=The disease is caused by mutations affecting the gene represented in this entry. | In adipose tissue and heart, it primarily hydrolyzes stored triglycerides to free fatty acids, while in steroidogenic tissues, it principally converts cholesteryl esters to free cholesterol for steroid hormone production. | 16.04 | ||||
| dfaLKHA4 | Leukotriene A-4 hydrolase | 3 | 480 | 97.87 | 96.63 | ND | 0.56 | 0.55 | 0.6 | Mammalian | Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts. | Protease | Inflammation
Leukemia, Myeloid Myocardial infarction Oesophageal cancer Solid tumors | Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity. {ECO:0000269|PubMed:11917124, ECO:0000269|PubMed:12207002, ECO:0000269|PubMed:15078870, ECO:0000269|PubMed:18804029, ECO:0000269|PubMed:1897988, ECO:0000269|PubMed:1975494, ECO:0000269|PubMed:2244921}. | 15.11 | |||
| dfaLMBL3 | Lethal(3)malignant brain tumor-like protein 3 | 1 | 93 | 96.34 | 97.29 | ND | 0.83 | 0.74 | 0.4 | Mammalian | Reader | Putative Polycomb group (PcG) protein. PcG proteins maintain the transcriptionally repressive state of genes, probably via a modification of chromatin, rendering it heritably changed in its expressibility. Required for normal maturation of myeloid progenitor cells (By similarity). {ECO:0000250}. | 15.11 | |||||
| dfaLOX12 | Arachidonate 12-lipoxygenase, 12S-type | 7 | 422 | 90.70 | 89.45 | ND | 0.55 | 0.63 | 0.4 | Mammalian | Expressed in vascular smooth muscle cells. {ECO:0000269|PubMed:23578768}. | Enzyme | Esophageal cancer (ESCR) [MIM:133239]: A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage. {ECO:0000269|PubMed:17460548}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Gln at position 261 may confer interindividual susceptibility to esophageal cancer (PubMed:17460548). {ECO:0000269|PubMed:17460548}. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:17151091}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Gln at position 261 may confer interindividual susceptibility to colorectal cancer (PubMed:17460548). {ECO:0000269|PubMed:17460548}. | Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators. Mainly converts arachidonic acid to (12S)- hydroperoxyeicosatetraenoic acid/(12S)-HPETE but can also metabolize linoleic acid. Has a dual activity since it also converts leukotriene A4/LTA4 into both the bioactive lipoxin A4/LXA4 and lipoxin B4/LXB4. Through the production of specific bioactive lipids like (12S)-HPETE it regulates different biological processes including platelet activation. It also probably positively regulates angiogenesis through regulation of the expression of the vascular endothelial growth factor. Plays a role in apoptotic process, promoting the survival of vascular smooth muscle cells for instance. May also play a role in the control of cell migration and proliferation. {ECO:0000269|PubMed:16638750, ECO:0000269|PubMed:22237009, ECO:0000269|PubMed:23578768, ECO:0000269|PubMed:8250832, ECO:0000269|PubMed:9751607}. | 16.04 | |||
| dfaLOX5 | Arachidonate 5-lipoxygenase | 3 | 2387 | 92.81 | 82.52 | ND | 0.46 | 0.57 | 0.6 | Mammalian | Oxidoreductase | Not Available | Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes. {ECO:0000269|PubMed:21233389}. | Arachidonate 5-lipoxygenase : Vitamin E Arachidonate 5-lipoxygenase inhibitor: Aminosalicylic Acid, Balsalazide, Diethylcarbamazine, Masoprocol, Meclofenamic acid, Mesalazine, Minocycline, Sulfasalazine, Zileuton Arachidonate 5-lipoxygenase other/unknown: Montelukast Arachidonate 5-lipoxygenase potentiator: Diclofenac | 16.04 | |||
| dfaLPAR1 | Lysophosphatidic acid receptor 1 | 4 | 132 | 96.51 | 97.92 | ND | 0.78 | 0.59 | 0.4 | Mammalian | Expressed in many adult organs, including brain, heart, colon, small intestine, placenta, prostate, ovary, pancreas, testes, spleen, skeletal muscle, and kidney. Little or no expression in liver, lung, thymus, or peripheral blood leukocytes (PubMed:9070858). Detected in lung fibroblasts from bronchoalveolar fluid from patients with idiopathic pulmonary fibrosis (PubMed:18066075). Detected in bone marrow-derived mesenchymal stem cells (PubMed:19733258). {ECO:0000269|PubMed:18066075, ECO:0000269|PubMed:19733258, ECO:0000269|PubMed:9070858}. | Family A G protein-coupled receptor | Multiple sclerosis | Receptor for lysophosphatidic acid (LPA) (PubMed:9070858, PubMed:19306925, PubMed:25025571, PubMed:26091040). Plays a role in the reorganization of the actin cytoskeleton, cell migration, differentiation and proliferation, and thereby contributes to the responses to tissue damage and infectious agents. Activates downstream signaling cascades via the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. Signaling inhibits adenylyl cyclase activity and decreases cellular cAMP levels (PubMed:26091040). Signaling triggers an increase of cytoplasmic Ca(2+) levels (PubMed:19656035, PubMed:19733258, PubMed:26091040). Activates RALA; this leads to the activation of phospholipase C (PLC) and the formation of inositol 1,4,5-trisphosphate (PubMed:19306925). Signaling mediates activation of down-stream MAP kinases (By similarity). Contributes to the regulation of cell shape. Promotes Rho-dependent reorganization of the actin cytoskeleton in neuronal cells and neurite retraction (PubMed:26091040). Promotes the activation of Rho and the formation of actin stress fibers (PubMed:26091040). Promotes formation of lamellipodia at the leading edge of migrating cells via activation of RAC1 (By similarity). Through its function as lysophosphatidic acid receptor, plays a role in chemotaxis and cell migration, including responses to injury and wounding (PubMed:18066075, PubMed:19656035, PubMed:19733258). Plays a role in triggering inflammation in response to bacterial lipopolysaccharide (LPS) via its interaction with CD14. Promotes cell proliferation in response to lysophosphatidic acid. Required for normal skeleton development. May play a role in osteoblast differentiation. Required for normal brain development. Required for normal proliferation, survival and maturation of newly formed neurons in the adult dentate gyrus. Plays a role in pain perception and in the initiation of neuropathic pain (By similarity). {ECO:0000250|UniProtKB:P61793, ECO:0000269|PubMed:18066075, ECO:0000269|PubMed:19306925, ECO:0000269|PubMed:19656035, ECO:0000269|PubMed:19733258, ECO:0000269|PubMed:25025571, ECO:0000269|PubMed:26091040, ECO:0000269|PubMed:9070858, ECO:0000305|PubMed:11093753, ECO:0000305|PubMed:9069262}. | 15.11 | |||
| dfaLPAR2 | Lysophosphatidic acid receptor 2 | 3 | 52 | 99.10 | 90.58 | ND | 0.71 | 0.83 | 0.6 | Mammalian | Expressed most abundantly in testes and peripheral blood leukocytes with less expression in pancreas, spleen, thymus and prostate. Little or no expression in heart, brain, placenta, lung, liver, skeletal muscle, kidney, ovary, small intestine, or colon. | Family A G protein-coupled receptor | Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. Seems to be coupled to the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. Plays a key role in phospholipase C-beta (PLC-beta) signaling pathway. Stimulates phospholipase C (PLC) activity in a manner that is independent of RALA activation. {ECO:0000269|PubMed:15143197, ECO:0000269|PubMed:19306925}. | 16.04 | ||||
| dfaLPAR3 | Lysophosphatidic acid receptor 3 | 4 | 44 | 99.46 | 99.74 | ND | 0.65 | 0.89 | 0.6 | Mammalian | Most abundantly expressed in prostate, testes, pancreas, and heart, with moderate levels in lung and ovary. No detectable expression in brain, placenta, liver, skeletal muscle, kidney, spleen, thymus, small intestine, colon, or peripheral blood leukocytes. | Family A G protein-coupled receptor | Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. May play a role in the development of ovarian cancer. Seems to be coupled to the G(i)/G(o) and G(q) families of heteromeric G proteins. | 16.04 | ||||
| dfaLT4R1 | Leukotriene B4 receptor 1 | 3 | 212 | 93.38 | 91.42 | ND | 0.56 | 0.56 | 0.7 | Mammalian | Expressed at highest levels in heart, skeletal muscle and at lower levels in brain and liver. High level of expression in lymphoid tissues. | Family A G protein-coupled receptor | Adverse Effects, Chemotherapy
Asthma Cancer Chronic Obstructive Pulmonary Disease (COPD) Cystic Fibrosis Immunological disorders Inflammation Renal Cell Carcinoma Rheumatoid arthritis | Receptor for extracellular ATP > UTP and ADP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. May be the cardiac P2Y receptor involved in the regulation of cardiac muscle contraction through modulation of L-type calcium currents. Is a receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response. | 16.04 | |||
| dfaLTK | Leukocyte tyrosine kinase receptor | 7 | 220 | 82.61 | 83.32 | ND | 0.69 | 0.74 | 0.5 | Mammalian | Expressed in non-hematopoietic cell lines and T- and B-cell lines. {ECO:0000269|PubMed:2156206}. | Kinase | Note=Genetic variations in LTK that cause up-regulation of the PI3K pathway may possibly contribute to susceptibility to abnormal proliferation of self-reactive B-cells and, therefore, to systemic lupus erythematosus (SLE). SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue, thought to represent a failure of the regulatory mechanisms of the autoimmune system. | Orphan receptor with a tyrosine-protein kinase activity. The exact function of this protein is not known. Studies with chimeric proteins (replacing its extracellular region with that of several known growth factor receptors, such as EGFR and CSFIR) demonstrate its ability to promote growth and specifically neurite outgrowth, and cell survival. Signaling appears to involve the PI3 kinase pathway. Involved in regulation of the secretory pathway involving endoplasmic reticulum (ER) export sites (ERESs) and ER to Golgi transport. {ECO:0000269|PubMed:20548102}. | 16.04 | |||
| dfaLYAM2 | E-selectin | 1 | 141 | 97.72 | 94.94 | ND | 0.49 | 0.74 | 0.9 | Mammalian | Adhesion | Asthma
Atopic Dermatitis Chronic Obstructive Pulmonary Disease (COPD) Inflammatory skin disorder Ischemic stroke Psoriasis and Psoriatic Disorders | Cell-surface glycoprotein having a role in immunoadhesion. Mediates in the adhesion of blood neutrophils in cytokine-activated endothelium through interaction with PSGL1/SELPLG. May have a role in capillary morphogenesis. {ECO:0000269|PubMed:1689848}. | E-selectin inhibitor: Carvedilol | 16.04 | |||
| dfaLYAM3 | P-selectin | 3 | 63 | 99.68 | 92.71 | ND | 0.25 | 0.64 | 0.4 | Mammalian | Stored in the alpha-granules of platelets and Weibel-Palade bodies of endothelial cells. Upon cell activation by agonists, P-selectin is transported rapidly to the cell surface. | Adhesion | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:14681304}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Ca(2+)-dependent receptor for myeloid cells that binds to carbohydrates on neutrophils and monocytes. Mediates the interaction of activated endothelial cells or platelets with leukocytes. The ligand recognized is sialyl-Lewis X. Mediates rapid rolling of leukocyte rolling over vascular surfaces during the initial steps in inflammation through interaction with PSGL1. {ECO:0000269|PubMed:7585950}. | P-selectin inhibitor: Dalteparin, Heparin, Nadroparin | 16.04 | ||
| dfaLYN | Tyrosine-protein kinase Lyn | 6 | 458 | 93.88 | 96.53 | ND | 0.53 | 0.70 | 0.6 | Mammalian | Detected in monocytes (at protein level). Detected in placenta, and in fetal brain, lung, liver and kidney. Widely expressed in a variety of organs, tissues, and cell types such as epidermoid, hematopoietic, and neuronal cells. Expressed in primary neuroblastoma tumors. {ECO:0000269|PubMed:3561390, ECO:0000269|PubMed:8064233}. | Kinase | Note=Constitutively phosphorylated and activated in cells from a number of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) patients. Mediates phosphorylation of the BCR-ABL fusion protein. Abnormally elevated expression levels or activation of LYN signaling may play a role in survival and proliferation of some types of cancer cells. | Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down- regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down- regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, PTK2B/PYK2, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3- kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr- 72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. {ECO:0000269|PubMed:10574931, ECO:0000269|PubMed:10748115, ECO:0000269|PubMed:10891478, ECO:0000269|PubMed:11435302, ECO:0000269|PubMed:11517336, ECO:0000269|PubMed:11825908, ECO:0000269|PubMed:14726379, ECO:0000269|PubMed:15795233, ECO:0000269|PubMed:16467205, ECO:0000269|PubMed:17640867, ECO:0000269|PubMed:17977829, ECO:0000269|PubMed:18056483, ECO:0000269|PubMed:18070987, ECO:0000269|PubMed:18235045, ECO:0000269|PubMed:18577747, ECO:0000269|PubMed:18802065, ECO:0000269|PubMed:19290919, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:7687428}. | Tyrosine-protein kinase Lyn : Bosutinib Tyrosine-protein kinase Lyn Inhibitor: Nintedanib Tyrosine-protein kinase Lyn inhibitor: Ponatinib | 15.11 | ||
| dfaM3K10 | Mitogen-activated protein kinase kinase kinase 10 | 6 | 87 | 93.24 | 95.17 | ND | 0.68 | 0.86 | 0.5 | Mammalian | Expressed in brain and skeletal muscle. | Kinase | Cancer, unspecific | Activates the JUN N-terminal pathway. {ECO:0000250}. | 16.04 | |||
| dfaM3K11 | Mitogen-activated protein kinase kinase kinase 11 | 2 | 110 | 91.73 | 97.40 | ND | 0.65 | 0.82 | 0.6 | Mammalian | Expressed in a wide variety of normal and neoplastic tissues including fetal lung, liver, heart and kidney, and adult lung, liver, heart, kidney, placenta, skeletal muscle, pancreas and brain. {ECO:0000269|PubMed:8183572, ECO:0000269|PubMed:8195146}. | Kinase | Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle. {ECO:0000269|PubMed:12529434, ECO:0000269|PubMed:15258589, ECO:0000269|PubMed:8195146, ECO:0000269|PubMed:9003778}. | 16.04 | ||||
| dfaM3K12 | Mitogen-activated protein kinase kinase kinase 12 | 4 | 58 | 99.77 | 96.03 | ND | 0.58 | 0.01 | 0.5 | Mammalian | Highly expressed in brain and kidney. | Enzyme | May be an activator of the JNK/SAPK pathway. Phosphorylates beta-casein, histone 1 and myelin basic protein in vitro. | 16.04 | ||||
| dfaM3K13 | Mitogen-activated protein kinase kinase kinase 13 | 5 | 59 | 99.90 | 98.32 | ND | 0.92 | 0.96 | 0.2 | Mammalian | Expressed in the adult brain, liver, placenta and pancreas, with expression strongest in the pancreas. {ECO:0000269|PubMed:9353328}. | Kinase | Activates the JUN N-terminal pathway through activation of the MAP kinase kinase MAP2K7. Acts synergistically with PRDX3 to regulate the activation of NF-kappa-B in the cytosol. This activation is kinase-dependent and involves activating the IKK complex, the IKBKB-containing complex that phosphorylates inhibitors of NF-kappa-B. {ECO:0000269|PubMed:11726277, ECO:0000269|PubMed:12492477, ECO:0000269|PubMed:9353328}. | 16.04 | ||||
| dfaM3K19 | Mitogen-activated protein kinase kinase kinase 19 | 5 | 61 | 82.56 | 89.62 | ND | 0.66 | 0.92 | 0.6 | Mammalian | Kinase | 16.04 | ||||||
| dfaM3K2 | Mitogen-activated protein kinase kinase kinase 2 | 5 | 60 | 89.40 | 91.84 | ND | 0.83 | 0.98 | 0.3 | Mammalian | Kinase | Not Available | Component of a protein kinase signal transduction cascade. Regulates the JNK and ERK5 pathways by phosphorylating and activating MAP2K5 and MAP2K7 (By similarity). Plays a role in caveolae kiss-and-run dynamics. {ECO:0000250, ECO:0000269|PubMed:10713157, ECO:0000269|PubMed:16001074}. | Mitogen-activated protein kinase kinase kinase 2 inhibitor: Bosutinib | 16.04 | |||
| dfaM3K3 | Mitogen-activated protein kinase kinase kinase 3 | 7 | 60 | 99.32 | 97.90 | ND | 0.68 | 0.99 | 0.4 | Mammalian | Kinase | Not Available | Component of a protein kinase signal transduction cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional regulators. {ECO:0000269|PubMed:12912994, ECO:0000269|PubMed:14661019, ECO:0000269|PubMed:14743216, ECO:0000269|PubMed:9006902}. | 16.04 | ||||
| dfaM3K4 | Mitogen-activated protein kinase kinase kinase 4 | 2 | 64 | 86.23 | 95.40 | ND | 0.34 | 0.93 | 0.4 | Mammalian | Expressed at high levels in heart, placenta, skeletal muscle and pancreas, and at lower levels in other tissues. {ECO:0000269|PubMed:9305639}. | Kinase | Breast cancer
Melanoma Ovarian cancer Pancreatic cancer Prostate cancer | Component of a protein kinase signal transduction cascade. Activates the CSBP2, P38 and JNK MAPK pathways, but not the ERK pathway. Specifically phosphorylates and activates MAP2K4 and MAP2K6. {ECO:0000269|PubMed:12052864, ECO:0000269|PubMed:9305639}. | 16.04 | |||
| dfaM3K5 | Mitogen-activated protein kinase kinase kinase 5 | 3 | 130 | 94.10 | 97.62 | ND | 0.91 | 0.82 | 0.3 | Mammalian | Abundantly expressed in heart and pancreas. | Kinase | Cardiac diseases
Malignant fibrous histiocytomas | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). {ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666, ECO:0000269|PubMed:10849426, ECO:0000269|PubMed:11029458, ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11689443, ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12697749, ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544, ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:17220297, ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:8940179, ECO:0000269|PubMed:8974401, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}. | 15.11 | |||
| dfaM3K7 | Mitogen-activated protein kinase kinase kinase 7 | 4 | 107 | 92.35 | 96.34 | ND | 0.65 | 0.82 | 0.5 | Mammalian | Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form. {ECO:0000269|PubMed:11118615}. | Kinase | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2- induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. {ECO:0000269|PubMed:10094049, ECO:0000269|PubMed:11460167, ECO:0000269|PubMed:12589052, ECO:0000269|PubMed:16845370, ECO:0000269|PubMed:16893890, ECO:0000269|PubMed:21512573, ECO:0000269|PubMed:8663074, ECO:0000269|PubMed:9079627}. | 15.11 | ||||
| dfaM3K8 | Mitogen-activated protein kinase kinase kinase 8 | 3 | 224 | 99.58 | 99.56 | ND | 0.67 | 0.50 | 0.6 | Mammalian | Expressed in several normal tissues and human tumor-derived cell lines. | Kinase | Not Available | Required for lipopolysaccharide (LPS)-induced, TLR4- mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF- alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B- cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant. {ECO:0000269|PubMed:11342626, ECO:0000269|PubMed:12667451, ECO:0000269|PubMed:15169888, ECO:0000269|PubMed:16371247, ECO:0000269|PubMed:1833717, ECO:0000269|PubMed:19001140, ECO:0000269|PubMed:19754427, ECO:0000269|PubMed:19808894}. | 15.11 | |||
| dfaM3K9 | Mitogen-activated protein kinase kinase kinase 9 | 3 | 117 | 98.13 | 95.72 | ND | 0.71 | 0.79 | 0.5 | Mammalian | Expressed in epithelial tumor cell lines of colonic, breast and esophageal origin. {ECO:0000269|PubMed:8477742}. | Kinase | Note=May play a role in esophageal cancer susceptibility and/or development. | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Plays also a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. {ECO:0000269|PubMed:11416147, ECO:0000269|PubMed:15610029}. | 15.11 | |||
| dfaM4K1 | Mitogen-activated protein kinase kinase kinase kinase 1 | 7 | 64 | 99.31 | 97.12 | ND | 0.29 | 0.94 | 0.9 | Mammalian | Expressed primarily in hematopoietic organs, including bone marrow, spleen and thymus. Also expressed at very low levels in lung, kidney, mammary glands and small intestine. {ECO:0000269|PubMed:8824585}. | Kinase | Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate. {ECO:0000269|PubMed:24362026, ECO:0000269|PubMed:8824585}. | 16.04 | ||||
| dfaM4K2 | Mitogen-activated protein kinase kinase kinase kinase 2 | 4 | 426 | 89.72 | 92.29 | ND | 0.33 | 0.50 | 0.6 | Mammalian | Highly expressed in germinal center but not mantle zone B-cells. Also expressed in lung, brain and placenta and at lower levels in other tissues examined. {ECO:0000269|PubMed:7515885}. | Kinase | Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extend of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion. {ECO:0000269|PubMed:11784851, ECO:0000269|PubMed:15456887, ECO:0000269|PubMed:17584736, ECO:0000269|PubMed:7477268, ECO:0000269|PubMed:7515885, ECO:0000269|PubMed:9712898}. | 16.04 | ||||
| dfaM4K3 | Mitogen-activated protein kinase kinase kinase kinase 3 | 4 | 66 | 98.98 | 95.84 | ND | 0.59 | 0.02 | 0.5 | Mammalian | Ubiquitously expressed in all tissues examined, with high levels in heart, brain, placenta, skeletal muscle, kidney and pancreas and lower levels in lung and liver. {ECO:0000269|PubMed:9275185}. | Kinase | May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. {ECO:0000269|PubMed:9275185}. | 16.04 | ||||
| dfaM4K4 | Mitogen-activated protein kinase kinase kinase kinase 4 | 6 | 596 | 88.02 | 92.62 | ND | 0.47 | 0.60 | 0.5 | Mammalian | Appears to be ubiquitous. Expressed in all tissue types examined. Isoform 5 appears to be more abundant in the brain. Isoform 4 is predominant in the liver, skeletal muscle and placenta. {ECO:0000269|PubMed:9890973}. | Kinase | Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322. {ECO:0000269|PubMed:21690388, ECO:0000269|PubMed:9890973}. | 15.11 | ||||
| dfaMAP11 | Methionine aminopeptidase 1 {ECO:0000255|HAMAP-Rule:MF_03174} | 4 | 187 | 97.03 | 91.65 | ND | 0.65 | 0.79 | 0.6 | Mammalian | Protease | Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Required for normal progression through the cell cycle. {ECO:0000255|HAMAP- Rule:MF_03174, ECO:0000269|PubMed:16274222, ECO:0000269|PubMed:17114291}. | 15.11 | |||||
| dfaMAP2 | Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} | 6 | 392 | 96.41 | 95.90 | ND | 0.80 | 0.69 | 0.6 | Mammalian | Protease | Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N- terminal Met-Val and Met-Thr sequences in vivo. Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis. | Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} inhibitor: Nitroxoline Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} product of: L-Methionine | 15.11 | ||||
| dfaMAPK2 | MAP kinase-activated protein kinase 2 | 4 | 909 | 96.42 | 95.45 | ND | 0.76 | 0.00 | 0.6 | Mammalian | Expressed in all tissues examined. | Kinase | Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, ELAVL1, HNRNPA0, HSF1, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat- shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilize GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:11844797, ECO:0000269|PubMed:12456657, ECO:0000269|PubMed:12565831, ECO:0000269|PubMed:14499342, ECO:0000269|PubMed:14517288, ECO:0000269|PubMed:15014438, ECO:0000269|PubMed:15629715, ECO:0000269|PubMed:16278218, ECO:0000269|PubMed:16456544, ECO:0000269|PubMed:17481585, ECO:0000269|PubMed:18021073, ECO:0000269|PubMed:20932473, ECO:0000269|PubMed:8093612, ECO:0000269|PubMed:8280084, ECO:0000269|PubMed:8774846}. | 15.11 | ||||
| dfaMAPK3 | MAP kinase-activated protein kinase 3 | 4 | 45 | 80.42 | 80.98 | ND | 0.01 | 0.87 | 0.4 | Mammalian | Widely expressed, with a higher expression level observed in heart and skeletal muscle. No expression in brain. {ECO:0000269|PubMed:8622688, ECO:0000269|PubMed:8626550}. | Kinase | Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38- alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression. {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:15563468, ECO:0000269|PubMed:18021073, ECO:0000269|PubMed:20599781, ECO:0000269|PubMed:8626550, ECO:0000269|PubMed:8774846}. | 16.04 | ||||
| dfaMAPK5 | MAP kinase-activated protein kinase 5 | 6 | 141 | 82.24 | 89.31 | ND | 0.80 | 0.91 | 0.4 | Mammalian | Expressed ubiquitously. {ECO:0000269|PubMed:9628874}. | Kinase | Tumor suppressor serine/threonine-protein kinase involved in mTORC1 signaling and post-transcriptional regulation. Phosphorylates FOXO3, ERK3/MAPK6, ERK4/MAPK4, HSP27/HSPB1, p53/TP53 and RHEB. Acts as a tumor suppressor by mediating Ras- induced senescence and phosphorylating p53/TP53. Involved in post- transcriptional regulation of MYC by mediating phosphorylation of FOXO3: phosphorylation of FOXO3 leads to promote nuclear localization of FOXO3, enabling expression of miR-34b and miR-34c, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent MYC translation. Acts as a negative regulator of mTORC1 signaling by mediating phosphorylation and inhibition of RHEB. Part of the atypical MAPK signaling via its interaction with ERK3/MAPK6 or ERK4/MAPK4: the precise role of the complex formed with ERK3/MAPK6 or ERK4/MAPK4 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPK (ERK3/MAPK6 or ERK4/MAPK4), ERK3/MAPK6 (or ERK4/MAPK4) is phosphorylated and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6 (or ERK4/MAPK4). Mediates phosphorylation of HSP27/HSPB1 in response to PKA/PRKACA stimulation, inducing F-actin rearrangement. {ECO:0000269|PubMed:17254968, ECO:0000269|PubMed:17728103, ECO:0000269|PubMed:19166925, ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:9628874}. | 16.04 | ||||
| dfaMARK1 | Serine/threonine-protein kinase MARK1 | 3 | 74 | 85.48 | 89.34 | ND | 0.90 | 0.82 | 0.2 | Mammalian | Highly expressed in heart, skeletal muscle, brain, fetal brain and fetal kidney. {ECO:0000269|PubMed:9108484}. | Kinase | Note=Genetic variations in MARK1 may be associated with susceptibility to autism. MARK1 is overexpressed in the prefrontal cortex of patients with autism and causes changes in the function of cortical dendrites. | Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2, MAP4 and MAPT/TAU. Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). {ECO:0000269|PubMed:11433294, ECO:0000269|PubMed:17573348}. | 16.04 | |||
| dfaMARK2 | Serine/threonine-protein kinase MARK2 | 5 | 281 | 86.63 | 88.63 | ND | 0.40 | 0.61 | 0.5 | Mammalian | High levels of expression in heart, brain, skeletal muscle and pancreas, lower levels observed in lung, liver and kidney. {ECO:0000269|PubMed:9730619}. | Kinase | Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates CRTC2/TORC2, DCX, HDAC7, KIF13B, MAP2, MAP4, MAPT/TAU, and RAB11FIP2. Plays a key role in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Regulates epithelial cell polarity by phosphorylating RAB11FIP2. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Regulates axogenesis by phosphorylating KIF13B, promoting interaction between KIF13B and 14-3-3 and inhibiting microtubule- dependent accumulation of KIF13B. Also required for neurite outgrowth and establishment of neuronal polarity. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Modulates the developmental decision to build a columnar versus a hepatic epithelial cell apparently by promoting a switch from a direct to a transcytotic mode of apical protein delivery. Essential for the asymmetric development of membrane domains of polarized epithelial cells. {ECO:0000269|PubMed:11433294, ECO:0000269|PubMed:12429843, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15158914, ECO:0000269|PubMed:15324659, ECO:0000269|PubMed:15365179, ECO:0000269|PubMed:16775013, ECO:0000269|PubMed:16980613, ECO:0000269|PubMed:18626018, ECO:0000269|PubMed:20194617}. | 16.04 | ||||
| dfaMARK3 | MAP/microtubule affinity-regulating kinase 3 | 4 | 304 | 89.77 | 91.62 | ND | 0.58 | 0.78 | 0.4 | Mammalian | Ubiquitous. | Kinase | Leukaemia
RCC | Involved in the specific phosphorylation of microtubule- associated proteins for tau, MAP2 and MAP4. Phosphorylates CDC25C on 'Ser-216'. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. {ECO:0000269|PubMed:16980613}. | 16.04 | |||
| dfaMARK4 | MAP/microtubule affinity-regulating kinase 4 | 7 | 74 | 83.46 | 87.03 | ND | 0.36 | 0.82 | 0.7 | Mammalian | Ubiquitous. Isoform 2 is brain-specific (PubMed:11326310). Expressed at highest levels in brain and testis. Also expressed in heart, lung, liver, muscle, kidney and spleen (PubMed:14594945). {ECO:0000269|PubMed:11326310, ECO:0000269|PubMed:14594945}. | Kinase | Serine/threonine-protein kinase (PubMed:15009667, PubMed:14594945, PubMed:23666762, PubMed:23184942). Phosphorylates the microtubule-associated protein MAPT (PubMed:14594945, PubMed:23666762). Also phosphorylates the microtubule-associated proteins MAP2 and MAP4 (PubMed:14594945). Involved in regulation of the microtubule network, causing reorganization of microtubules into bundles (PubMed:14594945, PubMed:25123532). Required for the initiation of axoneme extension during cilium assembly (PubMed:23400999). Regulates the centrosomal location of ODF2 and phosphorylates ODF2 in vitro (PubMed:23400999). Plays a role in cell cycle progression, specifically in the G1/S checkpoint (PubMed:25123532). Reduces neuronal cell survival (PubMed:15009667). Plays a role in energy homeostasis by regulating satiety and metabolic rate (By similarity). Promotes adipogenesis by activating JNK1 and inhibiting the p38MAPK pathway, and triggers apoptosis by activating the JNK1 pathway (By similarity). Phosphorylates mTORC1 complex member RPTOR and acts as a negative regulator of the mTORC1 complex, probably due to disruption of the interaction between phosphorylated RPTOR and the RRAGA/RRAGC heterodimer which is required for mTORC1 activation (PubMed:23184942). {ECO:0000250|UniProtKB:Q8CIP4, ECO:0000269|PubMed:14594945, ECO:0000269|PubMed:15009667, ECO:0000269|PubMed:23184942, ECO:0000269|PubMed:23400999, ECO:0000269|PubMed:23666762, ECO:0000269|PubMed:25123532}. | 16.04 | ||||
| dfaMAST1 | Microtubule-associated serine/threonine-protein kinase 1 | 3 | 59 | 100.00 | 99.89 | ND | 0.84 | 0.83 | 0.2 | Mammalian | Kinase | Appears to link the dystrophin/utrophin network with microtubule filaments via the syntrophins. Phosphorylation of DMD or UTRN may modulate their affinities for associated proteins (By similarity). {ECO:0000250|UniProtKB:Q9R1L5}. | 16.04 | |||||
| dfaMATK | Megakaryocyte-associated tyrosine-protein kinase | 8 | 96 | 83.15 | 81.32 | ND | 0.83 | 0.77 | 0.3 | Mammalian | Expressed in various myeloid cell lines, detected in brain and lung. | Kinase | Could play a significant role in the signal transduction of hematopoietic cells. May regulate tyrosine kinase activity of SRC-family members in brain by specifically phosphorylating their C-terminal regulatory tyrosine residue which acts as a negative regulatory site. It may play an inhibitory role in the control of T-cell proliferation. {ECO:0000269|PubMed:9171348}. | 16.04 | ||||
| dfaMC3R | Melanocortin receptor 3 | 1 | 388 | 99.63 | 99.38 | ND | 0.67 | 0.71 | 0.5 | Nature11159 | Mammalian | Brain, placental, and gut tissues. | Family A G protein-coupled receptor | Chronic inflammatory diseases
Gouty arthritis Obesity | Receptor for MSH (alpha, beta and gamma) and ACTH. This receptor is mediated by G proteins which activate adenylate cyclase. Required for expression of anticipatory patterns of activity and wakefulness during periods of limited nutrient availability and for the normal regulation of circadian clock activity in the brain. {ECO:0000250|UniProtKB:P33033}. | 16.04 | ||
| dfaMC4R | Melanocortin receptor 4 | 1 | 1502 | 98.32 | 96.92 | ND | 0.71 | 0.70 | 0.6 | Nature11159 | Mammalian | Brain, placental, and gut tissues. | Family A G protein-coupled receptor | Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:10199800, ECO:0000269|PubMed:11443223, ECO:0000269|PubMed:11487744, ECO:0000269|PubMed:12588803, ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:14671178, ECO:0000269|PubMed:14764818, ECO:0000269|PubMed:15486053}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP). {ECO:0000269|PubMed:12646665}. | 16.04 | ||
| dfaMC5R | Melanocortin receptor 5 | 2 | 374 | 98.12 | 99.39 | ND | 0.69 | 0.80 | 0.4 | Mammalian | Expressed in the brain but not in the melanoma cells. | Family A G protein-coupled receptor | Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. This receptor is a possible mediator of the immunomodulation properties of melanocortins. | 16.04 | ||||
| dfaMCHR1 | Melanin-concentrating hormone receptor 1 | 5 | 2457 | 97.20 | 96.09 | ND | 0.50 | 0.52 | 0.6 | Mammalian | Highest level in brain, particularly in the frontal cortex and hypothalamus, lower levels in the liver and heart. | Family A G protein-coupled receptor | Obesity
Social anxiety disorder Vitiligo | Receptor for melanin-concentrating hormone, coupled to both G proteins that inhibit adenylyl cyclase and G proteins that activate phosphoinositide hydrolysis. {ECO:0000269|PubMed:10421367}. | 16.04 | |||
| dfaMCHR2 | Melanin-concentrating hormone receptor 2 | 2 | 124 | 99.18 | 99.94 | ND | 0.92 | 0.73 | 0.3 | Mammalian | Specifically expressed in the brain, with highest levels in cerebral cortex, hippocampus and amygdala. No expression detected in the cerebellum, thalamus or hypothalamus. | Family A G protein-coupled receptor | Obesity
Social anxiety disorder | Receptor for melanin-concentrating hormone, coupled to G proteins that activate phosphoinositide hydrolysis. | 16.04 | |||
| dfaMCL1 | Induced myeloid leukemia cell differentiation protein Mcl-1 | 3 | 1005 | 80.22 | 84.98 | ND | 0.36 | 0.51 | 0.4 | Mammalian | Other cytosolic protein | Leukemia, Lymphoid
Lymphoma, Non-Hodgkin's Prostate cancer | Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis. {ECO:0000269|PubMed:10766760, ECO:0000269|PubMed:16543145}. | 16.04 | ||||
| dfaMCR | Mineralocorticoid receptor | 5 | 654 | 90.56 | 87.08 | ND | 0.52 | 0.51 | 0.5 | VirtualToxLab | Mammalian | Ubiquitous. Highly expressed in distal tubules, convoluted tubules and cortical collecting duct in kidney, and in sweat glands. Detected at lower levels in cardiomyocytes, in epidermis and in colon enterocytes. {ECO:0000269|PubMed:11518808, ECO:0000269|PubMed:9141514}. | Acne Adrenal insufficiency Amenorrhoea Cushingoid Depression Embolism arterial Endocrine disorder Euphoric mood Hyperglycaemia Hypokalaemia Menstrual disorder Muscular weakness Oedema Osteoporosis Peptic ulcer | Nuclear receptor | Pseudohypoaldosteronism 1, autosomal dominant (PHA1A) [MIM:177735]: A salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1A is a mild form characterized by target organ defects confined to kidney. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. {ECO:0000269|PubMed:16972228}. Note=The disease is caused by mutations affecting the gene represented in this entry. Early-onset hypertension with severe exacerbation in pregnancy (EOHSEP) [MIM:605115]: Inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, and by suppression of aldosterone secretion. {ECO:0000269|PubMed:10884226}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels. {ECO:0000269|PubMed:3037703}. | Mineralocorticoid receptor agonist: Fludrocortisone Mineralocorticoid receptor antagonist: Drospirenone, Eplerenone, Felodipine, Fluticasone Propionate, Nimodipine, Progesterone, Spironolactone | 15.11 |
| dfaMDM2 | E3 ubiquitin-protein ligase Mdm2 | 2 | 457 | 96.42 | 95.25 | ND | 0.81 | 0.88 | 0.7 | Mammalian | Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues. | Other nuclear protein | Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. | E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation. {ECO:0000269|PubMed:12821780, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:15195100, ECO:0000269|PubMed:15632057, ECO:0000269|PubMed:16337594, ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:19098711, ECO:0000269|PubMed:19219073, ECO:0000269|PubMed:19837670, ECO:0000269|PubMed:19965871, ECO:0000269|PubMed:20173098, ECO:0000269|PubMed:20385133, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:22128911}. | 15.11 | |||
| dfaMDR1 | Multidrug resistance protein 1 | 5 | 1143 | 90.67 | 90.53 | ND | 0.72 | 0.67 | 0.4 | Mammalian | Expressed in liver, kidney, small intestine and brain. | Alopecia Angioedema Azoospermia Bone marrow failure Hyperlipidaemia Mucosal inflammation Oligomenorrhoea Stomatitis | Primary active transporter | Inflammatory bowel disease 13 (IBD13) [MIM:612244]: A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. | Multidrug resistance protein 1 : Adenosine triphosphate, Clarithromycin, Clofazimine, Erythromycin, Roxithromycin Multidrug resistance protein 1 inducer: Cholic Acid, Levothyroxine, Liothyronine, Liotrix, Nefazodone, Norethindrone, Streptozocin, Trazodone Multidrug resistance protein 1 inhibitor: Albendazole, Alectinib, Alfentanil, Amantadine, Aminohippurate, Amiodarone, Amlodipine, Amprenavir, Amsacrine, Astemizole, Atorvastatin, Azelastine, Azithromycin, Benzocaine, Bepridil, Biperiden, Buprenorphine, Buspirone, Candesartan, Captopril, Carvedilol, Caspofungin, Chloroquine, Chlorpropamide, Chlorprothixene, Cilazapril, Clofazimine, Clomipramine, Clotrimazole, Cobicistat, Cyclophosphamide, Daclatasvir, Desipramine, Desloratadine, Dextromethorphan, Diclofenac, Dihydroergotamine, Doxazosin, Doxepin, Dronabinol, Dronedarone, Enalapril, Enzalutamide, Ergonovine, Ergotamine, Estramustine, Etravirine, Felodipine, Fentanyl, Fluconazole, Fluoxetine, Flupentixol, Fluphenazine, Flurazepam, Fluvoxamine, Glyburide, Gramicidin D, Isavuconazonium, Itraconazole, Ivacaftor, Ketamine, Lapatinib, Lidocaine, Lisinopril, Lomitapide, Lopinavir, Loratadine, Lovastatin, Maprotiline, Mebendazole, Mefloquine, Megestrol acetate, Meprobamate, Methadone, Miconazole, Mifepristone, Mitomycin, Naltrexone, Neostigmine, Nisoldipine, Nitrazepam, Nitrendipine, Omeprazole, Pantoprazole, Paroxetine, Perindopril, Pimozide, Posaconazole, Probenecid, Promethazine, Propafenone, Protriptyline, Quinacrine, Reboxetine, Regorafenib, Rilpivirine, Rolapitant, Scopolamine, Selegiline, Sertraline, Simvastatin, Sirolimus, Spironolactone, Sulfinpyrazone, Sumatriptan, Sunitinib, Telmisartan, Terazosin, Testosterone, Trifluoperazine, Triflupromazine, Trimethoprim, Trimipramine, Troleandomycin, Vinorelbine Multidrug resistance protein 1 inhibitor, competitive: Voacamine Multidrug resistance protein 1 substrate: Acebutolol, Acetaminophen, Acetylsalicylic acid, Afatinib, Alitretinoin, Ambrisentan, Amitriptyline, Apixaban, Arsenic trioxide, Atazanavir, Atenolol, Axitinib, Betamethasone, Boceprevir, Bosutinib, Brentuximab vedotin, Bromocriptine, Cabazitaxel, Caffeine, Canagliflozin, Carbamazepine, Carfilzomib, Ceritinib, Chlorpromazine, Cimetidine, Ciprofloxacin, Cisplatin, Citalopram, Clarithromycin, Clobazam, Clomifene, Clonidine, Clopidogrel, Clozapine, Cobimetinib, Colchicine, Conjugated Estrogens, Crizotinib, Cyclosporine, Dabigatran etexilate, Dabrafenib, Dactinomycin, Dapagliflozin, Dasatinib, Daunorubicin, Debrisoquin, Dexamethasone, Diazepam, Diethylstilbestrol, Digitoxin, Digoxin, Diltiazem, Dipyridamole, Docetaxel, Domperidone, Doxorubicin, Edoxaban, Eletriptan, Epinastine, Erlotinib, Erythromycin, Estradiol, Estriol, Estrone, Ethinyl Estradiol, Etoposide, Ezetimibe, Fesoterodine, Fexofenadine, Fidaxomicin, Fluticasone furoate, Gefitinib, Gemcitabine, Haloperidol, Hydrocortisone, Ibuprofen, Idelalisib, Imatinib, Imipramine, Indacaterol, Indinavir, Indomethacin, Irinotecan, Ivermectin, Ketazolam, Ketoconazole, Lamivudine, Lamotrigine, Lansoprazole, Lenalidomide, Lenvatinib, Levetiracetam, Levofloxacin, Levomilnacipran, Linagliptin, Loperamide, Losartan, Mannitol, Methotrexate, Methylprednisolone, Metoprolol, Midazolam, Mirabegron, Mitoxantrone, Morphine, Mycophenolate mofetil, Nadolol, Naloxone, Nelfinavir, Nicardipine, Nifedipine, Nilotinib, Nintedanib, Nizatidine, Olanzapine, Osimertinib, Paclitaxel, Panobinostat, Pazopanib, Phenobarbital, Phenytoin, Pitavastatin, Pomalidomide, Ponatinib, Pravastatin, Prazosin, Prednisolone, Prednisone, Progesterone, Propranolol, Quetiapine, Quinidine, Quinine, Ranitidine, Reserpine, Rifampicin, Risperidone, Ritonavir, Rivaroxaban, Salicylic acid, Saquinavir, Selexipag, Silodosin, Simeprevir, Sitagliptin, Sofosbuvir, Sorafenib, Sparfloxacin, Tacrolimus, Tamoxifen, Telaprevir, Temsirolimus, Ticagrelor, Timolol, Tolvaptan, Topotecan, Toremifene, Ulipristal, Umeclidinium, Vecuronium, Venlafaxine, Verapamil, Vinblastine, Vincristine, Vismodegib, Zidovudine, ado-trastuzumab emtansine | 16.04 | |
| dfaMDR1A | Multidrug resistance protein 1A | 3 | 76 | 97.56 | 97.88 | ND | 0.52 | 0.69 | 0.5 | Mammalian | Primary active transporter | Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. {ECO:0000269|PubMed:19325113}. | 16.04 | |||||
| dfaMDR1B | Multidrug resistance protein 1B | 1 | 73 | 88.24 | 91.61 | ND | 0.82 | 0.71 | 0.3 | Mammalian | Primary active transporter | Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. | 16.04 | |||||
| dfaMELK | Maternal embryonic leucine zipper kinase | 3 | 218 | 89.75 | 91.36 | ND | 0.71 | 0.77 | 0.5 | Mammalian | Expressed in placenta, kidney, thymus, testis, ovary and intestine. {ECO:0000269|PubMed:8724849}. | Kinase | Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation. | Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis. {ECO:0000269|PubMed:11802789, ECO:0000269|PubMed:12400006, ECO:0000269|PubMed:14699119, ECO:0000269|PubMed:15908796, ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:17280616}. | 15.11 | |||
| dfaMERTK | Tyrosine-protein kinase Mer | 5 | 185 | 94.70 | 95.54 | ND | 0.53 | 0.64 | 0.8 | Mammalian | Not expressed in normal B- and T-lymphocytes but is expressed in numerous neoplastic B- and T-cell lines. Highly expressed in testis, ovary, prostate, lung, and kidney, with lower expression in spleen, small intestine, colon, and liver. | Kinase | Retinitis pigmentosa 38 (RP38) [MIM:613862]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:11062461}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll- like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:17005688}. | 15.11 | |||
| dfaMET | Hepatocyte growth factor receptor | 8 | 1715 | 95.83 | 96.83 | ND | 0.77 | 0.00 | 0.6 | Mammalian | Expressed in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Found also in basal keratinocytes of esophagus and skin. High levels are found in liver, gastrointestinal tract, thyroid and kidney. Also present in the brain. {ECO:0000269|PubMed:1719465, ECO:0000269|PubMed:1917129}. | Kinase | Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. Note=Defects in MET may be associated with gastric cancer. Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:9927037}. Note=The disease is caused by mutations affecting the gene represented in this entry. Renal cell carcinoma papillary (RCCP) [MIM:605074]: A subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. {ECO:0000269|PubMed:10327054, ECO:0000269|PubMed:10417759, ECO:0000269|PubMed:10433944, ECO:0000269|PubMed:9140397, ECO:0000269|PubMed:9563489}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes. Note=MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies. | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells. | Hepatocyte growth factor receptor antagonist: Cabozantinib Hepatocyte growth factor receptor inhibitor: Crizotinib | 15.11 | ||
| dfaMGA | Maltase-glucoamylase, intestinal | 2 | 85 | 98.57 | 99.32 | ND | 0.58 | 0.67 | 0.6 | Mammalian | Expressed in small intestine, granulocyte, and kidney but not in salivary gland or pancreas. | Hydrolase | Diabetes mellitus | May serve as an alternate pathway for starch digestion when luminal alpha-amylase activity is reduced because of immaturity or malnutrition. May play a unique role in the digestion of malted dietary oligosaccharides used in food manufacturing. | Maltase-glucoamylase, intestinal antagonist: Miglitol Maltase-glucoamylase, intestinal inhibitor: Acarbose, Voglibose | 15.11 | ||
| dfaMGLL | Monoglyceride lipase {ECO:0000312|HGNC:HGNC:17038} | 6 | 312 | 94.82 | 83.12 | ND | 0.74 | 0.72 | 0.5 | Mammalian | Detected in adipose tissue, lung, liver, kidney, brain and heart. {ECO:0000269|PubMed:11470505}. | Enzyme | Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (By similarity). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth (PubMed:20079333). {ECO:0000250|UniProtKB:O35678, ECO:0000269|PubMed:20079333}. | 16.04 | ||||
| dfaMGMT | Methylated-DNA--protein-cysteine methyltransferase | 1 | 49 | 98.98 | 99.97 | ND | 0.71 | 0.65 | 0.6 | Mammalian | Enzyme | Cancer, unspecific | Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) in DNA. Repairs alkylated guanine in DNA by stoichiometrically transferring the alkyl group at the O-6 position to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated. | 16.04 | ||||
| dfaMIF | Macrophage migration inhibitory factor | 3 | 150 | 85.39 | 80.76 | ND | 0.26 | 0.70 | 0.7 | Mammalian | Enzyme | Rheumatoid arthritis systemic juvenile (RASJ) [MIM:604302]: An inflammatory articular disorder with systemic- onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. {ECO:0000269|PubMed:11508429}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. {ECO:0000305}. | Pro-inflammatory cytokine. Involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. Counteracts the anti- inflammatory activity of glucocorticoids. Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known. It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity. {ECO:0000269|PubMed:15908412, ECO:0000269|PubMed:17443469, ECO:0000269|PubMed:23776208}. | 15.11 | ||||
| dfaMINK1 | Misshapen-like kinase 1 | 4 | 328 | 88.70 | 90.52 | ND | 0.63 | 0.73 | 0.5 | Mammalian | Expressed in the brain, isoform 2 is more abundant than isoform 1. Isoform 3 is ubiquitously expressed. Isoform 1 is most abundant in the skeletal muscle. Isoform 4 is ubiquitously expressed with relative high levels in brain, skeletal muscle, pancreas and testis. {ECO:0000269|PubMed:15469942}. | Kinase | Serine/threonine kinase which acts as a negative regulator of Ras-related Rap2-mediated signal transduction to control neuronal structure and AMPA receptor trafficking. Required for normal synaptic density, dendrite complexity, as well as surface AMPA receptor expression in hippocampal neurons. Can activate the JNK and MAPK14/p38 pathways and mediates stimulation of the stress-activated protein kinase MAPK14/p38 MAPK downstream of the Raf/ERK pathway. Phosphorylates: TANC1 upon stimulation by RAP2A, MBP and SMAD1. Has an essential function in negative selection of thymocytes, perhaps by coupling NCK1 to activation of JNK1. Isoform 4 can activate the JNK pathway. Involved in the regulation of actin cytoskeleton reorganization, cell-matrix adhesion, cell-cell adhesion and cell migration. | 16.04 | ||||
| dfaMK01 | Mitogen-activated protein kinase 1 | 4 | 1563 | 86.03 | 87.17 | ND | 0.77 | 0.84 | 0.5 | Mammalian | Kinase | Neurodegenerative diseases
Proliferative diseases | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in respons to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity. | Mitogen-activated protein kinase 1 inducer: Arsenic trioxide, Isoprenaline | 15.11 | |||
| dfaMK03 | Mitogen-activated protein kinase 3 | 5 | 171 | 88.13 | 85.67 | ND | 0.82 | 0.83 | 0.4 | Mammalian | Kinase | Neurodegenerative diseases
Proliferative diseases Traumatic brain injury | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. {ECO:0000269|PubMed:10393181, ECO:0000269|PubMed:10617468, ECO:0000269|PubMed:12110590, ECO:0000269|PubMed:12356731, ECO:0000269|PubMed:12974390, ECO:0000269|PubMed:15788397, ECO:0000269|PubMed:15952796, ECO:0000269|PubMed:16581800, ECO:0000269|PubMed:19265199, ECO:0000269|PubMed:8325880, ECO:0000269|PubMed:9155018, ECO:0000269|PubMed:9480836}. | Mitogen-activated protein kinase 3 inducer: Arsenic trioxide Mitogen-activated protein kinase 3 inhibitor: Sulindac | 15.11 | |||
| dfaMK07 | Mitogen-activated protein kinase 7 | 6 | 86 | 99.07 | 97.82 | ND | 0.51 | 0.76 | 0.6 | Mammalian | Expressed in many adult tissues. Abundant in heart, placenta, lung, kidney and skeletal muscle. Not detectable in liver. {ECO:0000269|PubMed:7759517}. | Kinase | Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras- independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction. {ECO:0000269|PubMed:11254654, ECO:0000269|PubMed:11278431, ECO:0000269|PubMed:22869143, ECO:0000269|PubMed:9384584, ECO:0000269|PubMed:9790194}. | 15.11 | ||||
| dfaMK08 | Mitogen-activated protein kinase 8 | 7 | 1096 | 94.04 | 91.51 | ND | 0.71 | 0.69 | 0.5 | Mammalian | Kinase | Cancer, unspecific
Crohn's disease, unspecified Hearing Loss Inflammatory Disorders, Unspecified Insulin resistance Obesity | Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:22441692}. JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta- 2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. | 15.11 | ||||
| dfaMK09 | Mitogen-activated protein kinase 9 | 8 | 794 | 90.41 | 87.56 | ND | 0.42 | 0.71 | 1.0 | Mammalian | Kinase | Not Available | Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:22441692}. MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it. | 15.11 | ||||
| dfaMK10 | Mitogen-activated protein kinase 10 | 5 | 832 | 94.60 | 91.47 | ND | 0.72 | 0.08 | 0.5 | Mammalian | Specific to a subset of neurons in the nervous system. Present in the hippocampus and areas, cerebellum, striatum, brain stem, and weakly in the spinal cord. Very weak expression in testis and kidney. | Kinase | Note=A chromosomal aberration involving MAPK10 has been found in a single patient with pharmacoresistant epileptic encephalopathy. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. {ECO:0000269|PubMed:16249883}. | Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress- activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the photic regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:11718727, ECO:0000269|PubMed:22441692}. | 15.11 | |||
| dfaMK11 | Mitogen-activated protein kinase 11 | 3 | 223 | 94.37 | 96.17 | ND | 0.71 | 0.71 | 0.5 | Mammalian | Highest levels in the brain and heart. Also expressed in the placenta, lung, liver, skeletal muscle, kidney and pancreas. | Kinase | Inflammation
Psoriasis Rheumatoid arthritis, unspecified | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK11 functions are mostly redundant with those of MAPK14. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane- associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. {ECO:0000269|PubMed:10330143, ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:15356147, ECO:0000269|PubMed:9430721, ECO:0000269|PubMed:9687510}. | Mitogen-activated protein kinase 11 inhibitor: Regorafenib | 15.11 | ||
| dfaMK12 | Mitogen-activated protein kinase 12 | 7 | 183 | 88.32 | 86.96 | ND | 0.53 | 0.78 | 0.5 | Mammalian | Highly expressed in skeletal muscle and heart. {ECO:0000269|PubMed:11991731, ECO:0000269|PubMed:8633070}. | Kinase | Note=MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma- radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration. {ECO:0000269|PubMed:10848581, ECO:0000269|PubMed:14592936, ECO:0000269|PubMed:17724032, ECO:0000269|PubMed:20605917, ECO:0000269|PubMed:21172807, ECO:0000269|PubMed:8633070, ECO:0000269|PubMed:9430721}. | 15.11 | |||
| dfaMK13 | Mitogen-activated protein kinase 13 | 7 | 213 | 97.03 | 96.99 | ND | 0.64 | 0.88 | 0.7 | Mammalian | Expressed in testes, pancreas, small intestine, lung and kidney. Abundant in macrophages, also present in neutrophils, CD4+ T-cells, and endothelial cells. {ECO:0000269|PubMed:10201954, ECO:0000269|PubMed:9374491}. | Kinase | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells. {ECO:0000269|PubMed:11500363, ECO:0000269|PubMed:11943212, ECO:0000269|PubMed:15632108, ECO:0000269|PubMed:17256148, ECO:0000269|PubMed:18006338, ECO:0000269|PubMed:18367666, ECO:0000269|PubMed:20478268, ECO:0000269|PubMed:9731215}. | 15.11 | ||||
| dfaMK14 | Mitogen-activated protein kinase 14 | 6 | 3356 | 96.78 | 96.43 | ND | 0.69 | 0.00 | 0.6 | Mammalian | Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney. | Abdominal pain upper | Kinase | Adult respiratory distress syndrome
Alzheimer's disease Crescentic glomerulonephritis Crohn's disease, unspecified Cytokine-mediated diseases Endotoxemia Inflammation Insulin resistance Multiple myeloma Psoriasis Rheumatoid arthritis, unspecified Skin diseases Thrombosis | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF- induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14- mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF- kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'. {ECO:0000269|PubMed:10330143, ECO:0000269|PubMed:10747897, ECO:0000269|PubMed:10943842, ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:11333986, ECO:0000269|PubMed:15905572, ECO:0000269|PubMed:16932740, ECO:0000269|PubMed:17003045, ECO:0000269|PubMed:17724032, ECO:0000269|PubMed:19893488, ECO:0000269|PubMed:20188673, ECO:0000269|PubMed:20932473, ECO:0000269|PubMed:9430721, ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9792677, ECO:0000269|PubMed:9858528}. | 15.11 | ||
| dfaMKNK1 | MAP kinase-interacting serine/threonine-protein kinase 1 | 5 | 100 | 89.47 | 85.26 | ND | 0.73 | 0.90 | 0.3 | Mammalian | Ubiquitous. {ECO:0000269|PubMed:15350534}. | Kinase | May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7- methylguanosine-containing mRNA cap. {ECO:0000269|PubMed:11463832, ECO:0000269|PubMed:15350534, ECO:0000269|PubMed:9155018, ECO:0000269|PubMed:9878069}. | 16.04 | ||||
| dfaMKNK2 | MAP kinase-interacting serine/threonine-protein kinase 2 | 6 | 332 | 93.67 | 93.19 | ND | 0.45 | 0.71 | 0.4 | Mammalian | Ubiquitously expressed in all tissues examined. Isoform 2 is expressed at higher levels in the ovary than is isoform 1. {ECO:0000269|PubMed:11013076}. | Kinase | Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal. {ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:11463832, ECO:0000269|PubMed:12897141, ECO:0000269|PubMed:16111636, ECO:0000269|PubMed:17965020, ECO:0000269|PubMed:18299328, ECO:0000269|PubMed:20823271, ECO:0000269|PubMed:20927323, ECO:0000269|PubMed:21149447}. | 15.11 | ||||
| dfaMLTK | Mitogen-activated protein kinase kinase kinase MLT | 5 | 216 | 89.51 | 92.45 | ND | 0.21 | 0.62 | 0.4 | Mammalian | Ubiquitously expressed. Isoform 2 is the predominant form in all tissues examined, except for liver, in which isoform 1 is more highly expressed. {ECO:0000269|PubMed:10924358, ECO:0000269|PubMed:11836244}. | Kinase | Stress-activated component of a protein kinase signal transduction cascade. Regulates the JNK and p38 pathways. Part of a signaling cascade that begins with the activation of the adrenergic receptor ADRA1B and leads to the activation of MAPK14. Pro-apoptotic. Role in regulation of S and G2 cell cycle checkpoint by direct phosphorylation of CHEK2. Isoform 1, but not isoform 2, causes cell shrinkage and disruption of actin stress fibers. Isoform 1 may have role in neoplastic cell transformation and cancer development. Isoform 1, but not isoform 2, phosphorylates histone H3 at 'Ser-28'. {ECO:0000269|PubMed:10924358, ECO:0000269|PubMed:11042189, ECO:0000269|PubMed:11836244, ECO:0000269|PubMed:15172994, ECO:0000269|PubMed:15342622, ECO:0000269|PubMed:15684425, ECO:0000269|PubMed:21224381}. | 16.04 | ||||
| dfaMMP1 | Interstitial collagenase | 4 | 2529 | 94.62 | 92.24 | ND | 0.61 | 0.60 | 0.7 | Mammalian | Protease | Cancer, unspecific
Chondrosarcoma Emphysema Hormone-refractory Prostate cancer Kaposi's Sarcoma Lung Cancer Myocardial infarction (MI) Non-small Cell Lung Cancer Osteoarthritis Pancreatic Cancer | Cleaves collagens of types I, II, and III at one site in the helical domain. Also cleaves collagens of types VII and X. In case of HIV infection, interacts and cleaves the secreted viral Tat protein, leading to a decrease in neuronal Tat's mediated neurotoxicity. {ECO:0000269|PubMed:1645757}. | Interstitial collagenase inhibitor: Marimastat | 15.11 | |||
| dfaMMP12 | Macrophage metalloelastase | 3 | 408 | 96.89 | 97.21 | ND | 0.80 | 0.82 | 0.7 | Mammalian | Found in alveolar macrophages but not in peripheral blood monocytes. | Protease | Atherosclerosis
Crohn's disease, unspecified Emphysema Gastro-intestinal ulcers Non-small Cell Lung Cancer (NSCLC) Prostate cancer Renal Cell Carcinoma Ulcerative colitis | May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3. | Macrophage metalloelastase inhibitor: Acetohydroxamic Acid, Marimastat | 15.11 | ||
| dfaMMP13 | Collagenase 3 | 5 | 1903 | 96.78 | 96.84 | ND | 0.70 | 0.71 | 0.7 | Mammalian | Detected in fetal cartilage and calvaria, in chondrocytes of hypertrophic cartilage in vertebrae and in the dorsal end of ribs undergoing ossification, as well as in osteoblasts and periosteal cells below the inner periosteal region of ossified ribs. Detected in chondrocytes from in joint cartilage that have been treated with TNF and IL1B, but not in untreated chondrocytes. Detected in T lymphocytes. Detected in breast carcinoma tissue. {ECO:0000269|PubMed:8207000, ECO:0000269|PubMed:8798568, ECO:0000269|PubMed:9056642, ECO:0000269|PubMed:9562863}. | Protease | Spondyloepimetaphyseal dysplasia Missouri type (SEMD-MO) [MIM:602111]: A bone disease characterized by moderate to severe metaphyseal changes, mild epiphyseal involvement, rhizomelic shortening of the lower limbs with bowing of the femora and/or tibiae, coxa vara, genu varum and pear-shaped vertebrae in childhood. Epimetaphyseal changes improve with age. {ECO:0000269|PubMed:16167086}. Note=The disease is caused by mutations affecting the gene represented in this entry. Metaphyseal anadysplasia 1 (MANDP1) [MIM:602111]: A bone development disorder characterized by skeletal anomalies that resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia. {ECO:0000269|PubMed:19615667}. Note=The disease is caused by mutations affecting the gene represented in this entry. Metaphyseal dysplasia, Spahr type (MDST) [MIM:250400]: An autosomal recessive, rare disease characterized by moderate short stature, mild genua vara, and radiographic signs of metaphyseal dysplasia, but no biochemical signs of rickets. {ECO:0000269|PubMed:24648384, ECO:0000269|PubMed:24781753}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a role in the degradation of extracellular matrix proteins including fibrillar collagen, fibronectin, TNC and ACAN. Cleaves triple helical collagens, including type I, type II and type III collagen, but has the highest activity with soluble type II collagen. Can also degrade collagen type IV, type XIV and type X. May also function by activating or degrading key regulatory proteins, such as TGFB1 and CTGF. Plays a role in wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization and ossification. Required for normal embryonic bone development and ossification. Plays a role in the healing of bone fractures via endochondral ossification. Plays a role in wound healing, probably by a mechanism that involves proteolytic activation of TGFB1 and degradation of CTGF. Plays a role in keratinocyte migration during wound healing. May play a role in cell migration and in tumor cell invasion. {ECO:0000269|PubMed:16167086, ECO:0000269|PubMed:17623656, ECO:0000269|PubMed:19422229, ECO:0000269|PubMed:19615667, ECO:0000269|PubMed:20726512, ECO:0000269|PubMed:22689580, ECO:0000269|PubMed:23810497, ECO:0000269|PubMed:8207000, ECO:0000269|PubMed:8576151, ECO:0000269|PubMed:8603731, ECO:0000269|PubMed:8663255, ECO:0000269|PubMed:9065415}. | Collagenase 3 inhibitor: Marimastat | 15.11 | ||
| dfaMMP14 | Matrix metalloproteinase-14 | 4 | 573 | 94.57 | 92.44 | ND | 0.52 | 0.62 | 0.8 | Mammalian | Expressed in stromal cells of colon, breast, and head and neck. Expressed in lung tumors. {ECO:0000269|PubMed:18223680}. | Protease | Winchester syndrome (WNCHRS) [MIM:277950]: A disease characterized by severe osteolysis in the hands and feet, generalized osteoporosis, bone thinning, and absence of subcutaneous nodules. Various additional features include coarse face, corneal opacities, gum hypertrophy, and EKG changes. {ECO:0000269|PubMed:22922033}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Seems to specifically activate progelatinase A. May thus trigger invasion by tumor cells by activating progelatinase A on the tumor cell surface. May be involved in actin cytoskeleton reorganization by cleaving PTK7. Acts as a positive regulator of cell growth and migration via activation of MMP15. Involved in the formation of the fibrovascular tissues in association with pro- MMP2. {ECO:0000269|PubMed:12714657, ECO:0000269|PubMed:20837484, ECO:0000269|PubMed:22065321}. | Matrix metalloproteinase-14 inhibitor: Marimastat | 16.04 | ||
| dfaMMP16 | Matrix metalloproteinase-16 | 5 | 50 | 99.83 | 96.32 | ND | 0.45 | 0.69 | 0.9 | Mammalian | Expressed in heart, brain, placenta, ovary and small intestine. Isoform Short is found in the ovary. | Protease | Endopeptidase that degrades various components of the extracellular matrix, such as collagen type III and fibronectin. Activates progelatinase A. Involved in the matrix remodeling of blood vessels. Isoform short cleaves fibronectin and also collagen type III, but at lower rate. It has no effect on type I, II, IV and V collagen. However, upon interaction with CSPG4, it may be involved in degradation and invasion of type I collagen by melanoma cells. {ECO:0000269|PubMed:11278606}. | Matrix metalloproteinase-16 inhibitor: Marimastat | 16.04 | |||
| dfaMMP2 | 72 kDa type IV collagenase | 5 | 2531 | 96.92 | 94.65 | ND | 0.69 | 0.68 | 0.8 | Mammalian | Produced by normal skin fibroblasts. PEX is expressed in a number of tumors including gliomas, breast and prostate. {ECO:0000269|PubMed:11751392}. | Protease | Multicentric osteolysis, nodulosis, and arthropathy (MONA) [MIM:259600]: An autosomal recessive syndrome characterized by severe multicentric osteolysis with predominant involvement of the hands and feet. Additional features include coarse face, corneal opacities, patches of thickened, hyperpigmented skin, hypertrichosis and gum hypertrophy. {ECO:0000269|PubMed:11431697, ECO:0000269|PubMed:15691365, ECO:0000269|PubMed:16542393}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ubiquitinous metalloproteinase that is involved in diverse functions such as remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. As well as degrading extracellular matrix proteins, can also act on several nonmatrix proteins such as big endothelial 1 and beta-type CGRP promoting vasoconstriction. Also cleaves KISS at a Gly-|-Leu bond. Appears to have a role in myocardial cell death pathways. Contributes to myocardial oxidative stress by regulating the activity of GSK3beta. Cleaves GSK3beta in vitro. Involved in the formation of the fibrovascular tissues in association with MMP14. PEX, the C-terminal non-catalytic fragment of MMP2, posseses anti-angiogenic and anti-tumor properties and inhibits cell migration and cell adhesion to FGF2 and vitronectin. Ligand for integrinv/beta3 on the surface of blood vessels. Isoform 2: Mediates the proteolysis of CHUK/IKKA and initiates a primary innate immune response by inducing mitochondrial-nuclear stress signaling with activation of the pro- inflammatory NF-kappaB, NFAT and IRF transcriptional pathways. | 72 kDa type IV collagenase inhibitor: Captopril, Marimastat | 16.04 | ||
| dfaMMP3 | Stromelysin-1 | 3 | 1279 | 96.85 | 96.12 | ND | 0.64 | 0.69 | 0.6 | Mammalian | Protease | Coronary heart disease 6 (CHDS6) [MIM:614466]: A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. {ECO:0000269|PubMed:12477941, ECO:0000269|PubMed:8662692}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions. | Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase. | Stromelysin-1 antagonist: Marimastat | 15.11 | |||
| dfaMMP7 | Matrilysin | 4 | 472 | 95.47 | 98.40 | ND | 0.68 | 0.73 | 0.5 | Mammalian | Protease | Cancer, unspecific
Inflammation | Degrades casein, gelatins of types I, III, IV, and V, and fibronectin. Activates procollagenase. {ECO:0000269|PubMed:2550050}. | Matrilysin antagonist: Marimastat | 15.11 | |||
| dfaMMP8 | Neutrophil collagenase | 4 | 749 | 95.71 | 97.43 | ND | 0.73 | 0.73 | 0.7 | Mammalian | Neutrophils. | Protease | Inflammatory diseases
Osteoarthritis Osteoporosis, unspecified Rheumatoid arthritis, unspecified Tumors | Can degrade fibrillar type I, II, and III collagens. | Neutrophil collagenase inhibitor: Marimastat | 15.11 | ||
| dfaMMP9 | Matrix metalloproteinase-9 | 5 | 2071 | 96.37 | 94.70 | ND | 0.69 | 0.61 | 0.7 | Mammalian | Produced by normal alveolar macrophages and granulocytes. | Protease | Intervertebral disc disease (IDD) [MIM:603932]: A common musculo-skeletal disorder caused by degeneration of intervertebral disks of the lumbar spine. It results in low-back pain and unilateral leg pain. {ECO:0000269|PubMed:18455130}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Metaphyseal anadysplasia 2 (MANDP2) [MIM:613073]: A bone development disorder characterized by skeletal anomalies that resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia. {ECO:0000269|PubMed:19615667}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. Could play a role in bone osteoclastic resorption. Cleaves KiSS1 at a Gly-|-Leu bond. Cleaves type IV and type V collagen into large C-terminal three quarter fragments and shorter N-terminal one quarter fragments. Degrades fibronectin but not laminin or Pz-peptide. {ECO:0000269|PubMed:1480034}. | Matrix metalloproteinase-9 antagonist: Glucosamine Matrix metalloproteinase-9 inhibitor: Captopril, Marimastat, Minocycline | 16.04 | ||
| dfaMOT1 | Monocarboxylate transporter 1 | 1 | 89 | 99.97 | 98.94 | ND | 0.58 | 0.72 | 0.5 | Mammalian | Detected in heart and in blood lymphocytes and monocytes (at protein level). Widely expressed. {ECO:0000269|PubMed:15505343}. | Electrochemical transporter | Symptomatic deficiency in lactate transport (SDLT) [MIM:245340]: Deficiency of lactate transporter may result in an acidic intracellular environment created by muscle activity with consequent degeneration of muscle and release of myoglobin and creatine kinase. This defect might compromise extreme performance in otherwise healthy individuals. {ECO:0000269|PubMed:10590411}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperinsulinemic hypoglycemia 7 (HHF7) [MIM:610021]: Dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load. {ECO:0000269|PubMed:17701893}. Note=The disease is caused by mutations affecting the gene represented in this entry. Monocarboxylate transporter 1 deficiency (MCT1D) [MIM:616095]: A metabolic disorder characterized by recurrent ketoacidosis, a pathologic state due to ketone formation exceeding ketone utilization. The clinical consequences of ketoacidosis are vomiting, osmotic diuresis, dehydration, and Kussmaul breathing. The condition may progress to decreased consciousness and, ultimately, death. {ECO:0000269|PubMed:25390740}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetate. Depending on the tissue and on cicumstances, mediates the import or export of lactic acid and ketone bodies. Required for normal nutrient assimilation, increase of white adipose tissue and body weight gain when on a high-fat diet. Plays a role in cellular responses to a high-fat diet by modulating the cellular levels of lactate and pyruvate, small molecules that contribute to the regulation of central metabolic pathways and insulin secretion, with concomitant effects on plasma insulin levels and blood glucose homeostasis. {ECO:0000269|PubMed:17701893}. | Monocarboxylate transporter 1 : Ampicillin, Benzoic Acid, Pravastatin, Pyruvic acid Monocarboxylate transporter 1 inhibitor: Gamma Hydroxybutyric Acid, Niflumic Acid, Probenecid Monocarboxylate transporter 1 substrate: Acetic acid, Aminohippurate, Foscarnet, Lactic Acid, Methotrexate, Nateglinide, Niacin, Pyruvic acid, Salicylic acid, Valproic Acid | 16.04 | ||
| dfaMP2K1 | Dual specificity mitogen-activated protein kinase kinase 1 | 5 | 693 | 91.49 | 89.53 | ND | 0.74 | 0.67 | 0.6 | Mammalian | Widely expressed, with extremely low levels in brain. {ECO:0000269|PubMed:1281467}. | Kinase | Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator- activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis. {ECO:0000269|PubMed:14737111, ECO:0000269|PubMed:17101779}. | Dual specificity mitogen-activated protein kinase kinase 1 inhibitor: Bosutinib, Cobimetinib, Trametinib | 15.11 | ||
| dfaMP2K5 | Dual specificity mitogen-activated protein kinase kinase 5 | 2 | 63 | 92.32 | 93.29 | ND | 0.47 | 0.99 | 0.6 | Mammalian | Expressed in many adult tissues. Abundant in heart and skeletal muscle. | Kinase | Breast cancer | Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex. Activation of this pathway appears to play a critical role in protecting cells from stress-induced apoptosis, neuronal survival and cardiac development and angiogenesis. {ECO:0000269|PubMed:7759517, ECO:0000269|PubMed:9384584}. | 16.04 | |||
| dfaMP2K6 | Dual specificity mitogen-activated protein kinase kinase 6 | 3 | 76 | 81.25 | 88.88 | ND | 0.91 | 0.60 | 0.1 | Mammalian | Isoform 2 is only expressed in skeletal muscle. Isoform 1 is expressed in skeletal muscle, heart, and in lesser extent in liver or pancreas. {ECO:0000269|PubMed:8621675}. | Kinase | Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG- dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases. {ECO:0000269|PubMed:10961885, ECO:0000269|PubMed:11727828, ECO:0000269|PubMed:15550393, ECO:0000269|PubMed:20869211, ECO:0000269|PubMed:8622669, ECO:0000269|PubMed:8626699, ECO:0000269|PubMed:8663074, ECO:0000269|PubMed:9218798}. | 15.11 | ||||
| dfaMPI | Mannose-6-phosphate isomerase | 4 | 237 | 89.39 | 89.46 | ND | 0.23 | 0.28 | 0.3 | Mammalian | Expressed in all tissues, but more abundant in heart, brain and skeletal muscle. | Enzyme | Congenital disorder of glycosylation 1B (CDG1B) [MIM:602579]: A multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N- glycoproteins during embryonic development, differentiation, and maintenance of cell functions. Congenital disorder of glycosylation type 1B is clinically characterized by protein- losing enteropathy. {ECO:0000269|PubMed:10980531, ECO:0000269|PubMed:11134235, ECO:0000269|PubMed:11350186, ECO:0000269|PubMed:12357336, ECO:0000269|PubMed:12414827, ECO:0000269|PubMed:9525984, ECO:0000269|PubMed:9585601}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions. | 16.04 | |||
| dfaMPIP1 | M-phase inducer phosphatase 1 | 6 | 178 | 91.18 | 82.51 | ND | 0.28 | 0.59 | 0.4 | Mammalian | Phosphatase | Breast cancer
Cancer, unspecific | Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Directly dephosphorylates CDK1 and stimulates its kinase activity. Also dephosphorylates CDK2 in complex with cyclin E, in vitro. | 16.04 | ||||
| dfaMPIP2 | M-phase inducer phosphatase 2 | 4 | 260 | 90.67 | 83.97 | ND | 0.63 | 0.70 | 0.4 | Mammalian | Phosphatase | Cancer, unspecific | Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Directly dephosphorylates CDK1 and stimulates its kinase activity. The three isoforms seem to have a different level of activity. {ECO:0000269|PubMed:17332740}. | 16.04 | ||||
| dfaMPIP3 | M-phase inducer phosphatase 3 | 7 | 67 | 98.12 | 92.09 | ND | 0.72 | 0.95 | 0.3 | Mammalian | Phosphatase | Cancer, unspecific | Functions as a dosage-dependent inducer in mitotic control. Tyrosine protein phosphatase required for progression of the cell cycle. When phosphorylated, highly effective in activating G2 cells into prophase. Directly dephosphorylates CDK1 and activates its kinase activity. {ECO:0000269|PubMed:8119945}. | 16.04 | ||||
| dfaMPP8 | M-phase phosphoprotein 8 | 7 | 120 | 99.37 | 96.62 | ND | 0.82 | 0.75 | 0.2 | Mammalian | Reader | Heterochromatin component that specifically recognizes and binds methylated 'Lys-9' of histone H3 (H3K9me) and promotes recruitment of proteins that mediate epigenetic repression (PubMed:20871592, PubMed:26022416). Mediates recruitment of the HUSH complex to H3K9me3 sites: the HUSH complex is recruited to genomic loci rich in H3K9me3 and is probably required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3 (PubMed:26022416). Binds H3K9me and promotes DNA methylation by recruiting DNMT3A to target CpG sites; these can be situated within the coding region of the gene (PubMed:20871592). Mediates down-regulation of CDH1 expression (PubMed:20871592). {ECO:0000269|PubMed:20871592, ECO:0000269|PubMed:26022416}. | 16.04 | |||||
| dfaMRCKA | Serine/threonine-protein kinase MRCK alpha | 7 | 262 | 90.34 | 90.82 | ND | 0.40 | 0.00 | 0.6 | Mammalian | Highly expressed in the brain and lung and present in lower levels in all other tissues tested. {ECO:0000269|PubMed:9418861}. | Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates: PPP1R12A, LIMK1 and LIMK2. May play a role in TFRC-mediated iron uptake. {ECO:0000269|PubMed:18854160, ECO:0000269|PubMed:21457715, ECO:0000269|PubMed:9418861}. | 15.11 | |||||
| dfaMRCKB | Serine/threonine-protein kinase MRCK beta | 2 | 64 | 99.82 | 93.05 | ND | 0.01 | 0.71 | 0.2 | Mammalian | Expressed in all tissues examined, with high levels in heart, brain, placenta and lung. {ECO:0000269|PubMed:10198171}. | Kinase | Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates PPP1R12A. {ECO:0000269|PubMed:18854160, ECO:0000269|PubMed:21457715, ECO:0000269|PubMed:21949762}. | 16.04 | ||||
| dfaMSHR | Melanocyte-stimulating hormone receptor | 1 | 371 | 97.38 | 98.32 | ND | 0.37 | 0.54 | 0.5 | Mammalian | Melanocytes and corticoadrenal tissue. | Family A G protein-coupled receptor | Melanoma, cutaneous malignant 5 (CMM5) [MIM:613099]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:17434924, ECO:0000269|PubMed:19338054}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. | 16.04 | |||
| dfaMTAP | S-methyl-5'-thioadenosine phosphorylase {ECO:0000255|HAMAP-Rule:MF_03155} | 1 | 66 | 99.96 | 99.97 | ND | 0.75 | 0.82 | 0.6 | Mammalian | Ubiquitously expressed. | Enzyme | Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) [MIM:112250]: An autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. Some patients show a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. {ECO:0000269|PubMed:22464254}. Note=The disease is caused by mutations affecting the gene represented in this entry. DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254). {ECO:0000269|PubMed:22464254}. Note=Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer. | Catalyzes the reversible phosphorylation of S-methyl-5'- thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S- adenosylmethionine. Has broad substrate specificity with 6- aminopurine nucleosides as preferred substrates. {ECO:0000255|HAMAP-Rule:MF_03155, ECO:0000269|PubMed:3091600}. | 15.11 | |||
| dfaMTLR | Motilin receptor | 3 | 222 | 98.45 | 99.73 | ND | 0.59 | 0.70 | 0.6 | Mammalian | Expressed only in thyroid, stomach, and bone marrow. | Family A G protein-coupled receptor | Eating disorders
Gastroesophageal Reflux Disease (GERD) Gastrointestinal Diseases and Disorders, miscellaneous Gastrointestinal reflux disorders Gastroparesis Irritable Bowel Syndrome (IBS) Obesity | Receptor for motilin. {ECO:0000269|PubMed:11322507}. | 16.04 | |||
| dfaMTOR | Serine/threonine-protein kinase mTOR | 4 | 1816 | 93.53 | 92.45 | ND | 0.83 | 0.86 | 0.6 | Mammalian | Expressed in numerous tissues, with highest levels in testis. {ECO:0000269|PubMed:12408816, ECO:0000269|PubMed:7809080}. | Enzyme | Smith-Kingsmore syndrome (SKS) [MIM:616638]: An autosomal dominant syndrome characterized by intellectual disability, macrocephaly, seizures, umbilical hernia, and facial dysmorphic features. {ECO:0000269|PubMed:25851998, ECO:0000269|PubMed:26542245}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1- mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1- pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser- 758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. Regulates osteoclastogensis by adjusting the expression of CEBPB isoforms (By similarity). {ECO:0000250|UniProtKB:Q9JLN9, ECO:0000269|PubMed:12087098, ECO:0000269|PubMed:12150925, ECO:0000269|PubMed:12150926, ECO:0000269|PubMed:12231510, ECO:0000269|PubMed:12718876, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15268862, ECO:0000269|PubMed:15467718, ECO:0000269|PubMed:15545625, ECO:0000269|PubMed:15718470, ECO:0000269|PubMed:18497260, ECO:0000269|PubMed:18762023, ECO:0000269|PubMed:18925875, ECO:0000269|PubMed:20516213, ECO:0000269|PubMed:20537536, ECO:0000269|PubMed:21659604, ECO:0000269|PubMed:23429703, ECO:0000269|PubMed:23429704}. | Serine/threonine-protein kinase mTOR inhibitor: Everolimus, Sirolimus, Temsirolimus Serine/threonine-protein kinase mTOR potentiator: Pimecrolimus | 15.11 | ||
| dfaMTP | Microsomal triglyceride transfer protein large subunit | 1 | 151 | 99.76 | 99.34 | ND | 0.70 | 0.70 | 0.5 | Mammalian | Liver and small intestine. Also found in ovary, testis and kidney. {ECO:0000269|PubMed:7961826}. | Other cytosolic protein | Abetalipoproteinemia (ABL) [MIM:200100]: An autosomal recessive disorder of lipoprotein metabolism. Affected individuals produce virtually no circulating apolipoprotein B-containing lipoproteins (chylomicrons, VLDL, LDL, lipoprotein(A)). Malabsorption of the antioxidant vitamin E occurs, leading to spinocerebellar and retinal degeneration. {ECO:0000269|PubMed:10679949, ECO:0000269|PubMed:10946006, ECO:0000269|PubMed:22236406, ECO:0000269|PubMed:23475612, ECO:0000269|PubMed:25108285, ECO:0000269|PubMed:26224785, ECO:0000269|PubMed:8939939}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces (PubMed:23475612, PubMed:8939939, PubMed:26224785, PubMed:25108285, PubMed:22236406). Required for the secretion of plasma lipoproteins that contain apolipoprotein B (PubMed:23475612, PubMed:8939939, PubMed:26224785). {ECO:0000269|PubMed:22236406, ECO:0000269|PubMed:23475612, ECO:0000269|PubMed:25108285, ECO:0000269|PubMed:26224785, ECO:0000269|PubMed:8939939}. | Microsomal triglyceride transfer protein large subunit antagonist: Hesperetin, Lomitapide | 16.04 | ||
| dfaMTR1A | Melatonin receptor type 1A | 1 | 586 | 97.46 | 95.83 | ND | 0.56 | 0.65 | 0.7 | Mammalian | Expressed in hypophyseal pars tuberalis and hypothalamic suprachiasmatic nuclei (SCN). Hippocampus. | Family A G protein-coupled receptor | Chronic Primary Insomnia
Insomnia Major Depressive Disorder | High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. | Melatonin receptor type 1A agonist: Agomelatine, Melatonin, Tasimelteon Melatonin receptor type 1A multitarget: Ramelteon | 16.04 | ||
| dfaMTR1B | Melatonin receptor type 1B | 2 | 487 | 95.51 | 97.84 | ND | 0.68 | 0.71 | 0.7 | Mammalian | Expressed in retina and less in brain and hippocampus. | Family A G protein-coupled receptor | Insomnia | High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. | Melatonin receptor type 1B agonist: Agomelatine, Melatonin, Tasimelteon Melatonin receptor type 1B multitarget: Ramelteon | 16.04 | ||
| dfaMYLK | Myosin light chain kinase, smooth muscle | 5 | 104 | 91.35 | 92.92 | ND | 0.76 | 0.00 | 0.5 | Mammalian | Smooth muscle and non-muscle isozymes are expressed in a wide variety of adult and fetal tissues and in cultured endothelium with qualitative expression appearing to be neither tissue- nor development-specific. Non-muscle isoform 2 is the dominant splice variant expressed in various tissues. Telokin has been found in a wide variety of adult and fetal tissues. Accumulates in well differentiated enterocytes of the intestinal epithelium in response to tumor necrosis factor (TNF). {ECO:0000269|PubMed:10536370, ECO:0000269|PubMed:16835238, ECO:0000269|PubMed:20053363, ECO:0000269|PubMed:8575746}. | Kinase | Aortic aneurysm, familial thoracic 7 (AAT7) [MIM:613780]: A disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance. {ECO:0000269|PubMed:21055718}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). Also regulates actin-myosin interaction through a non-kinase activity. Phosphorylates PTK2B/PYK2 and myosin light-chains. Involved in the inflammatory response (e.g. apoptosis, vascular permeability, leukocyte diapedesis), cell motility and morphology, airway hyperreactivity and other activities relevant to asthma. Required for tonic airway smooth muscle contraction that is necessary for physiological and asthmatic airway resistance. Necessary for gastrointestinal motility. Implicated in the regulation of endothelial as well as vascular permeability, probably via the regulation of cytoskeletal rearrangements. In the nervous system it has been shown to control the growth initiation of astrocytic processes in culture and to participate in transmitter release at synapses formed between cultured sympathetic ganglion cells. Critical participant in signaling sequences that result in fibroblast apoptosis. Plays a role in the regulation of epithelial cell survival. Required for epithelial wound healing, especially during actomyosin ring contraction during purse-string wound closure. Mediates RhoA- dependent membrane blebbing. Triggers TRPC5 channel activity in a calcium-dependent signaling, by inducing its subcellular localization at the plasma membrane. Promotes cell migration (including tumor cells) and tumor metastasis. PTK2B/PYK2 activation by phosphorylation mediates ITGB2 activation and is thus essential to trigger neutrophil transmigration during acute lung injury (ALI). May regulate optic nerve head astrocyte migration. Probably involved in mitotic cytoskeletal regulation. Regulates tight junction probably by modulating ZO-1 exchange in the perijunctional actomyosin ring. Mediates burn-induced microvascular barrier injury; triggers endothelial contraction in the development of microvascular hyperpermeability by phosphorylating MLC. Essential for intestinal barrier dysfunction. Mediates Giardia spp.-mediated reduced epithelial barrier function during giardiasis intestinal infection via reorganization of cytoskeletal F-actin and tight junctional ZO-1. Necessary for hypotonicity-induced Ca(2+) entry and subsequent activation of volume-sensitive organic osmolyte/anion channels (VSOAC) in cervical cancer cells. Responsible for high proliferative ability of breast cancer cells through anti-apoptosis. {ECO:0000269|PubMed:11113114, ECO:0000269|PubMed:11976941, ECO:0000269|PubMed:15020676, ECO:0000269|PubMed:15825080, ECO:0000269|PubMed:16284075, ECO:0000269|PubMed:16723733, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18710790, ECO:0000269|PubMed:19826488, ECO:0000269|PubMed:20139351, ECO:0000269|PubMed:20181817, ECO:0000269|PubMed:20375339, ECO:0000269|PubMed:20453870}. | 16.04 | |||
| dfaMYLK3 | Myosin light chain kinase 3 | 2 | 58 | 100.00 | 95.76 | ND | 0.94 | 0.97 | 0.2 | Mammalian | Restricted to heart. {ECO:0000269|PubMed:17885681}. | Kinase | Kinase that phosphorylates MYL2 in vitro. Promotes sarcomere formation in cardiomyocytes and increases cardiomyocyte contractility (By similarity). {ECO:0000250}. | 16.04 | ||||
| dfaMYLK4 | Myosin light chain kinase family member 4 | 6 | 65 | 96.52 | 96.58 | ND | 0.15 | 0.98 | 0.5 | Mammalian | Kinase | 15.11 | ||||||
| dfaMYO3A | Myosin-IIIa | 2 | 64 | 99.71 | 94.96 | ND | 0.31 | 0.93 | 0.4 | Mammalian | Strongest expression in retina, retinal pigment epithelial cells, cochlea and pancreas. | Kinase | Deafness, autosomal recessive, 30 (DFNB30) [MIM:607101]: A form of non-syndromic deafness characterized by bilateral progressive hearing loss, which first affects the high frequencies. Hearing loss begins in the second decade, and by age 50 is severe in high and middle frequencies and moderate at low frequencies. {ECO:0000269|PubMed:12032315}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Probable actin-based motor with a protein kinase activity. Probably plays a role in vision and hearing. {ECO:0000269|PubMed:12032315}. | 16.04 | |||
| dfaMYO3B | Myosin-IIIb | 3 | 64 | 99.89 | 99.58 | ND | 0.96 | 0.88 | 0.1 | Mammalian | Expressed in retina, kidney and testis. | Kinase | Probable actin-based motor with a protein kinase activity. | 16.04 | ||||
| dfaNAAA | N-acylethanolamine-hydrolyzing acid amidase | 2 | 54 | 99.38 | 97.94 | ND | 0.53 | 0.71 | 0.7 | Mammalian | Expressed in numerous tissues, with highest levels in liver and kidney, followed by pancreas. {ECO:0000269|PubMed:10610717}. | Enzyme | Degrades bioactive fatty acid amides to their corresponding acids, with the following preference: N- palmitoylethanolamine > N-myristoylethanolamine > N- lauroylethanolamine = N-stearoylethanolamine > N- arachidonoylethanolamine > N-oleoylethanolamine. Also exhibits weak hydrolytic activity against the ceramides N- lauroylsphingosine and N-palmitoylsphingosine. {ECO:0000269|PubMed:15655246}. | 16.04 | ||||
| dfaNAMPT | Nicotinamide phosphoribosyltransferase | 1 | 309 | 99.47 | 99.60 | ND | 0.57 | 0.59 | 0.7 | Mammalian | Expressed in large amounts in bone marrow, liver tissue, and muscle. Also present in heart, placenta, lung, and kidney tissues. | Enzyme | Catalyzes the condensation of nicotinamide with 5- phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway. The secreted form behaves both as a cytokine with immunomodulating properties and an adipokine with anti-diabetic properties, it has no enzymatic activity, partly because of lack of activation by ATP, which has a low level in extracellular space and plasma. Plays a role in the modulation of circadian clock function. NAMPT-dependent oscillatory production of NAD regulates oscillation of clock target gene expression by releasing the core clock component: CLOCK-ARNTL/BMAL1 heterodimer from NAD-dependent SIRT1-mediated suppression (By similarity). {ECO:0000250|UniProtKB:Q99KQ4, ECO:0000269|PubMed:24130902}. | 15.11 | ||||
| dfaNCEH1 | Neutral cholesterol ester hydrolase 1 | 2 | 107 | 94.51 | 99.49 | ND | 0.79 | 0.80 | 0.4 | Mammalian | Expressed in monocyte-derived macrophages. Up- regulated in invasive melanoma and breast carcinoma cell lines. {ECO:0000269|PubMed:12149457, ECO:0000269|PubMed:18782767}. | Enzyme | Hydrolyzes 2-acetyl monoalkylglycerol ether, the penultimate precursor of the pathway for de novo synthesis of platelet-activating factor. May be responsible for cholesterol ester hydrolysis in macrophages, thereby contributing to the development of atherosclerosis. Also involved in organ detoxification by hydrolyzing exogenous organophosphorus compounds. May contribute to cancer pathogenesis by promoting tumor cell migration. {ECO:0000269|PubMed:17052608}. | 16.04 | ||||
| dfaNEK2 | Serine/threonine-protein kinase Nek2 | 4 | 332 | 86.31 | 89.54 | ND | 0.34 | 0.52 | 0.5 | Mammalian | Isoform 1 and isoform 2 are expressed in peripheral blood T-cells and a wide variety of transformed cell types. Isoform 1 and isoform 4 are expressed in the testis. Up- regulated in various cancer cell lines, as well as primary breast tumors. {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:15659832}. | Kinase | Retinitis pigmentosa 67 (RP67) [MIM:615565]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:24043777}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGOL1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Phosphorylates CEP68 and CNTLN directly or indirectly (PubMed:24554434). NEK2-mediated phosphorylation of CEP68 promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis (PubMed:25704143). Involved in the regulation of centrosome disjunction (PubMed:26220856). {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:12857871, ECO:0000269|PubMed:14978040, ECO:0000269|PubMed:15358203, ECO:0000269|PubMed:15388344, ECO:0000269|PubMed:17283141, ECO:0000269|PubMed:17621308, ECO:0000269|PubMed:17626005, ECO:0000269|PubMed:18086858, ECO:0000269|PubMed:18297113, ECO:0000269|PubMed:20034488, ECO:0000269|PubMed:21076410, ECO:0000269|PubMed:24554434, ECO:0000269|PubMed:25704143, ECO:0000269|PubMed:26220856}. Isoform 1: Phosphorylates and activates NEK11 in G1/S- arrested cells. {ECO:0000269|PubMed:15161910}. Isoform 2: Not present in the nucleolus and, in contrast to isoform 1, does not phosphorylate and activate NEK11 in G1/S- arrested cells. {ECO:0000269|PubMed:15161910}. | 15.11 | |||
| dfaNEK4 | Serine/threonine-protein kinase Nek4 | 4 | 200 | 91.77 | 94.00 | ND | 0.47 | 0.50 | 0.5 | Mammalian | Highest expression in adult heart, followed by pancreas, skeletal muscle, brain, testis, retina, liver, kidney, lung and placenta. Present in most primary carcinomas. {ECO:0000269|PubMed:21685204, ECO:0000269|PubMed:8208544}. | Kinase | Protein kinase that seems to act exclusively upon threonine residues (By similarity). Required for normal entry into proliferative arrest after a limited number of cell divisions, also called replicative senescence. Required for normal cell cycle arrest in response to double-stranded DNA damage. {ECO:0000250|UniProtKB:Q9Z1J2, ECO:0000269|PubMed:22851694}. | 16.04 | ||||
| dfaNEK5 | Serine/threonine-protein kinase Nek5 | 4 | 64 | 97.17 | 95.99 | ND | 0.11 | 0.00 | 0.5 | Mammalian | Kinase | 16.04 | ||||||
| dfaNEK6 | Serine/threonine-protein kinase Nek6 | 2 | 97 | 81.32 | 94.74 | ND | 0.89 | 0.92 | 0.3 | Mammalian | Ubiquitous, with highest expression in heart and skeletal muscle. Up-regulated in a variety of malignant cancers, such as breast, colon, lung, and gastric cancers. {ECO:0000269|PubMed:12054534, ECO:0000269|PubMed:20407017}. | Kinase | Protein kinase which plays an important role in mitotic cell cycle progression. Required for chromosome segregation at metaphase-anaphase transition, robust mitotic spindle formation and cytokinesis. Phosphorylates ATF4, CIR1, PTN, RAD26L, RBBP6, RPS7, RPS6KB1, TRIP4, STAT3 and histones H1 and H3. Phosphorylates KIF11 to promote mitotic spindle formation. Involved in G2/M phase cell cycle arrest induced by DNA damage. Inhibition of activity results in apoptosis. May contribute to tumorigenesis by suppressing p53/TP53-induced cancer cell senescence. {ECO:0000269|PubMed:12054534, ECO:0000269|PubMed:14563848, ECO:0000269|PubMed:18728393, ECO:0000269|PubMed:19001501, ECO:0000269|PubMed:19414596, ECO:0000269|PubMed:20407017, ECO:0000269|PubMed:20873783, ECO:0000269|PubMed:21099361}. | 16.04 | ||||
| dfaNEK9 | Serine/threonine-protein kinase Nek9 | 2 | 64 | 99.80 | 92.06 | ND | 0.60 | 0.92 | 0.2 | Mammalian | Most abundant in heart, liver, kidney and testis. Also expressed in smooth muscle cells and fibroblasts. | Kinase | Pleiotropic regulator of mitotic progression, participating in the control of spindle dynamics and chromosome separation. Phosphorylates different histones, myelin basic protein, beta-casein, and BICD2. Phosphorylates histone H3 on serine and threonine residues and beta-casein on serine residues. Important for G1/S transition and S phase progression. Phosphorylates NEK6 and NEK7 and stimulates their activity by releasing the autoinhibitory functions of Tyr-108 and Tyr-97 respectively. {ECO:0000269|PubMed:12840024, ECO:0000269|PubMed:14660563, ECO:0000269|PubMed:19941817}. | 16.04 | ||||
| dfaNEP | Neprilysin | 1 | 835 | 98.97 | 98.53 | ND | 0.52 | 0.52 | 0.6 | Mammalian | Protease | Congestive Heart Failure
Hypertension Prostate cancer (early stage hormone sensitive) | Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:17101991). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:15283675). Involved in the degradation of atrial natriuretic factor (ANF) (PubMed:2531377, PubMed:2972276). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers (PubMed:20876573). {ECO:0000269|PubMed:15283675, ECO:0000269|PubMed:17101991, ECO:0000269|PubMed:20876573, ECO:0000269|PubMed:2531377, ECO:0000269|PubMed:2972276}. | Neprilysin antagonist: Sacubitril Neprilysin inhibitor: Candoxatril Neprilysin substrate: Liraglutide | 15.11 | |||
| dfaNIM1 | Serine/threonine-protein kinase NIM1 | 4 | 65 | 99.74 | 97.59 | ND | 0.33 | 0.97 | 0.3 | Mammalian | Kinase | 16.04 | ||||||
| dfaNISCH | Nischarin | 4 | 135 | 90.48 | 91.93 | ND | 0.54 | 0.67 | 0.9 | Mammalian | Isoform 1, isoform 3 and isoform 4 are expressed in brain. Isoform 1 is expressed in endocrine tissues. {ECO:0000269|PubMed:15028621, ECO:0000269|PubMed:9851558}. | Other cytosolic protein | Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-signaling cascades triggering to cell survival, growth and migration. Its activation by the agonist rilmenidine induces an increase in phosphorylation of mitogen-activated protein kinases MAPK1 and MAPK3 in rostral ventrolateral medulla (RVLM) neurons that exhibited rilmenidine-evoked hypotension (By similarity). Blocking its activation with efaroxan abolished rilmenidine-induced mitogen-activated protein kinase phosphorylation in RVLM neurons (By similarity). Acts as a modulator of Rac-regulated signal transduction pathways (By similarity). Suppresses Rac1-stimulated cell migration by interacting with PAK1 and inhibiting its kinase activity (By similarity). Also blocks Pak-independent Rac signaling by interacting with RAC1 and inhibiting Rac1-stimulated NF-kB response element and cyclin D1 promoter activation (By similarity). Inhibits also LIMK1 kinase activity by reducing LIMK1 'Tyr-508' phosphorylation (By similarity). Inhibits Rac-induced cell migration and invasion in breast and colon epithelial cells (By similarity). Inhibits lamellipodia formation, when overexpressed (By similarity). Plays a role in protection against apoptosis. Involved in association with IRS4 in the enhancement of insulin activation of MAPK1 and MAPK3. When overexpressed, induces a redistribution of cell surface ITGA5 integrin to intracellular endosomal structures. {ECO:0000250, ECO:0000269|PubMed:10882231, ECO:0000269|PubMed:12868002, ECO:0000269|PubMed:15028619, ECO:0000269|PubMed:15028621, ECO:0000269|PubMed:15475348}. | Nischarin agonist: Moxonidine, Tizanidine | 16.04 | |||
| dfaNK1R | Substance-P receptor | 1 | 1844 | 98.68 | 97.55 | ND | 0.59 | 0.60 | 0.8 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Analgesics
Asthma Mood [affective] disorders Neuropathic pain Visceral pain | This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance P > substance K > neuromedin-K. | Substance-P receptor antagonist: Aprepitant, Ketamine, Netupitant, Vapreotide | 16.04 | ||
| dfaNK2R | Substance-K receptor | 2 | 524 | 94.34 | 94.93 | ND | 0.80 | 0.79 | 0.6 | Mammalian | Family A G protein-coupled receptor | Analgesics
Anxiety Disorders Asthma Depression Generalized Anxiety Disorders (GAD) Pain, Acute or Chronic Urinary incontinence | This is a receptor for the tachykinin neuropeptide substance K (neurokinin A). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance K > neuromedin-K > substance P. {ECO:0000269|PubMed:1659297}. | 16.04 | ||||
| dfaNK3R | Neuromedin-K receptor | 4 | 440 | 98.04 | 99.55 | ND | 0.80 | 0.81 | 0.5 | Mammalian | Family A G protein-coupled receptor | Hypogonadotropic hypogonadism 11 with or without anosmia (HH11) [MIM:614840]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:19079066, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in TACR3 as well as in other HH-associated genes including FGFR1, SPRY4 and KAL1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}. | This is a receptor for the tachykinin neuropeptide neuromedin-K (neurokinin B). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: neuromedin-K > substance K > substance P. | 16.04 | ||||
| dfaNLK | Serine/threonine-protein kinase NLK | 7 | 83 | 98.82 | 96.97 | ND | 0.78 | 0.87 | 0.4 | Mammalian | Kinase | Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination. Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2. Activation of this pathway causes binding to and phosphorylation of the histone methyltransferase SETDB1. The NLK- SETDB1 complex subsequently interacts with PPARG, leading to methylation of PPARG target promoters at histone H3K9 and transcriptional silencing. The resulting loss of PPARG target gene transcription inhibits adipogenesis and promotes osteoblastogenesis in mesenchymal stem cells (MSCs). Negative regulator of the canonical Wnt/beta-catenin signaling pathway. Binds to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the ubiquitination and subsequent proteolysis of LEF1. Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes. Negative regulator of the Notch signaling pathway. Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1. Negative regulator of the MYB family of transcription factors. Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP. Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself. Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1. Upon IL1B stimulus, cooperates with ATF5 to activate the transactivation activity of C/EBP subfamily members. Phosphorylates ATF5 but also stabilizes ATF5 protein levels in a kinase-independent manner (PubMed:25512613). {ECO:0000250|UniProtKB:O54949, ECO:0000269|PubMed:12482967, ECO:0000269|PubMed:14960582, ECO:0000269|PubMed:15004007, ECO:0000269|PubMed:15764709, ECO:0000269|PubMed:17952062, ECO:0000269|PubMed:20061393, ECO:0000269|PubMed:20118921, ECO:0000269|PubMed:20874444, ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:25512613}. | 16.04 | |||||
| dfaNMBR | Neuromedin-B receptor | 2 | 129 | 99.77 | 99.80 | ND | 0.91 | 0.84 | 0.3 | Mammalian | Expressed in epididymis (at protein level). {ECO:0000269|PubMed:20736409}. | Family A G protein-coupled receptor | Receptor for neuromedin-B. | 16.04 | ||||
| dfaNMDE2 | Glutamate receptor ionotropic, NMDA 2B | 3 | 330 | 96.13 | 95.62 | ND | 0.63 | 0.60 | 0.7 | Mammalian | Ligand-gated ion channel | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. In concert with DAPK1 at extrasynaptic sites, acts as a central mediator for stroke damage. Its phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity inducing injurious Ca2+ influx through them, resulting in an irreversible neuronal death (By similarity). {ECO:0000250}. | 15.11 | |||||
| dfaNMDE3 | Glutamate receptor ionotropic, NMDA 2C | 7 | 169 | 91.97 | 87.59 | ND | 0.57 | 0.74 | 0.6 | Mammalian | Mainly expressed in brain with predominant expression is in the cerebellum, also present in the hippocampus, amygdala, caudate nucleus, corpus callosum, subthalamic nuclei and thalamus. Detected in the heart, skeletal muscle and pancreas. | Ligand-gated ion channel | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. | Glutamate receptor ionotropic, NMDA 2C : Glycine Glutamate receptor ionotropic, NMDA 2C antagonist: Pethidine | 16.04 | |||
| dfaNMDE4 | Glutamate receptor ionotropic, NMDA 2D | 2 | 43 | 99.86 | 99.97 | ND | 0.60 | 0.09 | 0.1 | Mammalian | Expressed in brain, mainly in the subcortical region. | Ligand-gated ion channel | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. | 15.11 | ||||
| dfaNMDZ1 | Glutamate receptor ionotropic, NMDA 1 | 5 | 606 | 95.40 | 88.96 | ND | 0.70 | 0.72 | 0.6 | Mammalian | Respiratory depression | Ligand-gated ion channel | Mental retardation, autosomal dominant 8 (MRD8) [MIM:614254]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21376300}. Note=The disease is caused by mutations affecting the gene represented in this entry. | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity). {ECO:0000250}. | Glutamate receptor ionotropic, NMDA 1 : Gabapentin Glutamate receptor ionotropic, NMDA 1 activator: Acetylcysteine Glutamate receptor ionotropic, NMDA 1 antagonist: Acamprosate, Ifenprodil, Ketobemidone, Orphenadrine, Pentobarbital, Pethidine, Phenobarbital, Secobarbital Glutamate receptor ionotropic, NMDA 1 binder: Memantine Glutamate receptor ionotropic, NMDA 1 blocker: Atomoxetine Glutamate receptor ionotropic, NMDA 1 inhibitor: Milnacipran | 15.11 | ||
| dfaNMT1 | Glycylpeptide N-tetradecanoyltransferase 1 | 1 | 40 | 98.46 | 82.96 | ND | 0.39 | 0.68 | 1.0 | Mammalian | Heart, gut, kidney, liver and placenta. | Enzyme | Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins. {ECO:0000269|PubMed:25255805, ECO:0000269|PubMed:9353336, ECO:0000269|PubMed:9506952}. | 15.11 | ||||
| dfaNOD1 | Nucleotide-binding oligomerization domain-containing protein 1 | 9 | 193 | 93.10 | 89.86 | ND | 0.03 | 0.62 | 0.6 | Mammalian | Highly expressed in adult heart, skeletal muscle, pancreas, spleen and ovary. Also detected in placenta, lung, liver, kidney, thymus, testis, small intestine and colon. | Enhances caspase-9-mediated apoptosis. Induces NF-kappa- B activity via RIPK2 and IKK-gamma. Confers responsiveness to intracellular bacterial lipopolysaccharides (LPS). Forms an intracellular sensing system along with ARHGEF2 for the detection of microbial effectors during cell invasion by pathogens. Required for RHOA and RIPK2 dependent NF-kappa-B signaling pathway activation upon S.flexneri cell invasion. Involved not only in sensing peptidoglycan (PGN)-derived muropeptides but also in the activation of NF-kappa-B by Shigella effector proteins IpgB2 and OspB. Recruits NLRP10 to the cell membrane following bacterial infection. {ECO:0000269|PubMed:11058605, ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:19043560, ECO:0000269|PubMed:22672233}. | 16.04 | |||||
| dfaNOS1 | Nitric oxide synthase, brain | 6 | 1028 | 91.31 | 89.33 | ND | 0.56 | 0.53 | 0.6 | Mammalian | Isoform 1 is ubiquitously expressed: detected in skeletal muscle and brain, also in testis, lung and kidney, and at low levels in heart, adrenal gland and retina. Not detected in the platelets. Isoform 3 is expressed only in testis. Isoform 4 is detected in testis, skeletal muscle, lung, and kidney, at low levels in the brain, but not in the heart and adrenal gland. | Enzyme | Helminth infection
Migraine and Cluster Headaches Schizophrenia | Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. | Nitric oxide synthase, brain : Flavin adenine dinucleotide, L-Citrulline Nitric oxide synthase, brain substrate: Doxorubicin | 15.11 | ||
| dfaNOS2 | Nitric oxide synthase, inducible | 3 | 1115 | 91.23 | 81.10 | ND | 0.64 | 0.68 | 0.7 | Mammalian | Expressed in the liver, retina, bone cells and airway epithelial cells of the lung. Not expressed in the platelets. | Enzyme | Ischemia reperfusion injuries | Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body (PubMed:7531687, PubMed:7544004). In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such PTGS2/COX2 (By similarity). As component of the iNOS-S100A8/9 transnitrosylase complex involved in the selective inflammatory stimulus-dependent S-nitrosylation of GAPDH on 'Cys-247' implicated in regulation of the GAIT complex activity and probably multiple targets including ANXA5, EZR, MSN and VIM (PubMed:25417112). Involved in inflammation, enhances the synthesis of proinflammatory mediators such as IL6 and IL8 (PubMed:19688109). {ECO:0000250|UniProtKB:P29477, ECO:0000269|PubMed:19688109, ECO:0000269|PubMed:25417112, ECO:0000269|PubMed:7531687, ECO:0000269|PubMed:7544004}. | Nitric oxide synthase, inducible : L-Arginine, L-Citrulline Nitric oxide synthase, inducible agonist: Triflusal Nitric oxide synthase, inducible inhibitor: Miconazole Nitric oxide synthase, inducible negative modulator: Dexamethasone Nitric oxide synthase, inducible substrate: Doxorubicin | 15.11 | ||
| dfaNOS3 | Nitric oxide synthase, endothelial | 6 | 784 | 93.02 | 86.36 | ND | 0.35 | 0.00 | 0.5 | Mammalian | Platelets, placenta, liver and kidney. {ECO:0000269|PubMed:7515611}. | Enzyme | Note=Variation in NOS3 seem to be associated with susceptibility to coronary spasm. {ECO:0000269|PubMed:11740345, ECO:0000269|PubMed:9737779}. | Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1. | Nitric oxide synthase, endothelial : Apremilast, L-Arginine, L-Citrulline Nitric oxide synthase, endothelial cofactor: Tetrahydrobiopterin Nitric oxide synthase, endothelial inhibitor: Miconazole Nitric oxide synthase, endothelial substrate: Doxorubicin | 15.11 | ||
| dfaNOX1 | NADPH oxidase 1 | 5 | 64 | 95.88 | 91.39 | ND | 0.04 | 0.79 | 0.5 | Mammalian | NOH-1L is detected in colon, uterus, prostate, and colon carcinoma, but not in peripheral blood leukocytes. NOH- 1S is detected only in colon and colon carcinoma cells. | Transmembrane 1-electron transfer carriers | Note=Defects in NOX1 may play a role in the pathogenesis of very early onset inflammatory bowel disease (VEOIBD), a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology diagnosed before 6 years of age. VEOIBD is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but the phenotype of children with onset of Crohn disease occurring younger than the age of 10 is predominantly colonic, with a lower risk of ileal disease. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. {ECO:0000269|PubMed:26301257}. | NOH-1S is a voltage-gated proton channel that mediates the H(+) currents of resting phagocytes and other tissues. It participates in the regulation of cellular pH and is blocked by zinc. NOH-1L is a pyridine nucleotide-dependent oxidoreductase that generates superoxide and might conduct H(+) ions as part of its electron transport mechanism, whereas NOH-1S does not contain an electron transport chain. | 16.04 | |||
| dfaNOX4 | NADPH oxidase 4 | 1 | 88 | 83.92 | 90.94 | ND | 0.69 | 0.77 | 0.4 | Mammalian | Expressed by distal tubular cells in kidney cortex and in endothelial cells (at protein level). Widely expressed. Strongly expressed in kidney and to a lower extent in heart, adipocytes, hepatoma, endothelial cells, skeletal muscle, brain, several brain tumor cell lines and airway epithelial cells. {ECO:0000269|PubMed:11032835, ECO:0000269|PubMed:11376945, ECO:0000269|PubMed:15210697, ECO:0000269|PubMed:16324151}. | Enzyme | Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 5 and isoform 6 display reduced activity. Isoform 4: Involved in redox signaling in vascular cells. Constitutively and NADPH-dependently generates reactive oxygen species (ROS). Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Displays an increased activity relative to isoform 1. | 16.04 | ||||
| dfaNPBW1 | Neuropeptides B/W receptor type 1 | 2 | 271 | 97.51 | 94.74 | ND | 0.77 | 0.71 | 0.4 | Mammalian | Found in cerebellum and frontal cortex. Detected at high levels in hippocampus, amygdala and trachea; at moderate levels in fetal brain, pituitary gland and prostate. Not in caudate, accumbens, kidney or liver. Also detected at high levels in lung carcinoma. {ECO:0000269|PubMed:12401809}. | Family A G protein-coupled receptor | Interacts specifically with a number of opioid ligands. Receptor for neuropeptides B and W, which may be involved in neuroendocrine system regulation, food intake and the organization of other signals. Has a higher affinity for neuropeptide B. | 16.04 | ||||
| dfaNPC1 | Niemann-Pick C1 protein | 2 | 6046 | 87.94 | 82.07 | ND | 0.12 | 0.00 | 0.3 | Mammalian | Niemann-Pick disease C1 (NPC1) [MIM:257220]: A lysosomal storage disorder that affects the viscera and the central nervous system. It is due to defective intracellular processing and transport of low-density lipoprotein derived cholesterol. It causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Niemann-Pick disease type C1 has a highly variable clinical phenotype. Clinical features include variable hepatosplenomegaly and severe progressive neurological dysfunction such as ataxia, dystonia and dementia. The age of onset can vary from infancy to late adulthood. An allelic variant of Niemann-Pick disease type C1 is found in people with Nova Scotia ancestry. Patients with the Nova Scotian clinical variant are less severely affected. {ECO:0000269|PubMed:10480349, ECO:0000269|PubMed:10521290, ECO:0000269|PubMed:10521297, ECO:0000269|PubMed:11182931, ECO:0000269|PubMed:11333381, ECO:0000269|PubMed:11349231, ECO:0000269|PubMed:11479732, ECO:0000269|PubMed:11545687, ECO:0000269|PubMed:11754101, ECO:0000269|PubMed:12401890, ECO:0000269|PubMed:12408188, ECO:0000269|PubMed:12554680, ECO:0000269|PubMed:12955717, ECO:0000269|PubMed:15774455, ECO:0000269|PubMed:16098014, ECO:0000269|PubMed:16126423, ECO:0000269|PubMed:16802107, ECO:0000269|PubMed:9211849, ECO:0000269|PubMed:9634529}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. Both NPC1 and NPC2 function as the cellular 'tag team duo' (TTD) to catalyze the mobilization of cholesterol within the multivesicular environment of the late endosome (LE) to effect egress through the limiting bilayer of the LE. NPC2 binds unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes and transfers it to the cholesterol-binding pocket of the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket and is exported from the limiting membrane of late endosomes/ lysosomes to the ER and plasma membrane by an unknown mechanism. Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals. {ECO:0000269|PubMed:18772377, ECO:0000269|PubMed:19563754}. (Microbial infection) Acts as an endosomal entry receptor for ebolavirus. {ECO:0000269|PubMed:21866103, ECO:0000269|PubMed:25855742}. | 16.04 | |||||
| dfaNPCL1 | Niemann-Pick C1-like protein 1 | 2 | 96 | 99.62 | 99.87 | ND | 0.68 | 0.76 | 0.2 | Mammalian | Widely expressed. Expressed in liver. Also expressed in small intestine, pancreas, kidney, lung, pancreas, spleen, heart, gall bladder, brain, testis, stomach and muscle. {ECO:0000269|PubMed:10783261, ECO:0000269|PubMed:14976318, ECO:0000269|PubMed:15671032}. | Other membrane protein | Hypercholesterolemia
Sitosterolemia | Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism. Acts as a negative regulator of NPC2 and down- regulates its expression and secretion by inhibiting its maturation and accelerating its degradation. {ECO:0000269|PubMed:15928087, ECO:0000269|PubMed:22095670}. | Niemann-Pick C1-like protein 1 inhibitor: Ezetimibe | 16.04 | ||
| dfaNPY1R | Neuropeptide Y receptor type 1 | 5 | 546 | 88.91 | 90.45 | ND | 0.64 | 0.78 | 0.7 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Analgesics
Anxiety disorder, unspecified Cardiovascular disease, unspecified Convulsions Drug dependence Metabolic disorder, unspecified Obesity Pain, unspecified Rhinitis | Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is NPY > [Pro-34] PYY, PYY and [Leu-31, Pro-34] NPY > NPY (2-36) > [Ile-31, Gln-34] PP and PYY (3-36) > PP > NPY free acid. | 16.04 | |||
| dfaNPY2R | Neuropeptide Y receptor type 2 | 2 | 336 | 84.63 | 89.18 | ND | 0.70 | 0.74 | 0.5 | Nature11159 | Mammalian | High levels in amygdala, corpus callosum, hippocampus and subthalamic nucleus. Also detectable in caudate nucleus, hypothalamus and substantia nigra. | Family A G protein-coupled receptor | Obesity | Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is PYY > NPY > PYY (3-36) > NPY (2-36) > [Ile-31, Gln-34] PP > [Leu- 31, Pro-34] NPY > PP, [Pro-34] PYY and NPY free acid. | Neuropeptide Y receptor type 2 other/unknown: Cysteamine | 16.04 | |
| dfaNPY5R | Neuropeptide Y receptor type 5 | 5 | 1068 | 97.36 | 96.01 | ND | 0.57 | 0.52 | 0.6 | Mammalian | Brain; hypothalamus. | Family A G protein-coupled receptor | Epilepsy
Obesity Opioid dependence Temporal lobe epilepsy | Receptor for neuropeptide Y and peptide YY. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity. Seems to be associated with food intake. Could be involved in feeding disorders. | 16.04 | |||
| dfaNQO1 | NAD(P)H dehydrogenase [quinone] 1 | 2 | 94 | 94.34 | 97.39 | ND | 0.72 | 0.82 | 0.8 | Mammalian | Enzyme | Cancer, unspecific
Nonsmall cell lung cancer | The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis. | NAD(P)H dehydrogenase [quinone] 1 : Flavin adenine dinucleotide, Menadione NAD(P)H dehydrogenase [quinone] 1 inducer: Vitamin E NAD(P)H dehydrogenase [quinone] 1 inhibitor: Dicoumarol NAD(P)H dehydrogenase [quinone] 1 substrate: Carboplatin, Cisplatin, Doxorubicin, Oxaliplatin | 15.11 | |||
| dfaNQO2 | Ribosyldihydronicotinamide dehydrogenase [quinone] | 6 | 220 | 91.13 | 86.11 | ND | 0.80 | 0.80 | 0.5 | Mammalian | Enzyme | Cancer, unspecific
Malaria Tumors | The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis. {ECO:0000269|PubMed:18254726}. | Ribosyldihydronicotinamide dehydrogenase [quinone] : Flavin adenine dinucleotide, Melatonin, Menadione Ribosyldihydronicotinamide dehydrogenase [quinone] inhibitor: Dabigatran etexilate, Primaquine | 15.11 | |||
| dfaNR1D1 | Nuclear receptor subfamily 1 group D member 1 | 1 | 60 | 99.94 | 99.46 | ND | 0.06 | 0.41 | 0.2 | Mammalian | Widely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Also expressed in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and macrophages. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues. Expression increases during the differentiation of pre-adipocytes into mature adipocytes. Expressed at high levels in some squamous carcinoma cell lines. {ECO:0000269|PubMed:2539258}. | Nuclear receptor | Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. {ECO:0000269|PubMed:12021280, ECO:0000269|PubMed:15761026, ECO:0000269|PubMed:16968709, ECO:0000269|PubMed:18006707, ECO:0000269|PubMed:19710360, ECO:0000269|PubMed:1971514, ECO:0000269|PubMed:21479263, ECO:0000269|PubMed:22184247, ECO:0000269|PubMed:23398316, ECO:0000269|PubMed:2539258}. | 16.04 | ||||
| dfaNR1H2 | Oxysterols receptor LXR-beta | 7 | 583 | 97.33 | 98.74 | ND | 0.72 | 0.63 | 0.5 | VirtualToxLab | Mammalian | Ubiquitous. | Nuclear receptor | Atherosclerosis
Dyslipidemia | Nuclear receptor. Binds preferentially to double- stranded oligonucleotide direct repeats having the consensus half- site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8; DLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Exhibits a ligand-dependent transcriptional activation activity (PubMed:25661920). {ECO:0000250|UniProtKB:Q60644, ECO:0000269|PubMed:25661920}. | 15.11 | ||
| dfaNR1H3 | Oxysterols receptor LXR-alpha | 3 | 521 | 95.78 | 94.32 | ND | 0.63 | 0.71 | 0.6 | VirtualToxLab | Mammalian | Visceral organs specific expression. Strong expression was found in liver, kidney and intestine followed by spleen and to a lesser extent the adrenals. | Nuclear receptor | Atherosclerosis
Cancer, unspecific | Nuclear receptor. Interaction with RXR shifts RXR from its role as a silent DNA-binding partner to an active ligand- binding subunit in mediating retinoid responses through target genes defined by LXRES. LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half- sites spaced by four nucleotides. Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Exhibits a ligand-dependent transcriptional activation activity (PubMed:25661920). {ECO:0000250|UniProtKB:Q9Z0Y9, ECO:0000269|PubMed:25661920}. | 15.11 | ||
| dfaNR1H4 | Bile acid receptor | 4 | 506 | 94.40 | 94.55 | ND | 0.73 | 0.67 | 0.4 | Mammalian | Liver and hepatocyte-related cells express mainly FXRalpha1-type isoforms with isoform 3 and isoform 4 in approximative equal proportions. In intestine and kidney mainly FXRalpha2-type isoforms are expressed with isoform 1 and isoform 2 in approximative equal proportions. Expressed in pancreatic beta cells and macrophages. {ECO:0000269|PubMed:19393742, ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:23928191}. | Nuclear receptor | Note=May be involved in intrahepatic cholestasis of pregnancy. {ECO:0000305|PubMed:17681172}. Note=May be involved in cholesterol cholelithiasis. {ECO:0000305|PubMed:17931734}. | Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'- AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homoestasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12660231, PubMed:12554753, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down- regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays a anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity). {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q62735, ECO:0000269|PubMed:10334992, ECO:0000269|PubMed:10334993, ECO:0000269|PubMed:10514450, ECO:0000269|PubMed:11579204, ECO:0000269|PubMed:11927623, ECO:0000269|PubMed:12554753, ECO:0000269|PubMed:12660231, ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12754200, ECO:0000269|PubMed:12806625, ECO:0000269|PubMed:12815072, ECO:0000269|PubMed:12891557, ECO:0000269|PubMed:14684751, ECO:0000269|PubMed:15239098, ECO:0000269|PubMed:15337761, ECO:0000269|PubMed:15471871, ECO:0000269|PubMed:16269519, ECO:0000269|PubMed:16946559, ECO:0000269|PubMed:17895379, ECO:0000269|PubMed:18621523, ECO:0000269|PubMed:19085950, ECO:0000269|PubMed:19410460, ECO:0000269|PubMed:19586769, ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:21242261, ECO:0000269|PubMed:21804189, ECO:0000269|PubMed:23928191, ECO:0000305|PubMed:21383957, ECO:0000305|PubMed:22820415}. Isoform 1: Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. Isoform 2: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA), NR0B2/SHP (inducible by unconjugated CDCA DCA and ACA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. Isoform 3: Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. Isoform 4: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, ACA and DCA), NR0B2/SHP (inducible by unconjugated CDCA, ACA and DCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; most efficient isoform compared to isoforms 1 to 3; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. | Bile acid receptor other: Chenodeoxycholic acid | 15.11 | ||
| dfaNR5A2 | Nuclear receptor subfamily 5 group A member 2 | 5 | 112 | 88.33 | 86.67 | ND | 0.42 | 0.57 | 0.4 | Mammalian | Abundantly expressed in pancreas, less in liver, very low levels in heart and lung. Expressed in the Hep-G2 cell line. Isoform 1 and isoform 2 seem to be present in fetal and adult liver and Hep-G2 cells. | Nuclear receptor | Binds to the sequence element 5'-AACGACCGACCTTGAG-3' of the enhancer II of hepatitis B virus genes, a critical cis-element of their expression and regulation. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development. | 16.04 | ||||
| dfaNTCP2 | Ileal sodium/bile acid cotransporter | 2 | 176 | 97.35 | 97.76 | ND | 0.49 | 0.58 | 0.7 | Mammalian | Hypokalaemia Pancreatitis | Electrochemical transporter | Primary bile acid malabsorption (PBAM) [MIM:613291]: An intestinal disorder associated with chronic watery diarrhea, excess fecal bile acids, steatorrhea and interruption of the enterohepatic circulation of bile acids. {ECO:0000269|PubMed:9109432}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine. Plays a key role in cholesterol metabolism. | Ileal sodium/bile acid cotransporter : Valaciclovir Ileal sodium/bile acid cotransporter inducer: Ileal sodium/bile acid cotransporter inhibitor: Cyclosporine, Deoxycholic Acid, Ursodeoxycholic acid Ileal sodium/bile acid cotransporter substrate: Aciclovir, Cholic Acid | 16.04 | ||
| dfaNTR1 | Neurotensin receptor type 1 | 6 | 168 | 87.63 | 87.65 | ND | 0.58 | 0.73 | 0.5 | Nature11159 | Mammalian | Expressed in prostate (at protein level). Detected in colon and peripheral blood mononuclear cells. Detected at very low levels in brain. {ECO:0000269|PubMed:20048080, ECO:0000269|PubMed:8381365}. | Family A G protein-coupled receptor | Analgesics
Colorectal Cancer Depression Lung Cancer NTR-positive tumors Pain, Acute or Chronic Pancreatic cancer Prostate cancer Psychosis Schizophrenia and Schizoaffective Disorders | G-protein coupled receptor for the tridecapeptide neurotensin (NTS) (PubMed:8381365, PubMed:21725197, PubMed:23140271). Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system. Signaling leads to the activation of downstream MAP kinases and protects cells against apoptosis (PubMed:21725197). {ECO:0000269|PubMed:21725197, ECO:0000269|PubMed:23140271, ECO:0000269|PubMed:8381365}. | 16.04 | ||
| dfaNTR2 | Neurotensin receptor type 2 | 2 | 56 | 99.96 | 99.98 | ND | 1.00 | 0.54 | 0.1 | Mammalian | Expressed in prostate (at protein level). {ECO:0000269|PubMed:20048080}. | Family A G protein-coupled receptor | Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol- calcium second messenger system. | Neurotensin receptor type 2 partial antagonist: Levocabastine | 16.04 | |||
| dfaNTRK1 | High affinity nerve growth factor receptor | 6 | 501 | 92.81 | 95.83 | ND | 0.65 | 0.69 | 0.6 | Mammalian | Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors. {ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:8325889}. | Kinase | Congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]: Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II. {ECO:0000269|PubMed:10090906, ECO:0000269|PubMed:10233776, ECO:0000269|PubMed:10330344, ECO:0000269|PubMed:10567924, ECO:0000269|PubMed:10861667, ECO:0000269|PubMed:10982191, ECO:0000269|PubMed:11310631, ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:8696348}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Chromosomal aberrations involving NTRK1 are found in papillary thyroid carcinomas (PTCs) (PubMed:2869410, PubMed:7565764, PubMed:1532241). Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1 (PubMed:7565764). A rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1 (PubMed:2869410). An intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein (PubMed:1532241). {ECO:0000269|PubMed:1532241, ECO:0000269|PubMed:2869410, ECO:0000269|PubMed:7565764}. | Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras- PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras- MAPK signaling cascade. Antagonizes the anti-proliferative NGF- NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed. | High affinity nerve growth factor receptor agonist: Amitriptyline High affinity nerve growth factor receptor antagonist: Imatinib High affinity nerve growth factor receptor inhibitor: Regorafenib | 15.11 | ||
| dfaNTRK2 | BDNF/NT-3 growth factors receptor | 5 | 291 | 88.84 | 89.38 | ND | 0.53 | 0.67 | 0.5 | Mammalian | Isoform TrkB is expressed in the central and peripheral nervous system. In the central nervous system (CNS), expression is observed in the cerebral cortex, hippocampus, thalamus, choroid plexus, granular layer of the cerebellum, brain stem, and spinal cord. In the peripheral nervous system, it is expressed in many cranial ganglia, the ophthalmic nerve, the vestibular system, multiple facial structures, the submaxillary glands, and dorsal root ganglia. Isoform TrkB-T1 is mainly expressed in the brain but also detected in other tissues including pancreas, kidney and heart. Isoform TrkB-T-Shc is predominantly expressed in the brain. {ECO:0000269|PubMed:11798182, ECO:0000269|PubMed:7936202}. | Kinase | Obesity, hyperphagia, and developmental delay (OBHD) [MIM:613886]: A disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language. {ECO:0000269|PubMed:15494731}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin- 4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin- dependent calcium signaling in glial cells and mediate communication between neurons and glia. {ECO:0000269|PubMed:15494731}. | BDNF/NT-3 growth factors receptor agonist: Amitriptyline | 15.11 | ||
| dfaNTRK3 | NT-3 growth factor receptor | 4 | 269 | 83.44 | 92.02 | ND | 0.66 | 0.71 | 0.5 | Mammalian | Widely expressed but mainly in nervous tissue. Isoform 2 is expressed at higher levels in adult brain than in fetal brain. | Kinase | Note=Defects in NTRK3 are associated with susceptibility to congenital heart defects (CHD). A disease characterized by congenital developmental abnormalities involving structures of the heart. CHD are the most common major birth defects and the leading cause of death from congenital malformations. {ECO:0000269|PubMed:25196463}. | Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation. {ECO:0000269|PubMed:25196463}. | 15.11 | |||
| dfaNU1M | NADH-ubiquinone oxidoreductase chain 1 | 6 | 61 | 99.46 | 97.64 | ND | 0.72 | 0.82 | 0.4 | Mammalian | Oxidoreductase | Leber hereditary optic neuropathy (LHON) [MIM:535000]: A maternally inherited disease resulting in acute or subacute loss of central vision, due to optic nerve dysfunction. Cardiac conduction defects and neurological defects have also been described in some patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. {ECO:0000269|PubMed:1417830, ECO:0000269|PubMed:1674640, ECO:0000269|PubMed:1900003, ECO:0000269|PubMed:1928099, ECO:0000269|PubMed:2018041}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) [MIM:540000]: Genetically heterogeneous disorder, characterized by episodic vomiting, seizures, and recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia, or cortical blindness. {ECO:0000269|PubMed:8723687}. Note=The disease is caused by mutations affecting the gene represented in this entry. Alzheimer disease mitochondrial (AD-MT) [MIM:502500]: Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. {ECO:0000269|PubMed:8104867}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15265369, ECO:0000269|PubMed:7733935}. Note=The gene represented in this entry may be involved in disease pathogenesis. Mitochondrial complex I deficiency (MT-C1D) [MIM:252010]: A disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. {ECO:0000269|PubMed:24105702}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed to belong to the minimal assembly required for catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (By similarity). {ECO:0000250}. | NADH-ubiquinone oxidoreductase chain 1 inhibitor: Halothane, Isoflurane NADH-ubiquinone oxidoreductase chain 1 unknown: Desflurane, Methoxyflurane, Sevoflurane | 16.04 | |||
| dfaNUAK1 | NUAK family SNF1-like kinase 1 | 5 | 104 | 99.46 | 95.75 | ND | 0.28 | 0.89 | 0.6 | Mammalian | Expressed at high levels in heart and brain, and at lower levels in skeletal muscle, kidney, ovary, placenta, lung and liver. Highly up-regulated in colorectal cancer cell lines. {ECO:0000269|PubMed:14982852}. | Kinase | Serine/threonine-protein kinase involved in various processes such as cell adhesion, regulation of cell ploidy and senescence, cell proliferation and tumor progression. Phosphorylates ATM, CASP6, LATS1, PPP1R12A and p53/TP53. Acts as a regulator of cellular senescence and cellular ploidy by mediating phosphorylation of 'Ser-464' of LATS1, thereby controlling its stability. Controls cell adhesion by regulating activity of the myosin protein phosphatase 1 (PP1) complex. Acts by mediating phosphorylation of PPP1R12A subunit of myosin PP1: phosphorylated PPP1R12A then interacts with 14-3-3, leading to reduced dephosphorylation of myosin MLC2 by myosin PP1. May be involved in DNA damage response: phosphorylates p53/TP53 at 'Ser-15' and 'Ser- 392' and is recruited to the CDKN1A/WAF1 promoter to participate to transcription activation by p53/TP53. May also act as a tumor malignancy-associated factor by promoting tumor invasion and metastasis under regulation and phosphorylation by AKT1. Suppresses Fas-induced apoptosis by mediating phosphorylation of CASP6, thereby suppressing the activation of the caspase and the subsequent cleavage of CFLAR. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with STK11, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair (PubMed:25329316). {ECO:0000269|PubMed:12409306, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15060171, ECO:0000269|PubMed:15273717, ECO:0000269|PubMed:19927127, ECO:0000269|PubMed:20354225, ECO:0000269|PubMed:21317932, ECO:0000269|PubMed:25329316}. | 16.04 | ||||
| dfaNUAK2 | NUAK family SNF1-like kinase 2 | 5 | 64 | 88.78 | 86.30 | ND | 0.31 | 0.94 | 0.5 | Mammalian | Kinase | Stress-activated kinase involved in tolerance to glucose starvation. Induces cell-cell detachment by increasing F-actin conversion to G-actin. Expression is induced by CD95 or TNF-alpha, via NF-kappa-B. Protects cells from CD95-mediated apoptosis and is required for the increased motility and invasiveness of CD95- activated tumor cells. Able to phosphorylate 'Ser-464' of LATS1. {ECO:0000269|PubMed:14575707, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15345718, ECO:0000269|PubMed:19927127}. | 16.04 | |||||
| dfaOPRD | Delta-type opioid receptor | 3 | 3726 | 94.57 | 94.27 | ND | 0.64 | 0.00 | 0.8 | Nature11159 | Mammalian | Detected in oocytes (at protein level). Detected in brain cortex, hypothalamus, hippocampus and olfactory bulb. Detected in oocytes. {ECO:0000269|PubMed:22417668, ECO:0000269|PubMed:7808419}. | Biliary colic Bladder disorder Bradycardia Cerebrovascular disorder Constipation Death Dependence Dermatitis contact Drug tolerance Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Restlessness Shock Somnolence Ureteral spasm Urticaria Withdrawal syndrome | Family A G protein-coupled receptor | Analgesics
Cough Dyspnea Ischemia Pain, unspecified Parkinson's disease | G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine. {ECO:0000269|PubMed:22184124, ECO:0000269|PubMed:7808419, ECO:0000269|PubMed:8201839}. | Delta-type opioid receptor : Tapentadol Delta-type opioid receptor agonist: Amitriptyline, Butorphanol, Codeine, Dextromethorphan, Dextropropoxyphene, Diphenoxylate, Fentanyl, Heroin, Hydrocodone, Ketobemidone, Levorphanol, Loperamide, Methadone, Morphine, Oxycodone, Remifentanil, Sufentanil, Tramadol Delta-type opioid receptor antagonist: Alvimopan, Buprenorphine, Eluxadoline, Nalbuphine, Naloxone, Naltrexone, Oxymorphone Delta-type opioid receptor binder: Ketamine Delta-type opioid receptor partial agonist: Hydromorphone | 15.11 |
| dfaOPRK | Kappa-type opioid receptor | 3 | 4133 | 93.52 | 87.95 | ND | 0.63 | 0.00 | 0.8 | Nature11159 | Mammalian | Detected in brain and placenta. {ECO:0000269|PubMed:7624359, ECO:0000269|PubMed:8060324}. | Biliary colic Bladder disorder Bradycardia Cerebrovascular disorder Coma Constipation Death Dependence Dermatitis contact Drug tolerance Dysphoria Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Respiratory disorder Restlessness Shock Somnolence Ureteral spasm Withdrawal syndrome | Family A G protein-coupled receptor | Alcohol dependence
Analgesics Behcet's disease Diarrhea Dyspnea Focal ischemia Immune disease Neurodegenerative diseases Pain, unspecified | G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions. {ECO:0000269|PubMed:12004055, ECO:0000269|PubMed:22437504, ECO:0000269|PubMed:7624359, ECO:0000269|PubMed:8060324}. | Kappa-type opioid receptor : Pethidine, Tapentadol Kappa-type opioid receptor activator: Progesterone Kappa-type opioid receptor agonist: Amitriptyline, Butorphanol, Dextromethorphan, Eluxadoline, Fentanyl, Heroin, Hydromorphone, Ketamine, Ketobemidone, Levorphanol, Loperamide, Menthol, Mianserin, Mirtazapine, Morphine, Nalbuphine, Oxycodone, Pentazocine, Remifentanil, Tramadol Kappa-type opioid receptor antagonist: Alvimopan, Buprenorphine, Dextropropoxyphene, Dezocine, Methylnaltrexone, Naloxone, Naltrexone Kappa-type opioid receptor other: Sufentanil Kappa-type opioid receptor partial agonist: Codeine | 15.11 |
| dfaOPRM | Mu-type opioid receptor | 5 | 4709 | 93.25 | 92.02 | ND | 0.67 | 0.00 | 0.8 | Nature11159 | Mammalian | Expressed in brain. Isoform 16 and isoform 17 are detected in brain. Ref.32 | Biliary colic Biliary tract disorder Bladder disorder Bradycardia Cerebrovascular disorder Coma Constipation Death Dependence Dermatitis contact Disorientation Drug tolerance Dry mouth Dysphoria Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle rigidity Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Respiratory disorder Restlessness Shock Somnolence Ureteral spasm Urticaria Withdrawal syndrome | Family A G protein-coupled receptor | Analgesics
Cough Diarrhea Dyspnea Opioid-induced bowel dysfunction Pain, unspecified | Receptor for endogenous opioids such as beta-endorphin and endomorphin. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist- specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 9 is involved in morphine-induced scratching and seems to cross-activate GRPR in response to morphine. {ECO:0000269|PubMed:10842167, ECO:0000269|PubMed:16682964, ECO:0000269|PubMed:21422164, ECO:0000269|PubMed:22437502, ECO:0000269|PubMed:7797593, ECO:0000269|PubMed:9037090}. | Mu opioid receptor agonist: Alfentanil, Anileridine, Buprenorphine, Difenoxin, Dihydrocodeine, Diphenoxylate, Fentanyl, Hydromorphone, Levomethadyl Acetate, Levorphanol, Loperamide, Meperidine, Methadone, Morphine, Oxycodone, Propoxyphene, Remifentanil, Sufentanil, Tapentadol, Tramadol Mu opioid receptor antagonist: Alvimopan, Levallorphan, Methylnaltrexone Mu opioid receptor partial agonist: Butorphanol, Dezocine | 15.11 |
| dfaOPRX | Nociceptin receptor | 3 | 1069 | 96.51 | 93.95 | ND | 0.64 | 0.61 | 0.6 | Mammalian | Detected in blood leukocytes. {ECO:0000269|PubMed:7500847}. | Hyperhidrosis | Family A G protein-coupled receptor | Analgesics
Anorexia nervosa Anxiety disorder, unspecified Cerebral ischemia Depression Drug dependence Epilepsy Erectile dysfunction Hypertension Neurogenic bladder Neuropathic pain Pain, unspecified | G-protein coupled opioid receptor that functions as receptor for the endogenous neuropeptide nociceptin. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling via G proteins mediates inhibition of adenylate cyclase activity and calcium channel activity. Arrestins modulate signaling via G proteins and mediate the activation of alternative signaling pathways that lead to the activation of MAP kinases. Plays a role in modulating nociception and the perception of pain. Plays a role in the regulation of locomotor activity by the neuropeptide nociceptin. {ECO:0000269|PubMed:11238602, ECO:0000269|PubMed:12568343, ECO:0000269|PubMed:22596163, ECO:0000269|PubMed:23086955, ECO:0000269|PubMed:8137918}. | 15.11 | ||
| dfaOX1R | Orexin receptor type 1 | 4 | 581 | 87.03 | 87.65 | ND | 0.69 | 0.64 | 0.6 | Mammalian | Family A G protein-coupled receptor | Gastrointestinal motility disorders
Insomnia Insulin disorders Nausea and vomiting Nutritional disorders Sleep Disorders Sleeping sickness | Moderately selective excitatory receptor for orexin-A and, with a lower affinity, for orexin-B neuropeptide. Seems to be exclusively coupled to the G(q) subclass of heteromeric G proteins, which activates the phospholipase C mediated signaling cascade (By similarity). {ECO:0000250}. | Orexin receptor type 1 antagonist: Suvorexant | 16.04 | |||
| dfaOX2R | Orexin receptor type 2 | 5 | 464 | 93.48 | 93.36 | ND | 0.41 | 0.61 | 0.8 | Mammalian | Family A G protein-coupled receptor | Gastrointestinal motility disorders
Nausea and vomiting | Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides. | Orexin receptor type 2 antagonist: Suvorexant | 15.11 | |||
| dfaOXDA | D-amino-acid oxidase | 3 | 139 | 96.36 | 97.25 | ND | 0.61 | 0.57 | 0.8 | Mammalian | Enzyme | Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D- amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids. {ECO:0000269|PubMed:17303072}. | D-amino-acid oxidase : Benzoic Acid, Flavin adenine dinucleotide | 15.11 | ||||
| dfaOXSR1 | Serine/threonine-protein kinase OSR1 | 4 | 59 | 99.14 | 93.44 | ND | 0.41 | 0.93 | 0.4 | Mammalian | Ubiquitously expressed in all tissue examined. {ECO:0000269|PubMed:10083736}. | Kinase | Regulates downstream kinases in response to environmental stress. May also have a function in regulating the actin cytoskeleton. {ECO:0000269|PubMed:14707132, ECO:0000303|PubMed:14707132}. | 15.11 | ||||
| dfaP2RX1 | P2X purinoceptor 1 | 2 | 46 | 86.06 | 89.15 | ND | 0.93 | 0.79 | 0.2 | Mammalian | Ligand-gated ion channel | Ligand-gated ion channel with relatively high calcium permeability. Binding to ATP mediates synaptic transmission between neurons and from neurons to smooth muscle. Seems to be linked to apoptosis, by increasing the intracellular concentration of calcium in the presence of ATP, leading to programmed cell death (By similarity). {ECO:0000250}. | 16.04 | |||||
| dfaP2RX2 | P2X purinoceptor 2 | 3 | 127 | 99.96 | 99.92 | ND | 0.72 | 0.63 | 0.4 | Mammalian | Ligand-gated ion channel | Deafness, autosomal dominant, 41 (DFNA41) [MIM:608224]: A form of non-syndromic deafness characterized by onset of progressive sensorineural hearing loss usually in the second decade. The hearing loss is severe and ultimately affects all frequencies. Exposure to noise exacerbates the hearing loss, particularly at high frequencies. {ECO:0000269|PubMed:23345450, ECO:0000269|PubMed:24211385}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ion channel gated by extracellular ATP involved in a variety of cellular responses, such as excitatory postsynaptic responses in sensory neurons, neuromuscular junctions (NMJ) formation, hearing, perception of taste and peristalsis. In the inner ear, regulates sound transduction and auditory neurotransmission, outer hair cell electromotility, inner ear gap junctions, and K(+) recycling. Mediates synaptic transmission between neurons and from neurons to smooth muscle. {ECO:0000269|PubMed:23345450}. | 16.04 | ||||
| dfaP2RX3 | P2X purinoceptor 3 | 5 | 173 | 99.47 | 94.22 | ND | 0.57 | 0.53 | 0.5 | Mammalian | Ligand-gated ion channel | Analgesics
Dysmotility Hypertonicity of bladder Inflammatory bowel disease Pain, unspecified | Receptor for ATP that acts as a ligand-gated ion channel. | 16.04 | ||||
| dfaP2RX4 | P2X purinoceptor 4 | 4 | 136 | 87.24 | 88.71 | ND | 0.41 | 0.53 | 0.3 | Mammalian | Ligand-gated ion channel | Analgesics
Pain, unspecific | Receptor for ATP that acts as a ligand-gated ion channel. This receptor is insensitive to the antagonists PPADS and suramin. {ECO:0000269|PubMed:10515189}. | 16.04 | ||||
| dfaP2RX7 | P2X purinoceptor 7 | 5 | 1289 | 96.48 | 95.94 | ND | 0.62 | 0.55 | 0.4 | Mammalian | Widely expressed with highest levels in brain and immune tissues. {ECO:0000269|PubMed:15896293}. | Ligand-gated ion channel | Analgesics
Diseases characterized by increased osteoclast number and excessive bone turnover Osteoporosis, unspecified Pain | Receptor for ATP that acts as a ligand-gated ion channel. Responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Could function in both fast synaptic transmission and the ATP-mediated lysis of antigen-presenting cells. | 16.04 | |||
| dfaP2RY1 | P2Y purinoceptor 1 | 3 | 287 | 98.53 | 98.75 | ND | 0.55 | 0.64 | 0.6 | Mammalian | Family A G protein-coupled receptor | Thrombosis | Receptor for extracellular adenine nucleotides such as ATP and ADP. In platelets binding to ADP leads to mobilization of intracellular calcium ions via activation of phospholipase C, a change in platelet shape, and probably to platelet aggregation. {ECO:0000269|PubMed:9442040}. | 15.11 | ||||
| dfaP2RY2 | P2Y purinoceptor 2 | 2 | 193 | 99.80 | 98.28 | ND | 0.54 | 0.58 | 0.5 | Mammalian | Spleen, testis, kidney, liver, lung, heart and brain. | Family A G protein-coupled receptor | Cystic fibrosis
Dry eye Glaucoma Oesophageal cancer | Receptor for ATP and UTP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. The affinity range is UTP = ATP > ATP-gamma-S >> 2-methylthio-ATP = ADP. | P2Y purinoceptor 2 antagonist: Suramin | 16.04 | ||
| dfaP2RY4 | P2Y purinoceptor 4 | 1 | 110 | 99.76 | 99.85 | ND | 0.47 | 0.59 | 0.5 | Mammalian | Pancreas. | Family A G protein-coupled receptor | Receptor for UTP and UDP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. Not activated by ATP or ADP. | 16.04 | ||||
| dfaP2RY6 | P2Y purinoceptor 6 | 2 | 161 | 99.63 | 99.81 | ND | 0.57 | 0.46 | 0.4 | Mammalian | Family A G protein-coupled receptor | Cystic fibrosis gallbladder disease | Receptor for extracellular UDP > UTP > ATP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. | 16.04 | ||||
| dfaP2Y12 | P2Y purinoceptor 12 | 5 | 445 | 97.18 | 96.49 | ND | 0.68 | 0.61 | 0.5 | Mammalian | Highly expressed in the platelets, lower levels in the brain. Lowest levels in the lung, appendix, pituitary and adrenal gland. Expressed in the spinal cord and in the fetal brain. {ECO:0000269|PubMed:11104774, ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:11502873}. | Family A G protein-coupled receptor | Bleeding disorder, platelet-type 8 (BDPLT8) [MIM:609821]: A condition characterized by mild to moderate mucocutaneous bleeding, and excessive bleeding after surgery or trauma. The defect is due to severe impairment of platelet response to ADP resulting in defective platelet aggregation. {ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:12578987, ECO:0000269|PubMed:25428217}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation. {ECO:0000269|PubMed:11104774, ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:11502873, ECO:0000269|PubMed:12578987, ECO:0000269|PubMed:24670650, ECO:0000269|PubMed:24784220}. | P2Y purinoceptor 12 agonist: Epoprostenol, Treprostinil P2Y purinoceptor 12 antagonist: Clopidogrel, Prasugrel, Ticlopidine P2Y purinoceptor 12 inhibitor: Cangrelor, Ticagrelor | 15.11 | ||
| dfaP2Y14 | P2Y purinoceptor 14 | 3 | 99 | 99.32 | 99.45 | ND | 0.46 | 0.61 | 0.6 | Mammalian | Highest expression in the placenta, adipose tissue, stomach and intestine, intermediate levels in the brain, spleen, lung and heart, lowest levels in the kidney. | Family A G protein-coupled receptor | Receptor for UDP-glucose and other UDP-sugar coupled to G-proteins. Not activated by ATP, ADP, UTP or ATP. {ECO:0000269|PubMed:10753868}. | 16.04 | ||||
| dfaP3C2B | Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta | 6 | 72 | 85.12 | 93.07 | ND | 0.69 | 0.92 | 0.2 | Mammalian | Expressed in columnar and transitional epithelia, mononuclear cells, and ganglion cells (at protein level). Widely expressed, with highest levels in thymus and placenta and lowest in peripheral blood, skeletal muscle and kidney. {ECO:0000269|PubMed:14563213, ECO:0000269|PubMed:9144573}. | Enzyme | Phosphorylates PtdIns and PtdIns4P with a preference for PtdIns. Does not phosphorylate PtdIns(4,5)P2. May be involved in EGF and PDGF signaling cascades. {ECO:0000269|PubMed:10805725}. | 16.04 | ||||
| dfaPA24A | Cytosolic phospholipase A2 | 3 | 174 | 97.58 | 99.87 | ND | 0.45 | 0.58 | 0.5 | Mammalian | Expressed in various tissues such as macrophages, platelets, neutrophils, fibroblasts and lung endothelium. | Enzyme | Note=PLA2G4A mutations resulting in phospholipase A2 deficiency have been found in a patient affected by recurrent episodes of multiple complicated ulcers of the small intestine, not due to cyclooxygenase inhibitors use. Disease features also include platelet dysfunction, and globally decreased eicosanoid synthesis (PubMed:18451993). {ECO:0000269|PubMed:18451993}. | Selectively hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid. Together with its lysophospholipid activity, it is implicated in the initiation of the inflammatory response. | Cytosolic phospholipase A2 : Niflumic Acid Cytosolic phospholipase A2 inducer: Aldesleukin, Carbachol, Streptokinase Cytosolic phospholipase A2 inhibitor: Carbenicillin, Epirubicin, Fluocinolone Acetonide, Fluticasone Propionate, Orlistat, Quinacrine, Suramin | 16.04 | ||
| dfaPA2GA | Phospholipase A2, membrane associated | 2 | 238 | 98.01 | 96.48 | ND | 0.48 | 0.61 | 0.7 | Mammalian | Enzyme | Atherosclerosis
Coronary Artery Disease | Thought to participate in the regulation of the phospholipid metabolism in biomembranes including eicosanoid biosynthesis. Catalyzes the calcium-dependent hydrolysis of the 2- acyl groups in 3-sn-phosphoglycerides. | Phospholipase A2, membrane associated : Isopropyl Alcohol Phospholipase A2, membrane associated inhibitor: Diclofenac, Ginkgo biloba, Indomethacin, Suramin | 15.11 | |||
| dfaPA2GX | Group 10 secretory phospholipase A2 | 3 | 43 | 99.77 | 100.00 | ND | 0.89 | 0.72 | 0.5 | Mammalian | Found in spleen, thymus, peripheral blood leukocytes, pancreas, lung, and colon. | Enzyme | PA2 catalyzes the calcium-dependent hydrolysis of the 2- acyl groups in 3-sn-phosphoglycerides. Has a powerful potency for releasing arachidonic acid from cell membrane phospholipids. Prefers phosphatidylethanolamine and phosphatidylcholine liposomes to those of phosphatidylserine. | 15.11 | ||||
| dfaPAFA | Platelet-activating factor acetylhydrolase | 2 | 208 | 99.41 | 98.85 | ND | 0.85 | 0.77 | 0.4 | Mammalian | Plasma. | Enzyme | Platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:614278]: An enzymatic deficiency that results in exacerbated bodily response to inflammatory agents. It can be associated with several disease states including inflammatory gastrointestinal disorders, asthma and atopy. Asthmatic individuals with PAFAD may manifest aggravated respiratory symptoms. {ECO:0000269|PubMed:8675689, ECO:0000269|PubMed:9245731, ECO:0000269|PubMed:9412624, ECO:0000269|PubMed:9472966, ECO:0000269|PubMed:9759612}. Note=The disease is caused by mutations affecting the gene represented in this entry. Asthma (ASTHMA) [MIM:600807]: The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with wheezing due to spasmodic contraction of the bronchi. {ECO:0000269|PubMed:10733466}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Atopic hypersensitivity (ATOPY) [MIM:147050]: A condition characterized by predisposition to develop hypersensitivity reactions. Atopic individuals can develop eczema, allergic rhinitis and allergic asthma. {ECO:0000269|PubMed:10733466}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Modulates the action of platelet-activating factor (PAF) by hydrolyzing the sn-2 ester bond to yield the biologically inactive lyso-PAF. Has a specificity for substrates with a short residue at the sn-2 position. It is inactive against long-chain phospholipids. | 15.11 | |||
| dfaPAI1 | Plasminogen activator inhibitor 1 | 6 | 172 | 96.50 | 96.71 | ND | 0.40 | 0.59 | 0.4 | Mammalian | Found in plasma and platelets and in endothelial, hepatoma and fibrosarcoma cells. | Secreted protein | Plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM:613329]: A hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of plasminogen activator inhibitor-1, which inhibits tissue and urinary activators of plasminogen. {ECO:0000269|PubMed:9207454}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=High concentrations of SERPINE1 seem to contribute to the development of venous but not arterial occlusions. | Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major control point in the regulation of fibrinolysis. {ECO:0000269|PubMed:15853774}. | Plasminogen activator inhibitor 1 : Alteplase, Anistreplase, Drotrecogin alfa, Reteplase, Tenecteplase, Urokinase | 16.04 | ||
| dfaPAK1 | Serine/threonine-protein kinase PAK 1 | 3 | 192 | 90.80 | 91.21 | ND | 0.53 | 0.72 | 0.5 | Mammalian | Overexpressed in gastric cancer cells and tissues (at protein level) (PubMed:25766321). {ECO:0000269|PubMed:25766321}. | Kinase | Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2- induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F- actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion (PubMed:25766321). {ECO:0000269|PubMed:10551809, ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:12624090, ECO:0000269|PubMed:12876277, ECO:0000269|PubMed:14585966, ECO:0000269|PubMed:15611088, ECO:0000269|PubMed:15831477, ECO:0000269|PubMed:15833848, ECO:0000269|PubMed:16278681, ECO:0000269|PubMed:17726028, ECO:0000269|PubMed:17989089, ECO:0000269|PubMed:22669945, ECO:0000269|PubMed:23633677, ECO:0000269|PubMed:25766321, ECO:0000269|PubMed:8805275, ECO:0000269|PubMed:9032240, ECO:0000269|PubMed:9395435, ECO:0000269|PubMed:9528787}. | 15.11 | ||||
| dfaPAK3 | Serine/threonine-protein kinase PAK 3 | 6 | 72 | 98.27 | 97.13 | ND | 0.90 | 0.81 | 0.2 | Mammalian | Restricted to the nervous system. Highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. {ECO:0000269|PubMed:12890786}. | Kinase | Mental retardation, X-linked 30 (MRX30) [MIM:300558]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:10946356, ECO:0000269|PubMed:12884430, ECO:0000269|PubMed:9731525}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments. May also be involved in early neuronal development. {ECO:0000269|PubMed:21177870}. | 16.04 | |||
| dfaPAK4 | Serine/threonine-protein kinase PAK 4 | 5 | 351 | 90.65 | 93.65 | ND | 0.65 | 0.77 | 0.6 | Mammalian | Highest expression in prostate, testis and colon. | Kinase | Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN. {ECO:0000269|PubMed:11278822, ECO:0000269|PubMed:11313478, ECO:0000269|PubMed:14560027, ECO:0000269|PubMed:15660133, ECO:0000269|PubMed:20507994, ECO:0000269|PubMed:20631255, ECO:0000269|PubMed:20805321}. | 15.11 | ||||
| dfaPAR1 | Proteinase-activated receptor 1 | 4 | 359 | 98.65 | 97.96 | ND | 0.65 | 0.56 | 0.4 | Mammalian | Platelets and vascular endothelial cells. | Family A G protein-coupled receptor | Acute Coronary Syndrome
Analgesics Cardiovascular Disorders Inflammation Ischemic Stroke Pain, unspecified Vascular disease | High affinity receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis. May play a role in platelets activation and in vascular development. {ECO:0000269|PubMed:10079109}. | Proteinase-activated receptor 1 antagonist: Vorapaxar Proteinase-activated receptor 1 cleavage: Streptokinase | 15.11 | ||
| dfaPARP1 | Poly [ADP-ribose] polymerase 1 | 6 | 1321 | 94.22 | 92.33 | ND | 0.68 | 0.72 | 0.6 | Mammalian | Enzyme | Asthma
Cancer, unspecific Chronic obstructive pulmonary disease Diabetic cardiovascular dysfunction Diabetic endothelial dysfunction Multiple sclerosis Traumatic brain injury Tumors | Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP- ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Required for PARP9 and DTX3L recruitment to DNA damage sites. PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. {ECO:0000269|PubMed:17177976, ECO:0000269|PubMed:18172500, ECO:0000269|PubMed:19344625, ECO:0000269|PubMed:19661379, ECO:0000269|PubMed:23230272}. | Poly [ADP-ribose] polymerase 1 binder: Nicotinamide Poly [ADP-ribose] polymerase 1 inhibitor: Olaparib | 16.04 | |||
| dfaPARP2 | Poly [ADP-ribose] polymerase 2 | 1 | 81 | 85.17 | 82.82 | ND | 0.95 | 0.92 | 0.4 | Mammalian | Widely expressed, mainly in actively dividing tissues. The highest levels are in the brain, heart, pancreas, skeletal muscle and testis; also detected in kidney, liver, lung, placenta, ovary and spleen; levels are low in leukocytes, colon, small intestine, prostate and thymus. | Enzyme | Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. | Poly [ADP-ribose] polymerase 2 Inhibitor: Olaparib | 15.11 | |||
| dfaPCP | Lysosomal Pro-X carboxypeptidase | 4 | 278 | 92.61 | 95.13 | ND | 0.59 | 0.59 | 0.7 | Mammalian | Highest levels in placenta, lung and liver. Also present in heart, brain, pancreas and kidney. | Protease | Cleaves C-terminal amino acids linked to proline in peptides such as angiotensin II, III and des-Arg9-bradykinin. This cleavage occurs at acidic pH, but enzymatic activity is retained with some substrates at neutral pH. | 16.04 | ||||
| dfaPD2R | Prostaglandin D2 receptor | 4 | 545 | 96.94 | 98.71 | ND | 0.75 | 0.83 | 0.7 | Mammalian | Expressed in retinal choroid, ciliary epithelium, longitudinal and circular ciliary muscles, iris, small intestine and platelet membranes. {ECO:0000269|PubMed:11082108, ECO:0000269|PubMed:6302737}. | Family A G protein-coupled receptor | Asthma-related traits 1 (ASRT1) [MIM:607277]: Asthma- related traits include clinical symptoms of asthma, such as coughing, wheezing, dyspnea, bronchial hyperresponsiveness as assessed by methacholine challenge test, serum IgE levels, atopy and atopic dermatitis. {ECO:0000269|PubMed:15496624}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for prostaglandin D2 (PGD2). The activity of this receptor is mainly mediated by G(s) proteins that stimulate adenylate cyclase, resulting in an elevation of intracellular cAMP. A mobilization of calcium is also observed, but without formation of inositol 1,4,5-trisphosphate (By similarity). {ECO:0000250}. | Prostaglandin D2 receptor unknown: Nedocromil | 16.04 | ||
| dfaPD2R2 | Prostaglandin D2 receptor 2 | 2 | 1161 | 99.18 | 98.83 | ND | 0.48 | 0.58 | 0.6 | Mammalian | Widespread expression. High expression in stomach, small intestine, heart and thymus. Intermediate expression in colon, spinal cord and peripheral blood and low expression in brain, skeletal muscle and spleen. Expressed also on Th2- and Tc2- type cells, eosinophils and basophils. {ECO:0000269|PubMed:11168006, ECO:0000269|PubMed:11208866, ECO:0000269|PubMed:12466225, ECO:0000269|PubMed:9973380}. | Family A G protein-coupled receptor | Asthma
Chronic obstructive pulmonary disease | Receptor for prostaglandin D2 (PGD2). Coupled to the G(i)-protein. Receptor activation may result in pertussis toxin- sensitive decreases in cAMP levels and Ca(2+) mobilization. PI3K signaling is also implicated in mediating PTGDR2 effects. PGD2 induced receptor internalization. CRTH2 internalization can be regulated by diverse kinases such as, PKC, PKA, ADRBK1/GRK2, GPRK5/GRK5 and GRK6. Receptor activation is responsible, at least in part, in immune regulation and allergic/inflammation responses. {ECO:0000269|PubMed:11208866, ECO:0000269|PubMed:11535533, ECO:0000269|PubMed:17196174}. | Prostaglandin D2 receptor 2 antagonist: Sulindac Prostaglandin D2 receptor 2 other/unknown: Indomethacin | 16.04 | ||
| dfaPDE10 | cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A | 8 | 871 | 94.85 | 94.37 | ND | 0.59 | 0.63 | 0.6 | Mammalian | Abundant in the putamen and caudate nucleus regions of brain and testis, moderately expressed in the thyroid gland, pituitary gland, thalamus and cerebellum. | Phosphodiesterase | Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate. {ECO:0000269|PubMed:17389385}. | cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A antagonist: Triflusal cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A inhibitor: Dipyridamole, Papaverine, Tofisopam | 15.11 | |||
| dfaPDE11 | Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A | 2 | 100 | 95.76 | 92.35 | ND | 0.71 | 0.82 | 0.7 | Mammalian | Isoform 1 is present in prostate, pituitary, heart and liver. It is however not present in testis nor in penis, suggesting that weak inhibition by Tadalafil (Cialis) is not relevant (at protein level). Isoform 2 may be expressed in testis. Isoform 4 is expressed in adrenal cortex. {ECO:0000269|PubMed:10725373, ECO:0000269|PubMed:11121118, ECO:0000269|PubMed:15800651, ECO:0000269|PubMed:16079899, ECO:0000269|PubMed:16767104}. | Phosphodiesterase | Primary pigmented nodular adrenocortical disease 2 (PPNAD2) [MIM:610475]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:16767104}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP. Catalyzes the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'- GMP, respectively. {ECO:0000269|PubMed:10725373, ECO:0000269|PubMed:10906126, ECO:0000269|PubMed:11050148}. | Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A inhibitor: Tadalafil | 16.04 | ||
| dfaPDE1A | Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A | 3 | 50 | 88.11 | 88.95 | ND | 0.99 | 0.94 | 0.1 | Mammalian | Several tissues, including brain, kidney, testes and heart. | Phosphodiesterase | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a higher affinity for cGMP than for cAMP. | Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A inhibitor: Bepridil, Felodipine, Nicardipine Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A inhibitor, competitive: Caffeine | 16.04 | |||
| dfaPDE1C | Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C | 1 | 48 | 99.39 | 98.74 | ND | 0.89 | 0.59 | 0.2 | Mammalian | Expressed in several tissues, including brain and heart. | Phosphodiesterase | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a high affinity for both cAMP and cGMP. | 16.04 | ||||
| dfaPDE2A | cGMP-dependent 3',5'-cyclic phosphodiesterase | 7 | 264 | 98.41 | 96.20 | ND | 0.92 | 0.01 | 0.5 | Mammalian | Expressed in brain and to a lesser extent in heart, placenta, lung, skeletal muscle, kidney and pancreas. | Dyspepsia Flushing Headache | Phosphodiesterase | Colorectal cancer
Erectile dysfunction | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Isoform PDE2A2: Regulates Mitochondrial cAMP Levels and Respiration. | cGMP-dependent 3',5'-cyclic phosphodiesterase inhibitor: Tofisopam | 15.11 | |
| dfaPDE3A | cGMP-inhibited 3',5'-cyclic phosphodiesterase A | 5 | 259 | 94.05 | 95.30 | ND | 0.80 | 0.79 | 0.6 | Nature11159 | Mammalian | Dyspepsia Palpitations | Phosphodiesterase | Hypertension and brachydactyly syndrome (HTNB) [MIM:112410]: A syndrome characterized by brachydactyly type E, severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, and altered baroreflex blood pressure regulation. It results in death from stroke before age 50 years when untreated. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. {ECO:0000269|PubMed:25961942}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. {ECO:0000250|UniProtKB:Q9Z0X4}. | cGMP-inhibited 3',5'-cyclic phosphodiesterase A inhibitor: Aminophylline, Amrinone, Anagrelide, Cilostazol, Enoximone, Ibudilast, Levosimendan, Milrinone, Oxtriphylline, Theophylline, Tofisopam | 16.04 | |
| dfaPDE3B | cGMP-inhibited 3',5'-cyclic phosphodiesterase B | 4 | 97 | 94.99 | 94.55 | ND | 0.93 | 0.87 | 0.4 | Mammalian | Abundant in adipose tissues. | Phosphodiesterase | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. May play a role in fat metabolism. Regulates cAMP binding of RAPGEF3. Through simultaneous binding to RAPGEF3 and PIK3R6 assembles a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis. {ECO:0000269|PubMed:15147193, ECO:0000269|PubMed:21393242}. | 16.04 | ||||
| dfaPDE4A | cAMP-specific 3',5'-cyclic phosphodiesterase 4A | 7 | 459 | 95.83 | 98.07 | ND | 0.73 | 0.78 | 0.6 | Mammalian | Isoform 1 is widely expressed. Isoform 2 is abundant in liver, stomach, testis, thyroid and adrenal glands. It is also found in placenta, kidney, pancreas, ovary, uterus, skin, monocytes, mast cells, macrophages, as well as in bronchial smooth muscle. Isoform 6 is expressed at high levels in the heart and small intestine. It is also found in the brain, kidney, spleen, colon, salivary gland, ovary and peripheral blood lymphocytes. Isoform 7 is expressed predominantly in skeletal muscle and brain and at lower levels in the testis. Isoform 7 is expressed in the brain. Found in specific neuronal subpopulations in cortex, spinal cord and cerebellum (at protein level). {ECO:0000269|PubMed:11306681, ECO:0000269|PubMed:15738310, ECO:0000269|PubMed:18095939}. | Diarrhoea Dyspepsia Flushing Palpitations | Phosphodiesterase | Chronic lymphocytic leukemia | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:11566027, ECO:0000269|PubMed:17727341}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4A antagonist: Apremilast cAMP-specific 3',5'-cyclic phosphodiesterase 4A inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4A inhibitor: Dipyridamole, Drotaverine, Dyphylline, Enprofylline, Ibudilast, Ketotifen, Oxtriphylline, Pentoxifylline, Roflumilast, Theophylline, Tofisopam | 15.11 | |
| dfaPDE4B | cAMP-specific 3',5'-cyclic phosphodiesterase 4B | 6 | 733 | 92.39 | 94.33 | ND | 0.68 | 0.76 | 0.7 | Mammalian | Expressed in brain, heart, lung and skeletal muscle. | Diarrhoea Dyspepsia Flushing Palpitations | Phosphodiesterase | Asthma
Chronic lymphocytic leukemia | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents. {ECO:0000269|PubMed:10846163, ECO:0000269|PubMed:15003452}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4B antagonist: Apremilast cAMP-specific 3',5'-cyclic phosphodiesterase 4B inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4B inhibitor: Amrinone, Caffeine, Dyphylline, Enprofylline, Ibudilast, Ketotifen, Papaverine, Pentoxifylline, Roflumilast, Theobromine, Theophylline cAMP-specific 3',5'-cyclic phosphodiesterase 4B product of: Adenosine monophosphate | 15.11 | |
| dfaPDE4C | cAMP-specific 3',5'-cyclic phosphodiesterase 4C | 3 | 94 | 99.56 | 93.43 | ND | 0.69 | 0.77 | 0.6 | Mammalian | Expressed in various tissues but not in cells of the immune system. | Phosphodiesterase | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:17727341}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4C inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4C inhibitor: Dyphylline, Ibudilast, Ketotifen, Roflumilast | 16.04 | |||
| dfaPDE4D | cAMP-specific 3',5'-cyclic phosphodiesterase 4D | 4 | 489 | 94.28 | 92.14 | ND | 0.87 | 0.85 | 0.5 | Nature11159 | Mammalian | Expressed in colonic epithelial cells (at protein level). Widespread; most abundant in skeletal muscle. Isoform 6 is detected in brain. Isoform 8 is detected in brain, placenta, lung and kidney. Isoform 7 is detected in heart and skeletal muscle. {ECO:0000269|PubMed:12834813, ECO:0000269|PubMed:17244609}. | Dyspepsia Flushing | Phosphodiesterase | Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. {ECO:0000269|PubMed:17006457}. Acrodysostosis 2, with or without hormone resistance (ACRDYS2) [MIM:614613]: A pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems. {ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:23033274, ECO:0000269|PubMed:23043190}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4D antagonist: Apremilast cAMP-specific 3',5'-cyclic phosphodiesterase 4D inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4D inhibitor: Dyphylline, Ibudilast, Ketotifen, Roflumilast cAMP-specific 3',5'-cyclic phosphodiesterase 4D product of: Adenosine monophosphate | 15.11 |
| dfaPDE5A | cGMP-specific 3',5'-cyclic phosphodiesterase | 5 | 1400 | 94.29 | 94.51 | ND | 0.79 | 0.80 | 0.7 | Mammalian | Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung. | Diarrhoea Dyspepsia Flushing Palpitations | Phosphodiesterase | Erectile dysfunction
Injury to spine and spinal cord Pulmonary hypertension Vascular disease | Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'- GMP (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334). {ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9714779}. | cGMP-specific 3',5'-cyclic phosphodiesterase inhibitor: Avanafil, Dipyridamole, Pentoxifylline, Sildenafil, Tadalafil, Theophylline, Udenafil, Vardenafil | 15.11 | |
| dfaPDE6A | Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha | 1 | 68 | 99.90 | 96.22 | ND | 0.77 | 0.88 | 0.4 | Mammalian | Phosphodiesterase | Retinitis pigmentosa 43 (RP43) [MIM:613810]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:10393062, ECO:0000269|PubMed:7493036}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This protein participates in processes of transmission and amplification of the visual signal. | 16.04 | ||||
| dfaPDE7A | High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A | 4 | 281 | 97.91 | 87.18 | ND | 0.75 | 0.74 | 0.5 | Mammalian | PDE7A1 is found at high levels in skeletal muscle and at low levels in a variety of tissues including brain and heart. It is expressed as well in two T-cell lines. PDE7A2 is found abundantly in skeletal muscle and at low levels in heart. | Phosphodiesterase | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May have a role in muscle signal transduction. {ECO:0000269|PubMed:19350606}. | High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A inhibitor: Dyphylline, Ketotifen | 15.11 | |||
| dfaPDE8B | High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B | 2 | 145 | 99.45 | 99.97 | ND | 0.63 | 0.57 | 0.6 | Mammalian | Abundantly expressed in the thyroid. Also very weakly expressed in brain, spinal cord and placenta. In the thyroid isoform 1 predominates, and isoforms 2 and 6 are also highly expressed. In the placenta isoforms 1 and 2 are expressed equally. In the brain isoform 2 predominates. {ECO:0000269|PubMed:12372422, ECO:0000269|PubMed:12681444}. | Phosphodiesterase | Striatal degeneration autosomal dominant (ADSD) [MIM:609161]: A movement disorder affecting the striatal part of the basal ganglia and characterized by bradykinesia, dysarthria and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. {ECO:0000269|PubMed:20085714}. Note=The disease is caused by mutations affecting the gene represented in this entry. Primary pigmented nodular adrenocortical disease 3 (PPNAD3) [MIM:614190]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:18431404}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in specific signaling in the thyroid gland. | High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B inhibitor: Ketotifen | 16.04 | ||
| dfaPDE9A | High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305} | 2 | 95 | 99.89 | 99.66 | ND | 0.84 | 0.82 | 0.5 | Mammalian | Expressed in all tissues examined (testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary and prostate) except blood (PubMed:9624146). Highest levels in brain, heart, kidney, spleen, prostate and colon. Isoform PDE9A12 is found in prostate (PubMed:12565835). In brain, present in the cortex, cerebellum, and subiculum (at protein level) (PubMed:22328573). In heart, primarily localizes to myocytes (PubMed:25799991). {ECO:0000269|PubMed:12565835, ECO:0000269|PubMed:22328573, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146}. | Phosphodiesterase | Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP (PubMed:9624146, PubMed:18757755, PubMed:21483814). Specifically regulates natriuretic-peptide- dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart (PubMed:25799991). Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory (By similarity). {ECO:0000250|UniProtKB:Q8QZV1, ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146, ECO:0000305}. | 15.11 | ||||
| dfaPDIA1 | Protein disulfide-isomerase | 6 | 113 | 80.54 | 84.18 | ND | 0.08 | 0.76 | 0.6 | Mammalian | Enzyme | Cole-Carpenter syndrome 1 (CLCRP1) [MIM:112240]: A form of Cole-Carpenter syndrome, a disorder characterized by features of osteogenesis imperfecta such as bone deformities and severe bone fragility with frequent fractures, in association with craniosynostosis, ocular proptosis, hydrocephalus, growth failure and distinctive facial features. Craniofacial findings include marked frontal bossing, midface hypoplasia, and micrognathia. Despite the craniosynostosis and hydrocephalus, intellectual development is normal. CLCRP1 inheritance is autosomal dominant. {ECO:0000269|PubMed:25683117}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. May therefore cause structural modifications of exofacial proteins. Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. At high concentrations, functions as a chaperone that inhibits aggregation of misfolded proteins. At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP. Receptor for LGALS9; the interaction retains P4HB at the cell surface of Th2 T helper cells, increasing disulfide reductase activity at the plasma membrane, altering the plasma membrane redox state and enhancing cell migration (PubMed:21670307). {ECO:0000269|PubMed:10636893, ECO:0000269|PubMed:12485997, ECO:0000269|PubMed:21670307}. | 16.04 | ||||
| dfaPDK1 | [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial | 2 | 79 | 97.06 | 89.26 | ND | 0.81 | 0.96 | 0.4 | Mammalian | Expressed predominantly in the heart. Detected at lower levels in liver, skeletal muscle and pancreas. {ECO:0000269|PubMed:7499431}. | Kinase | Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress. {ECO:0000269|PubMed:17683942, ECO:0000269|PubMed:18541534, ECO:0000269|PubMed:22195962, ECO:0000269|PubMed:7499431}. | 16.04 | ||||
| dfaPDPK1 | 3-phosphoinositide-dependent protein kinase 1 | 6 | 427 | 93.04 | 92.10 | ND | 0.74 | 0.74 | 0.6 | Mammalian | Appears to be expressed ubiquitously. The Tyr- 9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast. {ECO:0000269|PubMed:18024423}. | Kinase | Cancer, unspecific
Diabetes mellitus | Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF- kappa-B activation in macrophages. Isoform 3 is catalytically inactive. {ECO:0000269|PubMed:10226025, ECO:0000269|PubMed:10480933, ECO:0000269|PubMed:10995762, ECO:0000269|PubMed:12167717, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:14604990, ECO:0000269|PubMed:16207722, ECO:0000269|PubMed:16251192, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:17371830, ECO:0000269|PubMed:18835241, ECO:0000269|PubMed:9094314, ECO:0000269|PubMed:9445476, ECO:0000269|PubMed:9707564, ECO:0000269|PubMed:9768361}. | 3-phosphoinositide-dependent protein kinase 1 inhibitor: Celecoxib | 15.11 | ||
| dfaPE2R1 | Prostaglandin E2 receptor EP1 subtype | 4 | 827 | 98.63 | 98.31 | ND | 0.73 | 0.79 | 0.7 | Mammalian | Abundant in kidney. Lower level expression in lung, skeletal muscle and spleen, lowest expression in testis and not detected in liver brain and heart. | Family A G protein-coupled receptor | Analgesics
Visceral pain | Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(q) proteins which activate a phosphatidylinositol-calcium second messenger system. May play a role as an important modulator of renal function. Implicated the smooth muscle contractile response to PGE2 in various tissues. | Prostaglandin E2 receptor EP1 subtype agonist: Alprostadil, Bimatoprost, Carboprost Tromethamine, Dinoprostone, Iloprost Prostaglandin E2 receptor EP1 subtype other/unknown: Bupivacaine | 16.04 | ||
| dfaPE2R2 | Prostaglandin E2 receptor EP2 subtype | 6 | 492 | 95.57 | 97.97 | ND | 0.68 | 0.67 | 0.5 | Mammalian | Placenta and lung. | Flushing | Family A G protein-coupled receptor | Cerebral oxidative damage | Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the relaxing effect of this receptor on smooth muscle. | Prostaglandin E2 receptor EP2 subtype agonist: Alprostadil, Dinoprostone, Misoprostol | 16.04 | |
| dfaPE2R3 | Prostaglandin E2 receptor EP3 subtype | 5 | 809 | 96.49 | 97.56 | ND | 0.81 | 0.85 | 0.7 | Mammalian | Expressed in small intestine, heart, pancreas, gastric fundic mucosa, mammary artery and pulmonary vessels. {ECO:0000269|PubMed:18023986}. | Diarrhoea | Family A G protein-coupled receptor | Peripheral Vascular Disease | Receptor for prostaglandin E2 (PGE2); the EP3 receptor may be involved in inhibition of gastric acid secretion, modulation of neurotransmitter release in central and peripheral neurons, inhibition of sodium and water reabsorption in kidney tubulus and contraction in uterine smooth muscle. The activity of this receptor can couple to both the inhibition of adenylate cyclase mediated by G-I proteins, and to an elevation of intracellular calcium. The various isoforms have identical ligand binding properties but can interact with different second messenger systems (By similarity). {ECO:0000250}. | Prostaglandin E2 receptor EP3 subtype agonist: Bimatoprost, Dinoprostone, Misoprostol | 16.04 | |
| dfaPE2R4 | Prostaglandin E2 receptor EP4 subtype | 5 | 639 | 96.79 | 98.19 | ND | 0.83 | 0.82 | 0.6 | Mammalian | High in intestine and in peripheral blood mononuclear cells; low in lung, kidney, thymus, uterus, vasculature and brain. Not found in liver, heart, retina oe skeletal muscle. | Diarrhoea | Family A G protein-coupled receptor | Dry eye
Osteoporosis, unspecified Renal failure Ulcerative colitis | Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role in regulating renal hemodynamics, intestinal epithelial transport, adrenal aldosterone secretion, and uterine function. | Prostaglandin E2 receptor EP4 subtype agonist: Dinoprostone, Misoprostol | 16.04 | |
| dfaPERF | Perforin-1 | 2 | 164 | 99.60 | 99.12 | ND | 0.58 | 0.62 | 0.3 | Mammalian | Other ion channel | Familial hemophagocytic lymphohistiocytosis 2 (FHL2) [MIM:603553]: A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia. {ECO:0000269|PubMed:10583959, ECO:0000269|PubMed:11179007}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a key role in secretory granule-dependent cell death, and in defense against virus-infected or neoplastic cells. Plays an important role in killing other cells that are recognized as non-self by the immune system, e.g. in transplant rejection or some forms of autoimmune disease. Can insert into the membrane of target cells in its calcium-bound form, oligomerize and form large pores. Promotes cytolysis and apoptosis of target cells by facilitating the uptake of cytotoxic granzymes. {ECO:0000269|PubMed:20038786, ECO:0000269|PubMed:20225066, ECO:0000269|PubMed:20889983, ECO:0000269|PubMed:21037563, ECO:0000269|PubMed:9058810, ECO:0000269|PubMed:9164947}. | 16.04 | ||||
| dfaPF2R | Prostaglandin F2-alpha receptor | 2 | 169 | 99.24 | 99.07 | ND | 0.58 | 0.79 | 0.6 | Mammalian | Eye. {ECO:0000269|PubMed:18587449}. | Family A G protein-coupled receptor | Bone disorders
Dysmenorrhea, unspecified Glaucoma Inflammatory diseases Ocular hypertension | Receptor for prostaglandin F2-alpha (PGF2-alpha). The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. Initiates luteolysis in the corpus luteum (By similarity). Isoforms 2 to 7 do not bind PGF2-alpha but are proposed to modulate signaling by participating in variant receptor complexes; heterodimers between isoform 1 and isoform 5 are proposed to be a receptor for prostamides including the synthetic analog bimatoprost. {ECO:0000250, ECO:0000269|PubMed:18587449}. | Prostaglandin F2-alpha receptor agonist: Bimatoprost, Dinoprost Tromethamine, Latanoprost, Tafluprost, Travoprost | 16.04 | ||
| dfaPGES2 | Prostaglandin E synthase 2 | 1 | 40 | 99.94 | 99.67 | ND | 0.97 | 0.92 | 0.2 | Mammalian | Isomerase that catalyzes the conversion of PGH2 into the more stable prostaglandin E2 (PGE2). {ECO:0000269|PubMed:11866447, ECO:0000269|PubMed:17585783}. | 15.11 | ||||||
| dfaPGFRA | Platelet-derived growth factor receptor alpha | 4 | 389 | 91.10 | 89.93 | ND | 0.60 | 0.62 | 0.7 | Mammalian | Detected in platelets (at protein level). Widely expressed. Detected in brain, fibroblasts, smooth muscle, heart, and embryo. Expressed in primary and metastatic colon tumors and in normal colon tissue. {ECO:0000269|PubMed:2536956, ECO:0000269|PubMed:7896447, ECO:0000269|PubMed:8188664}. | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Note=A chromosomal aberration involving PDGFRA is found in some cases of hypereosinophilic syndrome. Interstitial chromosomal deletion del(4)(q12q12) causes the fusion of FIP1L1 and PDGFRA (FIP1L1-PDGFRA). Mutations that cause overexpression and/or constitutive activation of PDGFRA may be a cause of hypereosinophilic syndrome. {ECO:0000269|PubMed:12808148}. Gastrointestinal stromal tumor (GIST) [MIM:606764]: Common mesenchymal neoplasms arising in the gastrointestinal tract, most often in the stomach. They are histologically, immunohistochemically, and genetically different from typical leiomyomas, leiomyosarcomas, and schwannomas. Most GISTs are composed of a fairly uniform population of spindle-shaped cells. Some tumors are dominated by epithelioid cells or contain a mixture of spindle and epithelioid morphologies. Primary GISTs in the gastrointestinal tract commonly metastasize in the omentum and mesenteries, often as multiple nodules. However, primary tumors may also occur outside of the gastrointestinal tract, in other intra-abdominal locations, especially in the omentum and mesentery. {ECO:0000269|PubMed:12522257, ECO:0000269|PubMed:15928335}. Note=The gene represented in this entry may be involved in disease pathogenesis. Mutations causing PDGFRA constitutive activation have been found in gastrointestinal stromal tumors lacking KIT mutations (PubMed:12522257). {ECO:0000269|PubMed:12522257}. | Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:10734113, ECO:0000269|PubMed:10947961, ECO:0000269|PubMed:11297552, ECO:0000269|PubMed:12522257, ECO:0000269|PubMed:1646396, ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:17141222, ECO:0000269|PubMed:20972453, ECO:0000269|PubMed:21224473, ECO:0000269|PubMed:21596750, ECO:0000269|PubMed:2554309, ECO:0000269|PubMed:8188664, ECO:0000269|PubMed:8760137, ECO:0000269|PubMed:8943348}. | Platelet-derived growth factor receptor alpha : Becaplermin Platelet-derived growth factor receptor alpha antagonist: Imatinib, Sunitinib Platelet-derived growth factor receptor alpha inhibitor: Pazopanib, Ponatinib, Regorafenib | 16.04 | |
| dfaPGFRB | Platelet-derived growth factor receptor beta | 6 | 1291 | 94.01 | 93.49 | ND | 0.75 | 0.00 | 0.6 | Mammalian | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Note=A chromosomal aberration involving PDGFRB is found in a form of chronic myelomonocytic leukemia (CMML). Translocation t(5;12)(q33;p13) with EVT6/TEL. It is characterized by abnormal clonal myeloid proliferation and by progression to acute myelogenous leukemia (AML). Myeloproliferative disorder chronic with eosinophilia (MPE) [MIM:131440]: A hematologic disorder characterized by malignant eosinophils proliferation. Note=The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving PDGFRB have been found in many instances of chronic myeloproliferative disorder with eosinophilia. Translocation t(5;12) with ETV6 on chromosome 12 creating an PDGFRB-ETV6 fusion protein (PubMed:12181402). Translocation t(5;15)(q33;q22) with TP53BP1 creating a PDGFRB-TP53BP1 fusion protein (PubMed:15492236). Translocation t(1;5)(q23;q33) that forms a PDE4DIP-PDGFRB fusion protein (PubMed:12907457). Translocation t(5;6)(q33-34;q23) with CEP85L that fuses the 5'-end of CEP85L (isoform 4) to the 3'-end of PDGFRB (PubMed:21938754). {ECO:0000269|PubMed:12181402, ECO:0000269|PubMed:12907457, ECO:0000269|PubMed:15492236, ECO:0000269|PubMed:21938754}. Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving PDGFRB has been found in a patient with AML. Translocation t(5;14)(q33;q32) with TRIP11 (PubMed:9373237). {ECO:0000269|PubMed:9373237}. Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving PDGFRB has been found in a patient with JMML. Translocation t(5;17)(q33;p11.2) with SPECC1 (PubMed:15087372). {ECO:0000269|PubMed:15087372}. Basal ganglia calcification, idiopathic, 4 (IBGC4) [MIM:615007]: A form of basal ganglia calcification, an autosomal dominant condition characterized by symmetric calcification in the basal ganglia and other brain regions. Affected individuals can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, seizures, and chronic headache. Serum levels of calcium, phosphate, alkaline phosphatase and parathyroid hormone are normal. The neuropathological hallmark of the disease is vascular and pericapillary calcification, mainly of calcium phosphate, in the affected brain areas. {ECO:0000269|PubMed:23255827, ECO:0000269|PubMed:24065723, ECO:0000269|PubMed:26599395}. Note=The disease is caused by mutations affecting the gene represented in this entry. Myofibromatosis, infantile 1 (IMF1) [MIM:228550]: A rare mesenchymal disorder characterized by the development of benign tumors in the skin, striated muscles, bones, and, more rarely, visceral organs. Subcutaneous or soft tissue nodules commonly involve the skin of the head, neck, and trunk. Skeletal and muscular lesions occur in about half of the patients. Lesions may be solitary or multicentric, and they may be present at birth or become apparent in early infancy or occasionally in adult life. Visceral lesions are associated with high morbidity and mortality. {ECO:0000269|PubMed:23731537, ECO:0000269|PubMed:23731542}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5- trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:11297552, ECO:0000269|PubMed:11331881, ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1396585, ECO:0000269|PubMed:1653029, ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:1846866, ECO:0000269|PubMed:20494825, ECO:0000269|PubMed:20529858, ECO:0000269|PubMed:21098708, ECO:0000269|PubMed:21679854, ECO:0000269|PubMed:21733313, ECO:0000269|PubMed:2554309, ECO:0000269|PubMed:26599395, ECO:0000269|PubMed:2835772, ECO:0000269|PubMed:2850496, ECO:0000269|PubMed:7685273, ECO:0000269|PubMed:7691811, ECO:0000269|PubMed:7692233, ECO:0000269|PubMed:8195171}. | Platelet-derived growth factor receptor beta : Becaplermin Platelet-derived growth factor receptor beta antagonist: Dasatinib, Imatinib, Sorafenib, Sunitinib Platelet-derived growth factor receptor beta inhibitor: Pazopanib, Regorafenib | 16.04 | ||
| dfaPGH1 | Prostaglandin G/H synthase 1 | 7 | 3050 | 87.07 | 82.38 | ND | 0.54 | 0.53 | 0.5 | Nature11159 | Mammalian | Abdominal pain upper Aplastic anaemia Asthma Dyspepsia Erythema multiforme Gastrointestinal haemorrhage Haematuria Haemorrhagic diathesis Hepatitis Nephropathy Oedema Peptic ulcer Pruritus Rash Renal failure Renal tubular disorder Thrombocytopenia Tinnitus Toxic epidermal necrolysis | Oxidoreductase | Cardiovascular disease, unspecified
Chronic inflammatory diseases | Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells. | Prostaglandin G/H synthase 1 : Ibuprofen, Niflumic Acid Prostaglandin G/H synthase 1 antagonist: Triflusal Prostaglandin G/H synthase 1 inducer: Desmopressin, Minoxidil Prostaglandin G/H synthase 1 inhibitor: Acetaminophen, Acetylsalicylic acid, Antipyrine, Antrafenine, Balsalazide, Bromfenac, Carprofen, Diclofenac, Diethylcarbamazine, Diflunisal, Dihomo-gamma-linolenic acid, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Icosapent, Indomethacin, Ketoprofen, Ketorolac, Lornoxicam, Lumiracoxib, Magnesium salicylate, Meclofenamic acid, Mefenamic acid, Meloxicam, Mesalazine, Nabumetone, Naproxen, Nepafenac, Oxaprozin, Phenylbutazone, Piroxicam, Salicylate-sodium, Salicylic acid, Salsalate, Sulfasalazine, Sulindac, Suprofen, Tenoxicam, Tiaprofenic acid, Tolmetin, Trisalicylate-choline Prostaglandin G/H synthase 1 substrate: Bortezomib, Candesartan, Carvedilol, Chlorpropamide, Dapsone, Diazepam, Diclofenac, Diphenhydramine, Dronabinol, Eletriptan, Eszopiclone, Etoposide, Hexobarbital, Hydromorphone, Ifosfamide, Imatinib, Irbesartan, Ketamine, Ketobemidone, Montelukast, Nateglinide, Nortriptyline, Pioglitazone, Rosiglitazone, Sulfamethoxazole, Terbinafine, Thalidomide, Torasemide, Trabectedin, Valproic Acid, Voriconazole, Zafirlukast, Zileuton, Zolpidem, Zopiclone | 16.04 | |
| dfaPGH2 | Prostaglandin G/H synthase 2 | 1 | 3317 | 95.30 | 86.60 | ND | 0.53 | 0.42 | 0.8 | Nature11159 | Mammalian | Following colon injury, expressed in the wound bed mesenchyme during the first phase of repair, probably by colonic mesenchymal stem cells (at protein level). {ECO:0000269|PubMed:22465430}. | Abdominal pain upper Aplastic anaemia Dyspepsia Erythema multiforme Flatulence Gastrointestinal haemorrhage Haematuria Haemorrhagic diathesis Hepatitis Nephropathy Oedema Oliguria Peptic ulcer Pruritus Renal failure Thrombocytopenia Tinnitus | Enzyme | Abdominal aortic aneurysm
Adenomatous polyposis Alzheimer's disease Analgesics Arthritis Bladder cancer Breast cancer Cancer, unspecific Carcinoma in situ, unspecified Carpal tunnel syndrome Colorectal cancer Dysmenorrhea, unspecified Endometriosis Genitourinary tumors Gestational hypertension Inflammation Inflammatory diseases Lung cancer Malignant mesothelioma Meningioma Myocardial infarction Oropharyngeal squamous cell carcinoma Osteoarthritis Pain, unspecified Pathological angiogenesis Peutz-Jeghers syndrome Prostate cancer Pyresis Renal cell carcinoma Rheumatoid arthritis, unspecified Stroke Vascular lesion regression | Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis. {ECO:0000269|PubMed:12925531, ECO:0000269|PubMed:20463020, ECO:0000269|PubMed:20810665, ECO:0000269|PubMed:21489986, ECO:0000269|PubMed:22465430}. | Cyclooxygenase inhibitor: Acetaminophen, Aminosalicylic Acid, Aspirin, Balsalazide, Bismuth Subsalicylate, Bromfenac, Diclofenac, Diflunisal, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamic Acid, Mefenamic Acid, Mesalamine, Naproxen, Nepafenac, Olsalazine, Oxaprozin, Oxyphenbutazone, Phenylbutazone, Piroxicam, Sulfasalazine, Sulindac, Suprofen, Tolmetin Cyclooxygenase-2 inhibitor: Carprofen, Celecoxib, Etodolac, Meloxicam, Nabumetone, Rofecoxib, Valdecoxib | 15.11 |
| dfaPGTB1 | Geranylgeranyl transferase type-1 subunit beta | 3 | 87 | 99.45 | 99.11 | ND | 0.69 | 0.63 | 0.5 | Mammalian | Enzyme | Catalyzes the transfer of a geranylgeranyl moiety from geranylgeranyl diphosphate to a cysteine at the fourth position from the C-terminus of proteins with the C-terminal sequence Cys- aliphatic-aliphatic-X. Known substrates include RAC1, RAC2, RAP1A and RAP1B. {ECO:0000269|PubMed:14609943}. | 15.11 | |||||
| dfaPHKG1 | Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform | 4 | 64 | 98.55 | 97.77 | ND | 0.53 | 0.87 | 0.8 | Mammalian | Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. In vitro, phosphorylates PYGM, TNNI3, MAPT/TAU, GAP43 and NRGN/RC3. {ECO:0000269|PubMed:8454596, ECO:0000269|PubMed:8999860}. | 15.11 | ||||||
| dfaPHKG2 | Phosphorylase b kinase gamma catalytic chain, liver/testis isoform | 6 | 164 | 82.93 | 86.40 | ND | 0.62 | 0.64 | 0.5 | Mammalian | Kinase | Glycogen storage disease 9C (GSD9C) [MIM:613027]: A metabolic disorder manifesting in infancy with hepatomegaly, growth retardation, hypotonia, liver dysfunction, and elevated plasma aminotransferases and lipids. These symptoms improve with age in most cases; however, some patients may develop hepatic fibrosis or cirrhosis. {ECO:0000269|PubMed:12930917, ECO:0000269|PubMed:8896567, ECO:0000269|PubMed:9245685}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. May regulate glycogeneolysis in the testis. In vitro, phosphorylates PYGM (By similarity). {ECO:0000250, ECO:0000269|PubMed:10487978}. | 15.11 | ||||
| dfaPI2R | Prostacyclin receptor | 3 | 286 | 98.54 | 98.39 | ND | 0.57 | 0.68 | 0.5 | Mammalian | Family A G protein-coupled receptor | Analgesics
Diabetes mellitus Inflammatory pain | Receptor for prostacyclin (prostaglandin I2 or PGI2). The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase. | Prostacyclin receptor agonist: Epoprostenol, Iloprost, Selexipag, Treprostinil Prostacyclin receptor antagonist: Dinoprost Tromethamine | 16.04 | |||
| dfaPI42C | Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma | 10 | 61 | 99.75 | 95.42 | ND | 0.81 | 0.94 | 0.2 | Mammalian | Enzyme | May play an important role in the production of Phosphatidylinositol bisphosphate (PIP2), in the endoplasmic reticulum. {ECO:0000250}. | 16.04 | |||||
| dfaPI4KB | Phosphatidylinositol 4-kinase beta | 4 | 170 | 93.17 | 95.21 | ND | 0.55 | 0.69 | 0.4 | Mammalian | Widely expressed with highest levels in heart, skeletal muscle, pancreas, testis and ovary. Weakly expressed in liver. {ECO:0000269|PubMed:9020160, ECO:0000269|PubMed:9405935, ECO:0000269|PubMed:9405938}. | Enzyme | Phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol- 1,4,5,-trisphosphate (PIP). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation. Involved in Golgi-to-plasma membrane trafficking (By similarity). {ECO:0000250, ECO:0000269|PubMed:10559940, ECO:0000269|PubMed:12749687, ECO:0000269|PubMed:9405935}. | 15.11 | ||||
| dfaPI51A | Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha | 3 | 64 | 99.92 | 98.84 | ND | 0.49 | 0.96 | 0.5 | Mammalian | Highly expressed in heart, placenta, skeletal muscle, kidney and pancreas. Detected at lower levels in brain, lung and liver. | Kinase | Catalyzes the phosphorylation of phosphatidylinositol 4- phosphate (PtdIns4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). PtdIns(4,5)P2 is involved in a variety of cellular processes and is the substrate to form phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), another second messenger. The majority of PtdIns(4,5)P2 is thought to occur via type I phosphatidylinositol 4-phosphate 5-kinases given the abundance of PtdIns4P. Participates in a variety of cellular processes such as actin cytoskeleton organization, cell adhesion, migration and phagocytosis. Required for membrane ruffling formation, actin organization and focal adhesion formation during directional cell migration by controlling integrin-induced translocation of RAC1 to the plasma membrane. Together with PIP5K1C is required for phagocytosis, but they regulate different types of actin remodeling at sequential steps. Promotes particle ingestion by activating WAS that induces Arp2/3 dependent actin polymerization at the nascent phagocytic cup. Together with PIP5K1B is required after stimulation of G-protein coupled receptors for stable platelet adhesion. Plays a role during calcium-induced keratinocyte differentiation. Recruited to the plasma membrane by the E-cadherin/beta-catenin complex where it provides the substrate PtdIns(4,5)P2 for the production of PtdIns(3,4,5)P3, diacylglycerol and inositol 1,4,5-trisphosphate that mobilize internal calcium and drive keratinocyte differentiation. Together with PIP5K1C have a role during embryogenesis. Functions also in the nucleus where acts as an activator of TUT1 adenylyltransferase activity in nuclear speckles, thereby regulating mRNA polyadenylation of a select set of mRNAs. {ECO:0000269|PubMed:18288197, ECO:0000269|PubMed:19158393, ECO:0000269|PubMed:20660631}. | 16.04 | ||||
| dfaPIM1 | Serine/threonine-protein kinase pim-1 | 5 | 1191 | 91.91 | 88.96 | ND | 0.71 | 0.69 | 0.6 | Mammalian | Expressed primarily in cells of the hematopoietic and germline lineages. Isoform 1 and isoform 2 are both expressed in prostate cancer cell lines. {ECO:0000269|PubMed:16186805}. | Kinase | Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl- X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post- translational levels. Phosphorylation of CDKN1B,induces 14-3-3- proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis. {ECO:0000269|PubMed:10664448, ECO:0000269|PubMed:12431783, ECO:0000269|PubMed:15528381, ECO:0000269|PubMed:16356754, ECO:0000269|PubMed:1825810, ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:19749799}. | Serine/threonine-protein kinase pim-1 product of: Adenosine monophosphate | 15.11 | |||
| dfaPIM2 | Serine/threonine-protein kinase pim-2 | 3 | 561 | 94.32 | 93.10 | ND | 0.73 | 0.76 | 0.5 | Mammalian | Highly expressed in hematopoietic tissues, in leukemic and lymphoma cell lines, testis, small intestine, colon and colorectal adenocarcinoma cells. Weakly expressed in normal liver, but highly expressed in hepatocellular carcinoma tissues. {ECO:0000269|PubMed:18675992}. | Kinase | Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti- apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate. {ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:18675992, ECO:0000269|PubMed:20307683}. | 15.11 | ||||
| dfaPIM3 | Serine/threonine-protein kinase pim-3 | 5 | 421 | 86.94 | 86.43 | ND | 0.79 | 0.83 | 0.6 | Mammalian | Detected in various tissues, including the heart, brain, lung, kidney, spleen, placenta, skeletal muscle, and peripheral blood leukocytes. Not found or barely expressed in the normal adult endoderm-derived organs such as colon, thymus, liver, or small intestine. However, expression is augmented in premalignant and malignant lesions of these organs. {ECO:0000269|PubMed:15540201, ECO:0000269|PubMed:16818649, ECO:0000269|PubMed:17270021}. | Kinase | Proto-oncogene with serine/threonine kinase activity that can prevent apoptosis, promote cell survival and protein translation. May contribute to tumorigenesis through: the delivery of survival signaling through phosphorylation of BAD which induces release of the anti-apoptotic protein Bcl-X(L), the regulation of cell cycle progression, protein synthesis and by regulation of MYC transcriptional activity. Additionally to this role on tumorigenesis, can also negatively regulate insulin secretion by inhibiting the activation of MAPK1/3 (ERK1/2), through SOCS6. Involved also in the control of energy metabolism and regulation of AMPK activity in modulating MYC and PPARGC1A protein levels and cell growth. {ECO:0000269|PubMed:15540201, ECO:0000269|PubMed:16818649, ECO:0000269|PubMed:17270021, ECO:0000269|PubMed:17876606, ECO:0000269|PubMed:18593906}. | 16.04 | ||||
| dfaPIN1 | Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 | 4 | 160 | 86.40 | 88.65 | ND | 0.70 | 0.61 | 0.5 | Mammalian | The phosphorylated form at Ser-71 is expressed in normal breast tissue cells but not in breast cancer cells. {ECO:0000269|PubMed:17828269, ECO:0000269|PubMed:21497122}. | Enzyme | Alzheimer's disease
Cancer, unspecific Hepatocellular carcinoma | Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr- Pro) motifs in a subset of proteins, resulting in conformational changes in the proteins (PubMed:21497122, PubMed:22033920). Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923). {ECO:0000269|PubMed:15664191, ECO:0000269|PubMed:16644721, ECO:0000269|PubMed:17828269, ECO:0000269|PubMed:21497122, ECO:0000269|PubMed:22033920, ECO:0000269|PubMed:22608923}. | 15.11 | |||
| dfaPK3C3 | Phosphatidylinositol 3-kinase catalytic subunit type 3 | 6 | 41 | 99.83 | 99.72 | ND | 0.98 | 0.99 | 0.1 | Mammalian | Ubiquitously expressed, with a highest expression in skeletal muscle. {ECO:0000269|PubMed:7628435}. | Enzyme | Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123, PubMed:20208530). Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for transport from early to late endosomes (By similarity). {ECO:0000250|UniProtKB:O88763, ECO:0000269|PubMed:14617358, ECO:0000269|PubMed:20208530, ECO:0000269|PubMed:20643123, ECO:0000269|PubMed:7628435, ECO:0000305}. | 15.11 | ||||
| dfaPK3CA | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform | 7 | 2208 | 95.68 | 94.38 | ND | 0.71 | 0.76 | 0.6 | Mammalian | Enzyme | Note=PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. {ECO:0000269|PubMed:15016963, ECO:0000269|PubMed:15289301, ECO:0000269|PubMed:15520168, ECO:0000269|PubMed:15712344, ECO:0000269|PubMed:15784156, ECO:0000269|PubMed:15924253, ECO:0000269|PubMed:15930273, ECO:0000269|PubMed:15994075, ECO:0000269|PubMed:16114017, ECO:0000269|PubMed:16322209, ECO:0000269|PubMed:16353168, ECO:0000269|PubMed:16432179, ECO:0000269|PubMed:16533766, ECO:0000269|PubMed:17673550, ECO:0000269|PubMed:19805105, ECO:0000269|PubMed:21708979, ECO:0000269|PubMed:22658544, ECO:0000269|PubMed:22729224}. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:15930273, ECO:0000269|PubMed:15994075}. Note=The gene represented in this entry may be involved in disease pathogenesis. Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:16353168}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. {ECO:0000269|PubMed:15520168}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:15608678}. Note=The gene represented in this entry may be involved in disease pathogenesis. Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:17673550}. Note=The disease is caused by mutations affecting the gene represented in this entry. Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) [MIM:602501]: A syndrome characterized by a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria. {ECO:0000269|PubMed:22729224, ECO:0000269|PubMed:26593112}. Note=The disease is caused by mutations affecting the gene represented in this entry. Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:612918]: A sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth. {ECO:0000269|PubMed:22658544}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cowden syndrome 5 (CWS5) [MIM:615108]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. {ECO:0000269|PubMed:23246288}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Also has serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity). {ECO:0000250|UniProtKB:P42337, ECO:0000269|PubMed:21708979, ECO:0000269|PubMed:26593112}. | 15.11 | ||||
| dfaPK3CB | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform | 6 | 986 | 93.81 | 90.30 | ND | 0.68 | 0.75 | 0.6 | Mammalian | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors. {ECO:0000269|PubMed:18544649, ECO:0000269|PubMed:18594509, ECO:0000269|PubMed:19515725, ECO:0000269|PubMed:19940148, ECO:0000269|PubMed:20065293, ECO:0000269|PubMed:21059846}. | 15.11 | ||||||
| dfaPK3CD | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform | 7 | 1048 | 92.46 | 93.42 | ND | 0.63 | 0.70 | 0.6 | Mammalian | Isoform 1 is expressed in spleen and lung (at protein level). Isoform 1 is expressed predominantly in leukocytes. {ECO:0000269|PubMed:22020336}. | Enzyme | Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. {ECO:0000269|PubMed:12130661, ECO:0000269|PubMed:12235209, ECO:0000269|PubMed:15496927, ECO:0000269|PubMed:16116162, ECO:0000269|PubMed:18259608, ECO:0000269|PubMed:18809712, ECO:0000269|PubMed:19297623}. | 15.11 | ||||
| dfaPK3CG | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform | 7 | 1183 | 96.63 | 92.32 | ND | 0.72 | 0.70 | 0.6 | Mammalian | Pancreas, skeletal muscle, liver and heart. {ECO:0000269|PubMed:7624799}. | Enzyme | Angioedema
Cancer, unspecific Heart failure Myocardial infarction Solid tumors | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin- based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B- lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis. {ECO:0000269|PubMed:12163475, ECO:0000269|PubMed:15294162, ECO:0000269|PubMed:16094730, ECO:0000269|PubMed:21393242, ECO:0000269|PubMed:7624799}. | 15.11 | |||
| dfaPKN1 | Serine/threonine-protein kinase N1 | 7 | 85 | 99.55 | 91.10 | ND | 0.89 | 0.94 | 0.3 | Mammalian | Found ubiquitously. Expressed in heart, brain, placenta, lung, skeletal muscle, kidney and pancreas. Expressed in numerous tumor cell lines, especially in breast tumor cells. {ECO:0000269|PubMed:21754995}. | Kinase | PKC-related serine/threonine-protein kinase involved in various processes such as regulation of the intermediate filaments of the actin cytoskeleton, cell migration, tumor cell invasion and transcription regulation. Regulates the cytoskeletal network by phosphorylating proteins such as VIM and neurofilament proteins NEFH, NEFL and NEFM, leading to inhibit their polymerization. Phosphorylates 'Ser-575', 'Ser-637' and 'Ser-669' of MAPT/Tau, lowering its ability to bind to microtubules, resulting in disruption of tubulin assembly. Acts as a key coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-11' of histone H3 (H3T11ph), a specific tag for epigenetic transcriptional activation that promotes demethylation of histone H3 'Lys-9' (H3K9me) by KDM4C/JMJD2C. Phosphorylates HDAC5, HDAC7 and HDAC9, leading to impair their import in the nucleus. Phosphorylates 'Thr-38' of PPP1R14A, 'Ser- 159', 'Ser-163' and 'Ser-170' of MARCKS, and GFAP. Able to phosphorylate RPS6 in vitro. {ECO:0000269|PubMed:11104762, ECO:0000269|PubMed:12514133, ECO:0000269|PubMed:17332740, ECO:0000269|PubMed:18066052, ECO:0000269|PubMed:20188095, ECO:0000269|PubMed:21754995, ECO:0000269|PubMed:24248594, ECO:0000269|PubMed:8557118, ECO:0000269|PubMed:8621664, ECO:0000269|PubMed:9175763}. | 15.11 | ||||
| dfaPKN2 | Serine/threonine-protein kinase N2 | 5 | 308 | 93.30 | 90.12 | ND | 0.57 | 0.65 | 0.6 | Mammalian | Ubiquitous. Expressed in numerous tumor cell lines, especially in bladder tumor cells. {ECO:0000269|PubMed:10026169, ECO:0000269|PubMed:21754995}. | Kinase | PKC-related serine/threonine-protein kinase and Rho/Rac effector protein that participates in specific signal transduction responses in the cell. Plays a role in the regulation of cell cycle progression, actin cytoskeleton assembly, cell migration, cell adhesion, tumor cell invasion and transcription activation signaling processes. Phosphorylates CTTN in hyaluronan-induced astrocytes and hence decreases CTTN ability to associate with filamentous actin. Phosphorylates HDAC5, therefore lead to impair HDAC5 import. Direct RhoA target required for the regulation of the maturation of primordial junctions into apical junction formation in bronchial epithelial cells. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Stimulates FYN kinase activity that is required for establishment of skin cell-cell adhesion during keratinocytes differentiation. Regulates epithelial bladder cells speed and direction of movement during cell migration and tumor cell invasion. Inhibits Akt pro-survival-induced kinase activity. Mediates Rho protein-induced transcriptional activation via the c- fos serum response factor (SRF). Phosphorylates HCV NS5B leading to stimulation of HCV RNA replication. {ECO:0000269|PubMed:10226025, ECO:0000269|PubMed:10926925, ECO:0000269|PubMed:11777936, ECO:0000269|PubMed:11781095, ECO:0000269|PubMed:15364941, ECO:0000269|PubMed:17332740, ECO:0000269|PubMed:20188095, ECO:0000269|PubMed:20974804, ECO:0000269|PubMed:21754995, ECO:0000269|PubMed:9121475}. | 16.04 | ||||
| dfaPLCB | 1-acyl-sn-glycerol-3-phosphate acyltransferase beta | 2 | 99 | 99.53 | 99.99 | ND | 0.73 | 0.62 | 0.4 | Mammalian | Expressed predominantly in adipose tissue, pancreas and liver. {ECO:0000269|PubMed:21873652}. | Enzyme | Congenital generalized lipodystrophy 1 (CGL1) [MIM:608594]: An autosomal recessive disorder characterized by a near complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. {ECO:0000269|PubMed:11967537}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts lysophosphatidic acid (LPA) into phosphatidic acid by incorporating an acyl moiety at the sn-2 position of the glycerol backbone. {ECO:0000269|PubMed:15629135, ECO:0000269|PubMed:21873652, ECO:0000269|PubMed:9242711}. | 16.04 | |||
| dfaPLD1 | Phospholipase D1 | 1 | 148 | 99.93 | 99.94 | ND | 0.62 | 0.72 | 0.6 | Mammalian | Expressed abundantly in the pancreas and heart and at high levels in brain, placenta, spleen, uterus and small intestine. {ECO:0000269|PubMed:9582313}. | Enzyme | Inflammation | Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear intravesicular membrane traffic (By similarity). {ECO:0000250}. | Phospholipase D1 product of: Choline Phospholipase D1 substrate: Miltefosine | 16.04 | ||
| dfaPLD2 | Phospholipase D2 | 2 | 152 | 99.62 | 99.75 | ND | 0.35 | 0.59 | 0.4 | Mammalian | Ubiquitous. | Enzyme | May have a role in signal-induced cytoskeletal regulation and/or endocytosis. {ECO:0000250}. | Phospholipase D2 product of: Choline | 16.04 | |||
| dfaPLIN1 | Perilipin-1 | 1 | 151 | 81.42 | 87.86 | ND | 0.38 | 0.09 | 0.2 | Mammalian | Adipocytes. {ECO:0000269|PubMed:9521880}. | Lipodystrophy, familial partial, 4 (FPLD4) [MIM:613877]: A form of lipodystrophy characterized by loss of subcutaneous adipose tissue primarily affecting the lower limbs, insulin- resistant diabetes mellitus, hypertriglyceridemia, and hypertension. {ECO:0000269|PubMed:21345103}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Modulator of adipocyte lipid metabolism. Coats lipid storage droplets to protect them from breakdown by hormone- sensitive lipase (HSL). Its absence may result in leanness. Plays a role in unilocular lipid droplet formation by activating CIDEC. Their interaction promotes lipid droplet enlargement and directional net neutral lipid transfer. May modulate lipolysis and triglyceride levels. {ECO:0000269|PubMed:23399566}. | 16.04 | ||||
| dfaPLK1 | Serine/threonine-protein kinase PLK1 | 4 | 761 | 95.31 | 93.32 | ND | 0.76 | 0.79 | 0.6 | Mammalian | Placenta and colon. | Kinase | Note=Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis. | Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, CENPU, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, CENPU, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, CENPU, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGOL1: required for spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis. Phosphorylates MISP, leading to stabilization of cortical and astral microtubule attachments required for proper spindle positioning (PubMed:8991084, PubMed:11202906, PubMed:12207013, PubMed:12447691, PubMed:12524548, PubMed:12738781, PubMed:12852856, PubMed:12939256, PubMed:14532005, PubMed:14734534, PubMed:15070733, PubMed:15148369, PubMed:15469984, PubMed:16198290, PubMed:16247472, PubMed:16980960, PubMed:17081991, PubMed:17351640, PubMed:17376779, PubMed:17617734, PubMed:18174154, PubMed:18331714, PubMed:18418051, PubMed:18477460, PubMed:18521620, PubMed:18615013, PubMed:19160488, PubMed:19351716, PubMed:19468300, PubMed:19468302, PubMed:19473992, PubMed:19509060, PubMed:19597481, PubMed:23455478, PubMed:23509069). Together with MEIKIN, acts as a regulator of kinetochore function during meiosis I: required both for mono- orientation of kinetochores on sister chromosomes and protection of centromeric cohesin from separase-mediated cleavage (By similarity). Phosphorylates CEP68 and is required for its degradation (PubMed:25503564). {ECO:0000250|UniProtKB:Q5F2C3, ECO:0000269|PubMed:11202906, ECO:0000269|PubMed:12207013, ECO:0000269|PubMed:12447691, ECO:0000269|PubMed:12524548, ECO:0000269|PubMed:12738781, ECO:0000269|PubMed:12852856, ECO:0000269|PubMed:12939256, ECO:0000269|PubMed:14532005, ECO:0000269|PubMed:14734534, ECO:0000269|PubMed:15070733, ECO:0000269|PubMed:15148369, ECO:0000269|PubMed:15469984, ECO:0000269|PubMed:16198290, ECO:0000269|PubMed:16247472, ECO:0000269|PubMed:16980960, ECO:0000269|PubMed:17081991, ECO:0000269|PubMed:17351640, ECO:0000269|PubMed:17376779, ECO:0000269|PubMed:17617734, ECO:0000269|PubMed:18174154, ECO:0000269|PubMed:18331714, ECO:0000269|PubMed:18418051, ECO:0000269|PubMed:18477460, ECO:0000269|PubMed:18521620, ECO:0000269|PubMed:18615013, ECO:0000269|PubMed:19160488, ECO:0000269|PubMed:19351716, ECO:0000269|PubMed:19468300, ECO:0000269|PubMed:19468302, ECO:0000269|PubMed:19473992, ECO:0000269|PubMed:19509060, ECO:0000269|PubMed:19597481, ECO:0000269|PubMed:23455478, ECO:0000269|PubMed:23509069, ECO:0000269|PubMed:25503564, ECO:0000269|PubMed:8991084}. | 15.11 | |||
| dfaPLK2 | Serine/threonine-protein kinase PLK2 | 6 | 160 | 96.20 | 97.88 | ND | 0.82 | 0.78 | 0.4 | Mammalian | Expressed at higher level in the fetal lung, kidney, spleen and heart. {ECO:0000269|PubMed:11696980}. | Kinase | Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress. {ECO:0000269|PubMed:15242618, ECO:0000269|PubMed:19001868, ECO:0000269|PubMed:20352051, ECO:0000269|PubMed:20531387}. | 15.11 | ||||
| dfaPLK3 | Serine/threonine-protein kinase PLK3 | 4 | 339 | 95.56 | 95.02 | ND | 0.68 | 0.73 | 0.5 | Mammalian | Transcripts are highly detected in placenta, lung, followed by skeletal muscle, heart, pancreas, ovaries and kidney and weakly detected in liver and brain. May have a short half-live. In cells of hematopoietic origin, strongly and exclusively detected in terminally differentiated macrophages. Transcript expression appears to be down-regulated in primary lung tumor. | Kinase | Serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates ATF2, BCL2L1, CDC25A, CDC25C, CHEK2, HIF1A, JUN, p53/TP53, p73/TP73, PTEN, TOP2A and VRK1. Involved in cell cycle regulation: required for entry into S phase and cytokinesis. Phosphorylates BCL2L1, leading to regulate the G2 checkpoint and progression to cytokinesis during mitosis. Plays a key role in response to stress: rapidly activated upon stress stimulation, such as ionizing radiation, reactive oxygen species (ROS), hyperosmotic stress, UV irradiation and hypoxia. Involved in DNA damage response and G1/S transition checkpoint by phosphorylating CDC25A, p53/TP53 and p73/TP73. Phosphorylates p53/TP53 in response to reactive oxygen species (ROS), thereby promoting p53/TP53-mediated apoptosis. Phosphorylates CHEK2 in response to DNA damage, promoting the G2/M transition checkpoint. Phosphorylates the transcription factor p73/TP73 in response to DNA damage, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates HIF1A and JUN is response to hypoxia. Phosphorylates ATF2 following hyperosmotic stress in corneal epithelium. Also involved in Golgi disassembly during the cell cycle: part of a MEK1/MAP2K1-dependent pathway that induces Golgi fragmentation during mitosis by mediating phosphorylation of VRK1. May participate in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation, via its interaction with CIB1. {ECO:0000269|PubMed:10557092, ECO:0000269|PubMed:11156373, ECO:0000269|PubMed:11447225, ECO:0000269|PubMed:11551930, ECO:0000269|PubMed:11971976, ECO:0000269|PubMed:12242661, ECO:0000269|PubMed:14968113, ECO:0000269|PubMed:14980500, ECO:0000269|PubMed:15021912, ECO:0000269|PubMed:16478733, ECO:0000269|PubMed:16481012, ECO:0000269|PubMed:17264206, ECO:0000269|PubMed:17804415, ECO:0000269|PubMed:18062778, ECO:0000269|PubMed:18650425, ECO:0000269|PubMed:19103756, ECO:0000269|PubMed:19490146, ECO:0000269|PubMed:20889502, ECO:0000269|PubMed:20940307, ECO:0000269|PubMed:20951827, ECO:0000269|PubMed:21098032, ECO:0000269|PubMed:21264284, ECO:0000269|PubMed:21376736, ECO:0000269|PubMed:21840391, ECO:0000269|PubMed:9353331}. | 15.11 | ||||
| dfaPLK4 | Serine/threonine-protein kinase PLK4 | 5 | 357 | 89.41 | 92.29 | ND | 0.67 | 0.82 | 0.5 | Mammalian | Kinase | Microcephaly and chorioretinopathy, autosomal recessive, 2 (MCCRP2) [MIM:616171]: A severe disorder characterized by microcephaly, delayed psychomotor development, growth retardation with dwarfism, and ocular abnormalities. {ECO:0000269|PubMed:25344692}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2. {ECO:0000269|PubMed:16244668, ECO:0000269|PubMed:16326102, ECO:0000269|PubMed:17681131, ECO:0000269|PubMed:18239451, ECO:0000269|PubMed:19164942, ECO:0000269|PubMed:21725316}. | 15.11 | ||||
| dfaPLMN | Plasminogen | 4 | 673 | 95.96 | 97.63 | ND | 0.60 | 0.69 | 0.5 | Mammalian | Present in plasma and many other extracellular fluids. It is synthesized in the liver. | Protease | Plasminogen deficiency (PLGD) [MIM:217090]: A disorder characterized by decreased serum plasminogen activity. Two forms of the disorder are distinguished: type 1 deficiency is additionally characterized by decreased plasminogen antigen levels and clinical symptoms, whereas type 2 deficiency, also known as dysplasminogenemia, is characterized by normal, or slightly reduced antigen levels, and absence of clinical manifestations. Plasminogen deficiency type 1 results in markedly impaired extracellular fibrinolysis and chronic mucosal pseudomembranous lesions due to subepithelial fibrin deposition and inflammation. The most common clinical manifestation of type 1 deficiency is ligneous conjunctivitis in which pseudomembranes formation on the palpebral surfaces of the eye progresses to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. {ECO:0000269|PubMed:10233898, ECO:0000269|PubMed:1427790, ECO:0000269|PubMed:1986355, ECO:0000269|PubMed:6216475, ECO:0000269|PubMed:6238949, ECO:0000269|PubMed:8392398, ECO:0000269|PubMed:9242524, ECO:0000269|PubMed:9858247}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells. {ECO:0000269|PubMed:14699093}. Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. {ECO:0000269|PubMed:14699093}. | Plasminogen activator: Alteplase, Anistreplase, Reteplase, Streptokinase, Tenecteplase, Urokinase Plasminogen inhibitor: Aminocaproic Acid, Tranexamic Acid | 15.11 | ||
| dfaPNMT | Phenylethanolamine N-methyltransferase | 2 | 248 | 98.32 | 94.97 | ND | 0.60 | 0.56 | 0.6 | Mammalian | Enzyme | Converts noradrenaline to adrenaline. | 15.11 | |||||
| dfaPNPH | Purine nucleoside phosphorylase | 3 | 252 | 99.44 | 98.68 | ND | 0.44 | 0.58 | 0.8 | Mammalian | Enzyme | The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta- (deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate. {ECO:0000269|PubMed:7607309}. | 15.11 | |||||
| dfaPOLK | DNA polymerase kappa | 4 | 1529 | 87.44 | 82.01 | ND | 0.39 | 0.39 | 0.4 | Mammalian | Detected at low levels in testis, spleen, prostate and ovary. Detected at very low levels in kidney, colon, brain, heart, liver, lung, placenta, pancreas and peripheral blood leukocytes. {ECO:0000269|PubMed:10518552, ECO:0000269|PubMed:10620008}. | Enzyme | DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity. {ECO:0000269|PubMed:10620008, ECO:0000269|PubMed:11024016, ECO:0000269|PubMed:12145297, ECO:0000269|PubMed:12444249, ECO:0000269|PubMed:12952891, ECO:0000269|PubMed:14630940, ECO:0000269|PubMed:15533436}. | 16.04 | ||||
| dfaPORCN | Protein-serine O-palmitoleoyltransferase porcupine {ECO:0000250|UniProtKB:Q9JJJ7} | 1 | 51 | 99.86 | 99.99 | ND | 0.69 | 0.79 | 0.4 | Mammalian | Isoform 1 is expressed in fetal brain, brain, amygdala, caudate nucleus, cerebellum, hippocampus, pituitary, thalamus, heart, skeletal muscle and testis. Isoform 4 is expressed in amygdala, corpus callosum, hippocampus, spinal cord, kidney, liver, lung, spleen, uterus, testis. Isoform 2 and isoform 3 are expressed in substantia negra, spinal cord, heart and lung. {ECO:0000269|PubMed:12034504}. | Enzyme | Focal dermal hypoplasia (FODH) [MIM:305600]: A rare congenital ectomesodermal disorder characterized by a combination of skin defects, skeletal abnormalities, and ocular anomalies. Affected individuals have patchy dermal hypoplasia, often in a distribution pattern following the Blaschko lines, and areas of subcutaneous fat herniation or deposition of fat into the dermis. In addition, sparse and brittle hair, hypoplastic nails and papillomas have been described. Skeletal abnormalities usually comprise syndactyly, ectrodactyly, and brachydactyly, and in some cases osteopathia striata has been seen. Patients frequently have ocular anomalies, including microphthalmia/ anophthalmia, coloboma, pigmentary and vascularization defects of the retina. Dental abnormalities are often present. {ECO:0000269|PubMed:17546030, ECO:0000269|PubMed:17546031, ECO:0000269|PubMed:18325042, ECO:0000269|PubMed:19277062, ECO:0000269|PubMed:19309688, ECO:0000269|PubMed:19586929, ECO:0000269|PubMed:19863546, ECO:0000269|PubMed:21472892}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1), to Wnt proteins. Serine palmitoleylation of WNT proteins is required for efficient binding to frizzled receptors. {ECO:0000250|UniProtKB:Q9JJJ7, ECO:0000269|PubMed:12034504, ECO:0000269|PubMed:20826466, ECO:0000269|PubMed:24292069}. | 16.04 | |||
| dfaPPAC | Low molecular weight phosphotyrosine protein phosphatase | 2 | 221 | 83.77 | 80.05 | ND | 0.28 | 0.39 | 0.5 | Mammalian | T-lymphocytes express only isoform 2. {ECO:0000269|PubMed:9038134}. | Phosphatase | Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. Isoform 3 does not possess phosphatase activity. | 16.04 | ||||
| dfaPPARA | Peroxisome proliferator-activated receptor alpha | 3 | 2130 | 96.77 | 96.64 | ND | 0.45 | 0.49 | 0.8 | Mammalian | Skeletal muscle, liver, heart and kidney. {ECO:0000269|PubMed:7981125, ECO:0000269|PubMed:8993548}. | Myalgia | Nuclear receptor | Hyperglycemia
Hyperinsulinemia Insulin resistance Lipid metabolic disorders Obesity | Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl- 2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2. {ECO:0000269|PubMed:10195690, ECO:0000269|PubMed:24043310, ECO:0000269|PubMed:7629123, ECO:0000269|PubMed:7684926, ECO:0000269|PubMed:9556573}. | Peroxisome proliferator-activated receptor alpha agonist: Bezafibrate, Clofibrate, Fenofibrate, Gemfibrozil, Indomethacin | 15.11 | |
| dfaPPARD | Peroxisome proliferator-activated receptor delta | 2 | 1236 | 98.88 | 98.82 | ND | 0.69 | 0.76 | 0.7 | Mammalian | Ubiquitous with maximal levels in placenta and skeletal muscle. | Nuclear receptor | Atherosclerosis
Hyperlipidemia Inflammation Metabolic Disease Metabolic syndrome X Noninsulin-dependent diabetes mellitus Obesity Skin diseases | Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand. {ECO:0000269|PubMed:1333051, ECO:0000269|PubMed:15604518}. | Peroxisome proliferator-activated receptor delta agonist: Bezafibrate, Icosapent, Treprostinil Peroxisome proliferator-activated receptor delta negative modulator: Sulindac | 15.11 | ||
| dfaPPARG | Peroxisome proliferator-activated receptor gamma | 4 | 2583 | 95.30 | 94.36 | ND | 0.60 | 0.63 | 0.6 | VirtualToxLab | Mammalian | Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary. {ECO:0000269|PubMed:9065481}. | Dyspepsia | Nuclear receptor | Note=Defects in PPARG can lead to type 2 insulin- resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. {ECO:0000269|PubMed:10394368}. Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:9753710}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Lipodystrophy, familial partial, 3 (FPLD3) [MIM:604367]: A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. {ECO:0000269|PubMed:11788685, ECO:0000269|PubMed:12453919}. Note=The disease is caused by mutations affecting the gene represented in this entry. Glioma 1 (GLM1) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:10851250}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility. | Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity). {ECO:0000250|UniProtKB:P37238, ECO:0000269|PubMed:16150867, ECO:0000269|PubMed:20829347, ECO:0000269|PubMed:23525231, ECO:0000269|PubMed:9065481}. | Peroxisome proliferator-activated receptor gamma activator: Ibuprofen, Indomethacin Peroxisome proliferator-activated receptor gamma agonist: Balsalazide, Bezafibrate, Glipizide, Icosapent, Mesalazine, Mitiglinide, Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone, Sulfasalazine Peroxisome proliferator-activated receptor gamma partial agonist: Telmisartan | 15.11 |
| dfaPPBI | Intestinal-type alkaline phosphatase | 5 | 370 | 88.84 | 86.25 | ND | 0.30 | 0.42 | 0.5 | Mammalian | Enzyme | 16.04 | ||||||
| dfaPPCE | Prolyl endopeptidase | 1 | 524 | 97.68 | 96.59 | ND | 0.69 | 0.74 | 0.9 | Mammalian | Protease | Dementia
Neurological diseases | Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. | Prolyl endopeptidase substrate: Oxytocin | 15.11 | |||
| dfaPPIA | Peptidyl-prolyl cis-trans isomerase A | 2 | 80 | 96.49 | 96.36 | ND | 0.10 | 0.27 | 0.6 | Mammalian | Isomerase | PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. | Peptidyl-prolyl cis-trans isomerase A : Cyclosporine Peptidyl-prolyl cis-trans isomerase A binder: L-Proline | 15.11 | ||||
| dfaPPOX | Protoporphyrinogen oxidase | 2 | 72 | 99.46 | 99.93 | ND | 0.37 | 0.61 | 0.4 | Mammalian | Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. | Enzyme | Variegate porphyria (VP) [MIM:176200]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Variegate porphyria is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. {ECO:0000269|PubMed:10486317, ECO:0000269|PubMed:10870850, ECO:0000269|PubMed:11074242, ECO:0000269|PubMed:11102990, ECO:0000269|PubMed:11286631, ECO:0000269|PubMed:11348478, ECO:0000269|PubMed:11350188, ECO:0000269|PubMed:11474578, ECO:0000269|PubMed:12380696, ECO:0000269|PubMed:12655566, ECO:0000269|PubMed:12859407, ECO:0000269|PubMed:14669009, ECO:0000269|PubMed:16433813, ECO:0000269|PubMed:16922948, ECO:0000269|PubMed:16947091, ECO:0000269|PubMed:18350656, ECO:0000269|PubMed:18570668, ECO:0000269|PubMed:19320019, ECO:0000269|PubMed:23430901, ECO:0000269|PubMed:24073655, ECO:0000269|PubMed:8673113, ECO:0000269|PubMed:8817334, ECO:0000269|PubMed:8852667, ECO:0000269|PubMed:9541112, ECO:0000269|PubMed:9763307, ECO:0000269|PubMed:9811936}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations leading to severe PPOX deficiency cause the rare homozygous variant form of VP. Missense mutations that preserve 10%-25% of wild-type activity may not cause clinically overt VP in heterozygotes (PubMed:9811936). Mutations with intermediate effect on catalytic activity may cause VP, but with a low clinical penetrance (PubMed:10486317). {ECO:0000269|PubMed:10486317, ECO:0000269|PubMed:9811936}. | Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX. {ECO:0000269|PubMed:21048046, ECO:0000269|PubMed:23467411, ECO:0000269|PubMed:7713909}. | 16.04 | |||
| dfaPRGR | Progesterone receptor | 2 | 1519 | 95.84 | 91.85 | ND | 0.65 | 0.63 | 0.7 | Nature11159 VirtualToxLab | Mammalian | Acne Amenorrhoea Biliary tract disorder Breast pain Depression Fibrocystic breast disease Gynaecomastia Hirsutism Jaundice cholestatic Libido disorder Menstrual disorder Metrorrhagia Migraine Oedema Urticaria Weight increased | Nuclear receptor | Breast cancer | The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation. Isoform A: inactive in stimulating c-Src/MAPK signaling on hormone stimulation. Isoform 4: Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone. | Progesterone receptor agonist: Allylestrenol, Danazol, Desogestrel, Drospirenone, Dydrogesterone, Ethynodiol, Etonogestrel, Fluticasone Propionate, Medroxyprogesterone Acetate, Megestrol acetate, Norelgestromin, Norethindrone, Norgestimate, Progesterone, Spironolactone Progesterone receptor antagonist: Mifepristone Progesterone receptor binder: Levonorgestrel Progesterone receptor modulator: Ulipristal | 15.11 | |
| dfaPRKDC | DNA-dependent protein kinase catalytic subunit | 3 | 623 | 97.60 | 94.44 | ND | 0.72 | 0.74 | 0.5 | Mammalian | Kinase | Immunodeficiency 26 with or without neurologic abnormalities (IMD26) [MIM:615966]: A form of severe combined immunodeficiency characterized by reduced or absent T and B cells, recurrent candidiasis, and lower respiratory tract infections. Some patients show dysmorphic features, severe growth failure, microcephaly, seizures, and impaired neurological functions. {ECO:0000269|PubMed:19075392, ECO:0000269|PubMed:23722905}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Required to protect and align broken ends of DNA. May also act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX, thereby regulating DNA damage response mechanism. Phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect machanism. Interacts with CRY1 and CRY2; negatively regulates CRY1 phosphorylation. {ECO:0000269|PubMed:12649176, ECO:0000269|PubMed:14734805, ECO:0000269|PubMed:15574326, ECO:0000269|PubMed:9679063}. | 16.04 | ||||
| dfaPRKX | cAMP-dependent protein kinase catalytic subunit PRKX | 7 | 280 | 89.97 | 93.72 | ND | 0.52 | 0.72 | 0.6 | Mammalian | Widely expressed (at protein level). Specifically expressed in blood by macrophages and granulocytes according to PubMed:9860982. {ECO:0000269|PubMed:15879576, ECO:0000269|PubMed:16236808, ECO:0000269|PubMed:7633447, ECO:0000269|PubMed:9860982}. | Kinase | Note=A chromosomal aberration involving PRKX is a cause of sex reversal disorder. Translocation t(X;Y)(p22;p11) with PRKY. Chromosomal translocations proximal to PRKY account for about 30% of the cases of sex reversal disorder in XX males and XY females. | Serine/threonine protein kinase regulated by and mediating cAMP signaling in cells. Acts through phosphorylation of downstream targets that may include CREB, SMAD6 and PKD1 and has multiple functions in cellular differentiation and epithelial morphogenesis. Regulates myeloid cell differentiation through SMAD6 phosphorylation. Involved in nephrogenesis by stimulating renal epithelial cell migration and tubulogenesis. Also involved in angiogenesis through stimulation of endothelial cell proliferation, migration and vascular-like structure formation. {ECO:0000269|PubMed:12082174, ECO:0000269|PubMed:16236808, ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:17980165, ECO:0000269|PubMed:19367327, ECO:0000269|PubMed:21684272, ECO:0000269|PubMed:9860982}. | 16.04 | |||
| dfaPROC | Vitamin K-dependent protein C | 2 | 165 | 99.29 | 99.68 | ND | 0.38 | 0.71 | 0.4 | Mammalian | Plasma; synthesized in the liver. | Protease | Thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency. {ECO:0000269|PubMed:1301959, ECO:0000269|PubMed:1347706, ECO:0000269|PubMed:1511989, ECO:0000269|PubMed:1868249, ECO:0000269|PubMed:2437584, ECO:0000269|PubMed:25618265, ECO:0000269|PubMed:25748729, ECO:0000269|PubMed:2602169, ECO:0000269|PubMed:7792728, ECO:0000269|PubMed:7865674, ECO:0000269|PubMed:8292730, ECO:0000269|PubMed:8398832, ECO:0000269|PubMed:8499568, ECO:0000269|PubMed:8560401, ECO:0000269|PubMed:8829639, ECO:0000269|PubMed:9798967}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare. {ECO:0000269|PubMed:1511988, ECO:0000269|PubMed:1593215, ECO:0000269|PubMed:1611081, ECO:0000269|PubMed:25618265, ECO:0000269|PubMed:7841323, ECO:0000269|PubMed:7841324, ECO:0000269|PubMed:7878626}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids (PubMed:25618265). Exerts a protective effect on the endothelial cell barrier function (PubMed:25651845). {ECO:0000269|PubMed:25618265, ECO:0000269|PubMed:25651845}. | Vitamin K-dependent protein C activator: Menadione Vitamin K-dependent protein C inactivator: Antihemophilic Factor (Recombinant) Vitamin K-dependent protein C inhibitor: Sodium Tetradecyl Sulfate | 16.04 | ||
| dfaPRP4B | Serine/threonine-protein kinase PRP4 homolog | 6 | 58 | 98.17 | 99.28 | ND | 0.79 | 0.96 | 0.2 | Mammalian | Ubiquitous. | Enzyme | Has a role in pre-mRNA splicing. Phosphorylates SF2/ASF. | 15.11 | ||||
| dfaPSB1 | Proteasome subunit beta type-1 | 4 | 42 | 99.76 | 99.98 | ND | 0.06 | 0.38 | 0.3 | Mammalian | Protease | The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. | Proteasome subunit beta type-1 antagonist: Bortezomib Proteasome subunit beta type-1 inhibitor: Carfilzomib | 16.04 | ||||
| dfaPSB5 | Proteasome subunit beta type-5 | 4 | 68 | 95.74 | 94.86 | ND | 0.68 | 0.74 | 0.5 | Mammalian | Protease | The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This unit is responsible of the chymotrypsin-like activity of the proteasome and is one of the principal target of the proteasome inhibitor bortezomib. May catalyze basal processing of intracellular antigens. Plays a role in the protection against oxidative damage through the Nrf2-ARE pathway (By similarity). {ECO:0000250, ECO:0000269|PubMed:18502982, ECO:0000269|PubMed:18565852}. | Proteasome subunit beta type-5 antagonist: Bortezomib Proteasome subunit beta type-5 inhibitor: Carfilzomib | 16.04 | ||||
| dfaPTAFR | Platelet-activating factor receptor | 7 | 832 | 96.77 | 93.28 | ND | 0.64 | 0.56 | 0.6 | Mammalian | Expressed in the placenta, lung, left and right heart ventricles, heart atrium, leukocytes and differentiated HL-60 granulocytes. {ECO:0000269|PubMed:1281995, ECO:0000269|PubMed:1656963, ECO:0000269|PubMed:1657923}. | Family A G protein-coupled receptor | Ocular allergy | Receptor for platelet activating factor, a chemotactic phospholipid mediator that possesses potent inflammatory, smooth- muscle contractile and hypotensive activity. Seems to mediate its action via a G protein that activates a phosphatidylinositol- calcium second messenger system. {ECO:0000269|PubMed:1281995, ECO:0000269|PubMed:1374385, ECO:0000269|PubMed:1656963, ECO:0000269|PubMed:1657923}. | 16.04 | |||
| dfaPTGES | Prostaglandin E synthase | 3 | 442 | 94.76 | 91.81 | ND | 0.63 | 0.77 | 0.7 | Mammalian | Enzyme | Inflammation
Rheumatoid arthritis, unspecified | Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2). {ECO:0000269|PubMed:18682561}. | 15.11 | ||||
| dfaPTGIS | Prostacyclin synthase | 2 | 57 | 99.94 | 99.93 | ND | 0.68 | 0.41 | 0.5 | Mammalian | Widely expressed; particularly abundant in ovary, heart, skeletal muscle, lung and prostate. | Cytochrome P450 | Essential hypertension (EHT) [MIM:145500]: A condition in which blood pressure is consistently higher than normal with no identifiable cause. {ECO:0000269|PubMed:12372404}. Note=The disease may be caused by mutations affecting the gene represented in this entry. | Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2). | Prostacyclin synthase inducer: Epoprostenol Prostacyclin synthase inhibitor: Phenylbutazone | 15.11 | ||
| dfaPTK6 | Protein-tyrosine kinase 6 | 5 | 198 | 98.74 | 98.70 | ND | 0.64 | 0.73 | 0.7 | Mammalian | Epithelia-specific. Very high level in colon and high levels in small intestine and prostate, and low levels in some fetal tissues. Not expressed in breast or ovarian tissue but expressed in high percentage of breast and ovarian cancers. Also overexpressed in some metastatic melanomas, lymphomas, colon cancers, squamous cell carcinomas and prostate cancers. Also found in melanocytes. Not expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform 2 is present in prostate epithelial cell lines derived from normal prostate and prostate adenocarcinomas, as well as in a variety of cell lines. {ECO:0000269|PubMed:12833144, ECO:0000269|PubMed:15509496, ECO:0000269|PubMed:16651629, ECO:0000269|PubMed:9185712}. | Kinase | Breast cancer
Cancer, unspecific Pancreatic cancer Prostate tumor | Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage- independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways. Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins. | Protein-tyrosine kinase 6 inhibitor: Vandetanib | 16.04 | ||
| dfaPTN1 | Tyrosine-protein phosphatase non-receptor type 1 | 3 | 1669 | 93.85 | 87.70 | ND | 0.75 | 0.76 | 0.5 | Mammalian | Phosphatase | Type 2 Diabetes | Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of MET. {ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:21135139, ECO:0000269|PubMed:22169477}. | Tyrosine-protein phosphatase non-receptor type 1 inhibitor: Tiludronate | 15.11 | |||
| dfaPTN12 | Tyrosine-protein phosphatase non-receptor type 12 | 2 | 64 | 99.71 | 97.42 | ND | 0.69 | 0.76 | 0.2 | Mammalian | Phosphatase | Dephosphorylates cellular tyrosine kinases, including PTK2B/PYK2, and thereby regulates signaling via PTK2B/PYK2. {ECO:0000269|PubMed:17329398}. | 16.04 | |||||
| dfaPTN2 | Tyrosine-protein phosphatase non-receptor type 2 | 6 | 336 | 95.09 | 92.52 | ND | 0.78 | 0.90 | 0.4 | Mammalian | Ubiquitously expressed. Isoform 2 is probably the major isoform. Isoform 1 is expressed in T-cells and in placenta. {ECO:0000269|PubMed:1731319, ECO:0000269|PubMed:2546150}. | Phosphatase | Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT5A, STAT5B and STAT6 either in the nucleus or the cytoplasm. Negatively regulates numerous signaling pathways and biological processes like hematopoiesis, inflammatory response, cell proliferation and differentiation, and glucose homeostasis. Plays a multifaceted and important role in the development of the immune system. Functions in T-cell receptor signaling through dephosphorylation of FYN and LCK to control T-cells differentiation and activation. Dephosphorylates CSF1R, negatively regulating its downstream signaling and macrophage differentiation. Negatively regulates cytokine (IL2/interleukin-2 and interferon)-mediated signaling through dephosphorylation of the cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that propagate signaling downstream of the cytokine receptors. Also regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine signaling through dephosphorylation of STAT3 and STAT6 respectively. In addition to the immune system, it is involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth. Activated by the integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates EGF signaling. Dephosphorylates PDGFRB and negatively regulates platelet-derived growth factor receptor-beta signaling pathway and therefore cell proliferation. Negatively regulates tumor necrosis factor-mediated signaling downstream via MAPK through SRC dephosphorylation. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of the hepatocyte growth factor receptor MET. Plays also an important role in glucose homeostasis. For instance, negatively regulates the insulin receptor signaling pathway through the dephosphorylation of INSR and control gluconeogenesis and liver glucose production through negative regulation of the IL6 signaling pathways. Finally, it negatively regulates prolactin-mediated signaling pathway through dephosphorylation of STAT5A and STAT5B. May also bind DNA. {ECO:0000269|PubMed:10734133, ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:12138178, ECO:0000269|PubMed:12612081, ECO:0000269|PubMed:14966296, ECO:0000269|PubMed:15592458, ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:22080863, ECO:0000269|PubMed:9488479}. | 16.04 | ||||
| dfaPTN22 | Tyrosine-protein phosphatase non-receptor type 22 | 2 | 210 | 91.32 | 92.97 | ND | 0.59 | 0.69 | 0.3 | Mammalian | Expressed in bone marrow, B and T-cells, PBMCs, natural killer cells, monocytes, dendritic cells and neutrophils (PubMed:15208781). Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells. {ECO:0000269|PubMed:15208781}. | Phosphatase | Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:15273934}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15004560}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269|PubMed:15208781}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Vitiligo (VTLG) [MIM:193200]: A pigmentary disorder of the skin and mucous membranes. It is characterized by circumscribed depigmented macules and patches, commonly on extensor aspects of extremities, on the face or neck and in skin folds. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. It is a multifactorial disorder with a complex etiology probably including autoimmune mechanisms, and is associated with an elevated risk of other autoimmune diseases. {ECO:0000269|PubMed:16015369}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr- 493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro- inflammatory cytokine secretion and autophagy (PubMed:23991106). {ECO:0000250|UniProtKB:P29352, ECO:0000269|PubMed:16461343, ECO:0000269|PubMed:18056643, ECO:0000269|PubMed:19167335, ECO:0000269|PubMed:21719704, ECO:0000269|PubMed:23871208, ECO:0000269|PubMed:23991106}. | 15.11 | |||
| dfaPTN6 | Tyrosine-protein phosphatase non-receptor type 6 | 2 | 104 | 99.84 | 98.89 | ND | 0.43 | 0.66 | 0.4 | Mammalian | Isoform 1 is expressed in hematopoietic cells. Isoform 2 is expressed in non-hematopoietic cells. | Phosphatase | Solid tumors | Modulates signaling by tyrosine phosphorylated cell surface receptors such as KIT and the EGF receptor/EGFR. The SH2 regions may interact with other cellular components to modulate its own phosphatase activity against interacting substrates. Together with MTUS1, induces UBE2V2 expression upon angiotensin II stimulation. Plays a key role in hematopoiesis. {ECO:0000269|PubMed:11266449}. | 16.04 | |||
| dfaPTN7 | Tyrosine-protein phosphatase non-receptor type 7 | 6 | 278 | 88.49 | 81.69 | ND | 0.21 | 0.49 | 0.6 | Mammalian | Expressed exclusively in thymus and spleen. {ECO:0000269|PubMed:1510684, ECO:0000269|PubMed:1530918}. | Phosphatase | Protein phosphatase that acts preferentially on tyrosine-phosphorylated MAPK1. Plays a role in the regulation of T and B-lymphocyte development and signal transduction. {ECO:0000269|PubMed:10206983, ECO:0000269|PubMed:10559944, ECO:0000269|PubMed:10702794, ECO:0000269|PubMed:1510684, ECO:0000269|PubMed:1530918, ECO:0000269|PubMed:9624114}. | 16.04 | ||||
| dfaPTPRB | Receptor-type tyrosine-protein phosphatase beta | 1 | 52 | 93.16 | 98.04 | ND | 0.74 | 0.91 | 0.5 | Mammalian | Phosphatase | Plays an important role in blood vessel remodeling and angiogenesis. Not necessary for the initial formation of blood vessels, but is essential for their maintenance and remodeling. Can induce dephosphorylation of TEK/TIE2, CDH5/VE-cadherin and KDR/VEGFR-2. Regulates angiopoietin-TIE2 signaling in endothelial cells. Acts as a negative regulator of TIE2, and controls TIE2 driven endothelial cell proliferation, which in turn affects blood vessel remodeling during embryonic development and determines blood vessel size during perinatal growth. Essential for the maintenance of endothelial cell contact integrity and for the adhesive function of VE-cadherin in endothelial cells and this requires the presence of plakoglobin (By similarity). {ECO:0000250, ECO:0000269|PubMed:19116766, ECO:0000269|PubMed:19136612}. | 15.11 | |||||
| dfaPTPRC | Receptor-type tyrosine-protein phosphatase C | 1 | 169 | 99.30 | 96.91 | ND | 0.65 | 0.79 | 0.5 | Mammalian | Enzyme | Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-positive/NK-cell-positive (T(-)B(+)NK(+) SCID) [MIM:608971]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:11145714}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple sclerosis (MS) [MIM:126200]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. {ECO:0000269|PubMed:11101853}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. | Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor. Acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. Upon T-cell activation, recruits and dephosphorylates SKAP1 and FYN. Dephosphorylates LYN, and thereby modulates LYN activity (By similarity). {ECO:0000250, ECO:0000269|PubMed:11909961, ECO:0000269|PubMed:2845400}. | 16.04 | ||||
| dfaPTPRF | Receptor-type tyrosine-protein phosphatase F | 5 | 93 | 99.83 | 99.68 | ND | 0.88 | 0.88 | 0.2 | Mammalian | Phosphatase | Aplasia or hypoplasia of the breasts and/or nipples 2 (BNAH2) [MIM:616001]: A group of congenital deformities encompassing total absence of breasts and nipple (amastia), absence of the nipple (athelia), and absence of the mammary gland (amazia). {ECO:0000269|PubMed:24781087}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Possible cell adhesion receptor. It possesses an intrinsic protein tyrosine phosphatase activity (PTPase) and dephosphorylates EPHA2 regulating its activity. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. | 16.04 | ||||
| dfaPUR2 | Trifunctional purine biosynthetic protein adenosine-3 | 2 | 99 | 99.65 | 99.71 | ND | 0.59 | 0.64 | 0.8 | Mammalian | Ligase | Solid tumor | Trifunctional purine biosynthetic protein adenosine-3 inhibitor: Pemetrexed | 15.11 | ||||
| dfaPUR9 | Bifunctional purine biosynthesis protein PURH | 6 | 53 | 94.87 | 95.75 | ND | 0.08 | 0.66 | 0.7 | Mammalian | Enzyme | AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:608688]: A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA- riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness. {ECO:0000269|PubMed:15114530}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis. {ECO:0000269|PubMed:14966129}. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571). {ECO:0000269|PubMed:25687571}. | Bifunctional purine biosynthesis protein PURH cofactor: Tetrahydrofolic acid Bifunctional purine biosynthesis protein PURH inhibitor: Methotrexate, Pemetrexed | 15.11 | |||
| dfaPYGL | Glycogen phosphorylase, liver form | 5 | 428 | 98.62 | 99.41 | ND | 0.50 | 0.50 | 0.6 | Mammalian | Enzyme | Glycogen storage disease 6 (GSD6) [MIM:232700]: A metabolic disorder characterized by mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent hepatomegaly. Heart and skeletal muscle are not affected. {ECO:0000269|PubMed:9529348}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. | Glycogen phosphorylase, liver form activator: Adenosine monophosphate | 15.11 | |||
| dfaPYGM | Glycogen phosphorylase, muscle form | 7 | 380 | 92.74 | 92.21 | ND | 0.68 | 0.74 | 0.5 | Mammalian | Enzyme | Glycogen storage disease 5 (GSD5) [MIM:232600]: A metabolic disorder resulting in myopathy characterized by exercise intolerance, cramps, muscle weakness and recurrent myoglobinuria. {ECO:0000269|PubMed:10382911, ECO:0000269|PubMed:10382912, ECO:0000269|PubMed:10417800, ECO:0000269|PubMed:10590419, ECO:0000269|PubMed:10681080, ECO:0000269|PubMed:10714589, ECO:0000269|PubMed:10899452, ECO:0000269|PubMed:11706962, ECO:0000269|PubMed:12031624, ECO:0000269|PubMed:7603523, ECO:0000269|PubMed:8316268, ECO:0000269|PubMed:8535454, ECO:0000269|PubMed:9506549}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. | 15.11 | ||||
| dfaPYRD | Dihydroorotate dehydrogenase (quinone), mitochondrial | 2 | 526 | 98.85 | 97.23 | ND | 0.83 | 0.76 | 0.6 | Mammalian | Oxidoreductase | Postaxial acrofacial dysostosis (POADS) [MIM:263750]: POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases. {ECO:0000269|PubMed:19915526}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | Dihydroorotate dehydrogenase (quinone), mitochondrial inhibitor: Atovaquone, Leflunomide, Teriflunomide | 15.11 | |||
| dfaQPCT | Glutaminyl-peptide cyclotransferase | 3 | 140 | 96.40 | 92.91 | ND | 0.74 | 0.65 | 0.3 | Mammalian | Enzyme | Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides. {ECO:0000269|PubMed:15063747, ECO:0000269|PubMed:18486145, ECO:0000269|PubMed:21288892}. | 15.11 | |||||
| dfaRAB9A | Ras-related protein Rab-9A | 2 | 7285 | 88.80 | 80.32 | ND | 0.12 | 0.10 | 0.3 | Mammalian | Viral infection, unspecified | Involved in the transport of proteins between the endosomes and the trans Golgi network. | 16.04 | |||||
| dfaRAD52 | DNA repair protein RAD52 homolog | 2 | 493 | 87.51 | 85.89 | ND | 0.36 | 0.39 | 0.3 | Mammalian | Involved in double-stranded break repair. Plays a central role in genetic recombination and DNA repair by promoting the annealing of complementary single-stranded DNA and by stimulation of the RAD51 recombinase. {ECO:0000269|PubMed:12379650, ECO:0000269|PubMed:8702565}. | 16.04 | ||||||
| dfaRAD54 | DNA repair and recombination protein RAD54-like | 5 | 316 | 97.59 | 87.62 | ND | 0.52 | 0.58 | 0.2 | Mammalian | Enzyme | Involved in DNA repair and mitotic recombination. Functions in the recombinational DNA repair (RAD52) pathway. Dissociates RAD51 from nucleoprotein filaments formed on dsDNA. Could be involved in the turnover of RAD51 protein-dsDNA filaments (By similarity). May play also an essential role in telomere length maintenance and telomere capping in mammalian cells. {ECO:0000250, ECO:0000269|PubMed:11459989, ECO:0000269|PubMed:12205100, ECO:0000269|PubMed:9774452}. | 16.04 | |||||
| dfaRAF1 | RAF proto-oncogene serine/threonine-protein kinase | 6 | 447 | 96.08 | 98.12 | ND | 0.69 | 0.68 | 0.6 | Mammalian | In skeletal muscle, isoform 1 is more abundant than isoform 2. {ECO:0000269|PubMed:1886707}. | Kinase | Noonan syndrome 5 (NS5) [MIM:611553]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:17603482, ECO:0000269|PubMed:17603483, ECO:0000269|PubMed:20683980}. Note=The disease is caused by mutations affecting the gene represented in this entry. LEOPARD syndrome 2 (LPRD2) [MIM:611554]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:17603483}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cardiomyopathy, dilated 1NN (CMD1NN) [MIM:615916]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:24777450}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2- antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation. {ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:16924233, ECO:0000269|PubMed:9360956}. | RAF proto-oncogene serine/threonine-protein kinase inhibitor: Dabrafenib, Regorafenib, Sorafenib | 16.04 | ||
| dfaRARA | Retinoic acid receptor alpha | 1 | 240 | 99.11 | 99.03 | ND | 0.54 | 0.60 | 0.6 | Mammalian | Nuclear receptor | Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled- coil domain functions in blocking RA-mediated transactivation and cell differentiation. {ECO:0000269|PubMed:12691149, ECO:0000269|PubMed:8302850, ECO:0000269|PubMed:8562957}. | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Regulates expression of target genes in a ligand- dependent manner by recruiting chromatin complexes containing KMT2E/MLL5. Mediates retinoic acid-induced granulopoiesis. {ECO:0000250, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:19377461, ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:20215566}. | Retinoic acid receptor alpha agonist: Acitretin, Adapalene, Alitretinoin, Tamibarotene, Tazarotene Retinoic acid receptor alpha other/unknown: Isotretinoin | 15.11 | |||
| dfaRARB | Retinoic acid receptor beta | 2 | 244 | 99.59 | 98.21 | ND | 0.44 | 0.61 | 0.7 | Mammalian | Nuclear receptor | Microphthalmia, syndromic, 12 (MCOPS12) [MIM:615524]: A form of microphthalmia, a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS12 patients manifest variable features, including diaphragmatic hernia, pulmonary hypoplasia, and cardiac abnormalities. {ECO:0000269|PubMed:24075189}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. {ECO:0000269|PubMed:12554770}. | Retinoic acid receptor beta agonist: Acitretin, Adapalene, Alitretinoin, Tamibarotene, Tazarotene | 15.11 | |||
| dfaRARG | Retinoic acid receptor gamma | 1 | 236 | 98.66 | 97.97 | ND | 0.73 | 0.69 | 0.5 | Mammalian | Nuclear receptor | Acne
Emphysema Photoaging Psoriasis | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). {ECO:0000250}. | Retinoic acid receptor gamma agonist: Acitretin, Adapalene, Alitretinoin, Tazarotene, Tretinoin | 15.11 | |||
| dfaRENI | Renin | 4 | 739 | 95.48 | 97.10 | ND | 0.72 | 0.74 | 0.7 | Mammalian | Protease | Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial juvenile hyperuricemic nephropathy 2 (HNFJ2) [MIM:613092]: A renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia. {ECO:0000269|PubMed:19664745}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney. | Renin inhibitor: Aliskiren, Remikiren | 15.11 | |||
| dfaRET | Proto-oncogene tyrosine-protein kinase receptor Ret | 5 | 571 | 89.94 | 92.01 | ND | 0.48 | 0.55 | 0.7 | Mammalian | Kinase | Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry. Hirschsprung disease 1 (HSCR1) [MIM:142623]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. {ECO:0000269|PubMed:10090908, ECO:0000269|PubMed:10484767, ECO:0000269|PubMed:10618407, ECO:0000269|PubMed:22174939, ECO:0000269|PubMed:7581377, ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:7704557, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8114938, ECO:0000269|PubMed:8114939, ECO:0000269|PubMed:9043870, ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9094028, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9384613, ECO:0000269|Ref.56}. Note=The disease is caused by mutations affecting the gene represented in this entry. Medullary thyroid carcinoma (MTC) [MIM:155240]: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. {ECO:0000269|PubMed:10323403, ECO:0000269|PubMed:10826520, ECO:0000269|PubMed:11692159, ECO:0000269|PubMed:7784092, ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:7849720, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8557249, ECO:0000269|PubMed:8625130, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9223675, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9398735, ECO:0000269|PubMed:9452077, ECO:0000269|PubMed:9506724, ECO:0000269|PubMed:9621513, ECO:0000269|PubMed:9677065}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple neoplasia 2B (MEN2B) [MIM:162300]: Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. {ECO:0000269|PubMed:7906417, ECO:0000269|PubMed:7906866, ECO:0000269|PubMed:7911697, ECO:0000269|PubMed:8595427, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9294615, ECO:0000269|PubMed:9360560}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pheochromocytoma (PCC) [MIM:171300]: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:12000816}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. {ECO:0000269|PubMed:10522989, ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8099202, ECO:0000269|PubMed:8626834, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9097963, ECO:0000269|PubMed:9384613, ECO:0000269|PubMed:9452064}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene (PubMed:2406025). Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene (PubMed:2734021). Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916). Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene (PubMed:3037315). {ECO:0000269|PubMed:10439047, ECO:0000269|PubMed:10980597, ECO:0000269|PubMed:12787916, ECO:0000269|PubMed:2406025, ECO:0000269|PubMed:2734021, ECO:0000269|PubMed:3037315}. Note=Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis. Congenital central hypoventilation syndrome (CCHS) [MIM:209880]: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. {ECO:0000269|PubMed:12086152, ECO:0000269|PubMed:14566559, ECO:0000269|PubMed:9497256}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut- associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. {ECO:0000269|PubMed:20064382, ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698}. | Proto-oncogene tyrosine-protein kinase receptor Ret antagonist: Cabozantinib Proto-oncogene tyrosine-protein kinase receptor Ret inhibitor: Ponatinib, Regorafenib, Sorafenib | 15.11 | |||
| dfaRIOK1 | Serine/threonine-protein kinase RIO1 | 2 | 64 | 87.81 | 91.97 | ND | 0.03 | 0.90 | 0.5 | Mammalian | Kinase | 15.11 | ||||||
| dfaRIOK2 | Serine/threonine-protein kinase RIO2 | 4 | 60 | 83.73 | 91.03 | ND | 0.34 | 0.72 | 0.8 | Mammalian | Kinase | 16.04 | ||||||
| dfaRIOK3 | Serine/threonine-protein kinase RIO3 | 4 | 64 | 99.65 | 99.90 | ND | 0.69 | 0.96 | 0.4 | Mammalian | Widely expressed. {ECO:0000269|PubMed:9602165}. | Kinase | 16.04 | |||||
| dfaRIPK1 | Receptor-interacting serine/threonine-protein kinase 1 | 4 | 93 | 94.31 | 98.18 | ND | 0.94 | 0.81 | 0.3 | Mammalian | Kinase | Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex. {ECO:0000269|PubMed:11101870, ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:19524513}. | 15.11 | |||||
| dfaRIPK2 | Receptor-interacting serine/threonine-protein kinase 2 | 6 | 75 | 92.55 | 94.83 | ND | 0.87 | 0.87 | 0.3 | Mammalian | Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node. | Kinase | Not Available | Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. {ECO:0000269|PubMed:14638696, ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:18079694, ECO:0000269|PubMed:21123652, ECO:0000269|PubMed:21887730}. | 15.11 | |||
| dfaRIPK4 | Receptor-interacting serine/threonine-protein kinase 4 | 2 | 60 | 81.37 | 86.57 | ND | 0.60 | 0.97 | 0.3 | Mammalian | Kinase | Popliteal pterygium syndrome, lethal type (PPS-L) [MIM:263650]: An autosomal recessive disorder characterized by multiple popliteal pterygia leading to severe arthrogryposis, ankyloblepharon filiforme adnatum, filiform bands between the jaws, synostosis of the carpal/tarsal and phalangeal bones in the hands and feet, digital hypoplasia/aplasia, complete soft-tissue syndactyly, lack of nails, lack of scalp hair, eyebrows and eyelashes, blepharophimosis, cleft lip and/or palate, and hypoplastic external genitalia. Early lethality is common, although survival into childhood and beyond has been reported. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in stratified epithelial development. It is a direct transcriptional target of TP63. Plays a role in NF-kappa-B activation. {ECO:0000269|PubMed:12446564, ECO:0000269|PubMed:22197488}. | 16.04 | ||||
| dfaRK | Rhodopsin kinase | 7 | 60 | 81.49 | 85.95 | ND | 0.25 | 0.87 | 0.6 | Mammalian | Rod outer segments of retina photoreceptor cells (at protein level) (PubMed:1656454, PubMed:1730692, PubMed:1527025). Retina (PubMed:1656454). {ECO:0000269|PubMed:1527025, ECO:0000269|PubMed:1656454, ECO:0000269|PubMed:1730692}. | Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade. This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination. {ECO:0000303|PubMed:1656454, ECO:0000303|PubMed:1730692}. | 15.11 | |||||
| dfaROCK1 | Rho-associated protein kinase 1 | 4 | 873 | 87.49 | 87.23 | ND | 0.58 | 0.67 | 0.7 | Mammalian | Detected in blood platelets. {ECO:0000269|PubMed:8617235}. | Kinase | Asthma
Atherosclerotic cardiovascular disease Cardiac allograft vasculopathy Glaucoma Hepatic fibrosis Hypertensive vascular disease Intimal hyperplasia Liver fibrogenesis Primary pulmonary hypertension Pulmonary hypertension Restenosis Vascular disease Ventricular hypertrophy | Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A. Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress. Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Required for centrosome positioning and centrosome-dependent exit from mitosis. Plays a role in terminal erythroid differentiation. May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles. Promotes keratinocyte terminal differentiation. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization. {ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:10652353, ECO:0000269|PubMed:11018042, ECO:0000269|PubMed:11283607, ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:18573880, ECO:0000269|PubMed:18694941, ECO:0000269|PubMed:19036714, ECO:0000269|PubMed:19131646, ECO:0000269|PubMed:19181962, ECO:0000269|PubMed:19997641, ECO:0000269|PubMed:21072057, ECO:0000269|PubMed:8617235, ECO:0000269|PubMed:9722579}. | 15.11 | |||
| dfaROCK2 | Rho-associated protein kinase 2 | 3 | 989 | 92.47 | 92.39 | ND | 0.64 | 0.58 | 0.6 | Mammalian | Kinase | Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation. {ECO:0000269|PubMed:10579722, ECO:0000269|PubMed:15699075, ECO:0000269|PubMed:16574662, ECO:0000269|PubMed:17015463, ECO:0000269|PubMed:19131646, ECO:0000269|PubMed:19997641, ECO:0000269|PubMed:21084279, ECO:0000269|PubMed:21147781}. | 15.11 | |||||
| dfaRON | Macrophage-stimulating protein receptor | 7 | 235 | 85.53 | 87.91 | ND | 0.36 | 0.53 | 0.7 | Mammalian | Expressed in colon, skin, lung and bone marrow. {ECO:0000269|PubMed:8062829}. | Kinase | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to MST1 ligand. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces autophosphorylation of RON on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1 or the adapter GAB1. Recruitment of these downstream effectors by RON leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. RON signaling activates the wound healing response by promoting epithelial cell migration, proliferation as well as survival at the wound site. Plays also a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Alternatively, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligand. {ECO:0000269|PubMed:18836480, ECO:0000269|PubMed:7939629, ECO:0000269|PubMed:9764835}. | 15.11 | ||||
| dfaRORA | Nuclear receptor ROR-alpha | 2 | 66 | 96.69 | 86.92 | ND | 0.44 | 0.62 | 0.2 | Mammalian | Widely expressed in a number of tissues. Expressed in both regulatory T-cells (Treg) and effector T-cells (Teff). {ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:7916608}. | Nuclear receptor | Cholesterol-related diseases
Chronic inflammatory diseases | Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium- mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti- inflammatory role by inducing CHUK expression and inhibiting NF- kappa-B signaling. {ECO:0000269|PubMed:10478845, ECO:0000269|PubMed:11053433, ECO:0000269|PubMed:11252722, ECO:0000269|PubMed:11554739, ECO:0000269|PubMed:12467577, ECO:0000269|PubMed:14570920, ECO:0000269|PubMed:15781255, ECO:0000269|PubMed:15790933, ECO:0000269|PubMed:16462772, ECO:0000269|PubMed:17512500, ECO:0000269|PubMed:18005000, ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19965867, ECO:0000269|PubMed:21499262, ECO:0000269|PubMed:7926749, ECO:0000269|PubMed:9328355, ECO:0000269|PubMed:9862959}. | 15.11 | |||
| dfaROS1 | Proto-oncogene tyrosine-protein kinase ROS | 3 | 188 | 86.23 | 92.84 | ND | 0.64 | 0.73 | 0.6 | Mammalian | Expressed in brain. Expression is increased in primary gliomas. {ECO:0000269|PubMed:8143271}. | Kinase | Note=A chromosomal aberration involving ROS1 is found in a glioblastoma multiforme sample. An intra-chromosomal deletion del(6)(q21q21) is responsible for the formation of GOPC-ROS1 chimeric protein which is localized to the Golgi and has a constitutive receptor tyrosine kinase activity. A SLC34A2-ROS1 chimeric protein produced in non-small cell lung cancer cells also retains a constitutive kinase activity. A third type of chimeric protein CD74-ROS1 was also identified in those cells. {ECO:0000269|PubMed:12661006}. | Orphan receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2. {ECO:0000269|PubMed:11094073, ECO:0000269|PubMed:16885344}. | 15.11 | |||
| dfaRXRA | Retinoic acid receptor RXR-alpha | 1 | 463 | 95.73 | 93.06 | ND | 0.76 | 0.66 | 0.5 | Mammalian | Highly expressed in liver, also found in lung, kidney and heart. | Arthralgia | Nuclear receptor | Prostate cancer | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes. {ECO:0000269|PubMed:10195690, ECO:0000269|PubMed:11162439, ECO:0000269|PubMed:11915042, ECO:0000269|PubMed:20215566}. | Retinoic acid receptor RXR-alpha agonist: Acitretin, Alitretinoin, Bexarotene Retinoic acid receptor RXR-alpha other: Etodolac Retinoic acid receptor RXR-alpha other/unknown: Adapalene | 15.11 | |
| dfaRXRB | Retinoic acid receptor RXR-beta | 1 | 165 | 99.36 | 99.79 | ND | 0.61 | 0.52 | 0.5 | Mammalian | Expressed in a variety of tumor cell lines. {ECO:0000269|PubMed:8381386}. | Nuclear receptor | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (By similarity). Specifically binds 9-cis retinoic acid (9C-RA). {ECO:0000250}. | Retinoic acid receptor RXR-beta agonist: Acitretin, Adapalene, Alitretinoin, Bexarotene, Tazarotene, Tretinoin | 15.11 | |||
| dfaRXRG | Retinoic acid receptor RXR-gamma | 1 | 159 | 97.02 | 98.56 | ND | 0.42 | 0.63 | 0.6 | Mammalian | Nuclear receptor | Cancer, unspecific | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid (By similarity). {ECO:0000250}. | Retinoic acid receptor RXR-gamma agonist: Acitretin, Adapalene, Alitretinoin, Bexarotene, Tretinoin | 16.04 | |||
| dfaS15A2 | Solute carrier family 15 member 2 | 1 | 100 | 98.16 | 90.22 | ND | 0.34 | 0.62 | 0.3 | Mammalian | Electrochemical transporter | Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. | Solute carrier family 15 member 2 : Ampicillin, Benzylpenicillin, Cefotaxime, Oxacillin, Tranexamic Acid, Valganciclovir Solute carrier family 15 member 2 inhibitor: Aminolevulinic acid, Amoxicillin, Ampicillin, Azidocillin, Benzylpenicillin, Cefaclor, Cefadroxil, Cefalotin, Cefdinir, Cefepime, Cefixime, Cefmetazole, Cefotaxime, Cefradine, Ceftazidime, Ceftibuten, Ceftriaxone, Cefuroxime, Cephalexin, Chlorpropamide, Cloxacillin, Cyclacillin, Dicloxacillin, Glyburide, Nateglinide, Oxacillin, Tolbutamide, Valaciclovir Solute carrier family 15 member 2 substrate: Benazepril, Cilazapril, Fosinopril, Moexipril, Perindopril, Quinapril, Ramipril, Spirapril, Trandolapril | 16.04 | ||||
| dfaS1PR1 | Sphingosine 1-phosphate receptor 1 | 2 | 1052 | 95.31 | 93.92 | ND | 0.55 | 0.59 | 0.8 | Mammalian | Endothelial cells, and to a lesser extent, in vascular smooth muscle cells, fibroblasts, melanocytes, and cells of epithelioid origin. | Family A G protein-coupled receptor | Autoimmune diseases | G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization and bone homeostasis (By similarity). Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3- phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury. {ECO:0000250, ECO:0000269|PubMed:10982820, ECO:0000269|PubMed:11230698, ECO:0000269|PubMed:11583630, ECO:0000269|PubMed:11604399, ECO:0000269|PubMed:19286607, ECO:0000269|PubMed:22344443, ECO:0000269|PubMed:8626678, ECO:0000269|PubMed:9488656}. | 15.11 | |||
| dfaS1PR2 | Sphingosine 1-phosphate receptor 2 | 6 | 234 | 81.79 | 82.41 | ND | 0.81 | 0.82 | 0.5 | Mammalian | Family A G protein-coupled receptor | Receptor for the lysosphingolipid sphingosine 1- phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis. | 16.04 | |||||
| dfaS1PR3 | Sphingosine 1-phosphate receptor 3 | 5 | 808 | 93.45 | 97.02 | ND | 0.64 | 0.63 | 0.5 | Mammalian | Expressed in all tissues, but most abundantly in heart, placenta, kidney, and liver. | Family A G protein-coupled receptor | Receptor for the lysosphingolipid sphingosine 1- phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis. {ECO:0000269|PubMed:10617617}. | 16.04 | ||||
| dfaS1PR4 | Sphingosine 1-phosphate receptor 4 | 5 | 376 | 88.60 | 88.91 | ND | 0.67 | 0.73 | 0.5 | Mammalian | Specifically expressed in fetal and adult lymphoid and hematopoietic tissue as well as in lung. Considerable level of expression in adult and fetal spleen as well as adult peripheral leukocytes and lung. Lower expression in adult thymus, lymph node, bone marrow, and appendix as well as in fetal liver, thymus, and lung. | Family A G protein-coupled receptor | Receptor for the lysosphingolipid sphingosine 1- phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. May be involved in cell migration processes that are specific for lymphocytes. {ECO:0000269|PubMed:10679247, ECO:0000269|PubMed:10753843}. | 16.04 | ||||
| dfaS1PR5 | Sphingosine 1-phosphate receptor 5 | 3 | 198 | 96.60 | 93.27 | ND | 0.60 | 0.73 | 0.6 | Mammalian | Widely expressed in the brain, most prominently in the corpus callosum, which is predominantly white matter. Detected in spleen, peripheral blood leukocytes, placenta, lung, aorta and fetal spleen. Low-level signal detected in many tissue extracts. Overexpressed in leukemic large granular lymphocytes. Isoform 1 is predominantly expressed in peripheral tissues. Isoform 2 is expressed in brain, spleen and peripheral blood leukocytes. {ECO:0000269|PubMed:11705398, ECO:0000269|PubMed:12234605, ECO:0000269|PubMed:12427546}. | Family A G protein-coupled receptor | Receptor for the lysosphingolipid sphingosine 1- phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. Is coupled to both the G(i/0)alpha and G(12) subclass of heteromeric G-proteins (By similarity). May play a regulatory role in the transformation of radial glial cells into astrocytes and may affect proliferative activity of these cells. {ECO:0000250}. | Sphingosine 1-phosphate receptor 5 modulator: Fingolimod | 16.04 | |||
| dfaS22A8 | Solute carrier family 22 member 8 | 1 | 90 | 97.59 | 98.95 | ND | 0.00 | 0.40 | ND | Mammalian | Expressed in kidney. {ECO:0000269|PubMed:11912245}. | Electrochemical transporter | Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone- 3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA). {ECO:0000269|PubMed:14586168, ECO:0000269|PubMed:15644426, ECO:0000269|PubMed:15846473, ECO:0000269|PubMed:16455804}. | Solute carrier family 22 member 8 : Benzylpenicillin, Cefotaxime, Ceftriaxone, Dinoprost Tromethamine, Estradiol, Zidovudine Solute carrier family 22 member 8 inducer: Methyltestosterone, Testosterone Solute carrier family 22 member 8 inhibitor: Aspartame, Baclofen, Benzoic Acid, Bumetanide, Cefadroxil, Cefalotin, Cefamandole, Cefazolin, Cefoperazone, Cefotaxime, Ceftriaxone, Cephalexin, Cholic Acid, Cilastatin, Dabrafenib, Diclofenac, Digoxin, Doxycycline, Enalapril, Furosemide, Ganciclovir, Guanidine, Ibuprofen, Indomethacin, Ketoprofen, Liothyronine, Liotrix, Melatonin, Minocycline, Novobiocin, Ouabain, Oxytetracycline, Phenylbutazone, Piroxicam, Probenecid, Quinidine, Salicylic acid, Tenoxicam, Tetracycline Solute carrier family 22 member 8 substrate: Aciclovir, Adefovir Dipivoxil, Allopurinol, Aminohippurate, Avibactam, Benzylpenicillin, Cefacetrile, Cimetidine, Conjugated Estrogens, Dinoprostone, Eluxadoline, Famotidine, L-Carnitine, Mercaptopurine, Methotrexate, Oseltamivir, Pravastatin, Ranitidine, Saxagliptin, Succinic acid, Tenofovir, Valaciclovir, Valproic Acid | 16.04 | |||
| dfaS27A1 | Long-chain fatty acid transport protein 1 | 1 | 59 | 99.86 | 90.31 | ND | 0.02 | 0.20 | 0.3 | Mammalian | Highest levels of expression are detected in muscle and adipose tissue small, intermediate levels in small intestine, and barely detectable in liver. {ECO:0000269|PubMed:10873384}. | Electrochemical transporter | Involved in translocation of long-chain fatty acids (LFCA) across the plasma membrane. The LFCA import appears to be hormone-regulated in a tissue-specific manner. In adipocytes, but not myocytes, insulin induces a rapid translocation of FATP1 from intracellular compartments to the plasma membrane, paralleled by increased LFCA uptake. May act directly as a bona fide transporter, or alternatively, in a cytoplasmic or membrane- associated multimeric protein complex to trap and draw fatty acids towards accumulation. Plays a pivotal role in regulating available LFCA substrates from exogenous sources in tissues undergoing high levels of beta-oxidation or triglyceride synthesis. May be involved in regulation of cholesterol metabolism. Has acyl-CoA ligase activity for long-chain and very-long-chain fatty acids (By similarity). {ECO:0000250, ECO:0000269|PubMed:12235169}. | 16.04 | ||||
| dfaS29A1 | Equilibrative nucleoside transporter 1 | 3 | 204 | 98.06 | 99.54 | ND | 0.70 | 0.67 | 0.6 | Nature11159 | Mammalian | Detected in erythrocytes (at protein level). Expressed in heart, brain, mammary gland, erythrocytes and placenta, and also in fetal liver and spleen. {ECO:0000269|PubMed:12527552, ECO:0000269|PubMed:23219802}. | Electrochemical transporter | Malaria | Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) and is sodium-independent. It has a higher affinity for adenosine. Inhibited by dipyridamole and dilazep (anticancer chemotherapeutics drugs). | Equilibrative nucleoside transporter 1 : Didanosine, Ethanol, Zalcitabine Equilibrative nucleoside transporter 1 inducer: Pemetrexed Equilibrative nucleoside transporter 1 substrate: Cytarabine, Fludarabine, Fluorouracil, Gemcitabine, Mercaptopurine, Ribavirin | 16.04 | |
| dfaS5A1 | 3-oxo-5-alpha-steroid 4-dehydrogenase 1 | 3 | 364 | 94.88 | 94.55 | ND | 0.79 | 0.70 | 0.5 | Mammalian | Liver and prostate (at a low level). | Oxidoreductase | Acne
Alopecia, unspecified Benign prostate hyperplasia Hirsutism Prostate cancer | Converts testosterone into 5-alpha-dihydrotestosterone and progesterone or corticosterone into their corresponding 5- alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology. | 3-oxo-5-alpha-steroid 4-dehydrogenase 1 antagonist: Spironolactone 3-oxo-5-alpha-steroid 4-dehydrogenase 1 inhibitor: Dutasteride, Finasteride, Levonorgestrel | 16.04 | ||
| dfaS5A2 | 3-oxo-5-alpha-steroid 4-dehydrogenase 2 | 3 | 393 | 95.03 | 92.64 | ND | 0.84 | 0.81 | 0.6 | Mammalian | Expressed in high levels in the prostate and many other androgen-sensitive tissues. | Gynaecomastia | Oxidoreductase | Pseudovaginal perineoscrotal hypospadias (PPSH) [MIM:264600]: A form of male pseudohermaphroditism in which 46,XY males show ambiguous genitalia at birth, including perineal hypospadias and a blind perineal pouch, and develop masculinization at puberty. The name of the disorder stems from the finding of a blind-ending perineal opening resembling a vagina and a severely hypospadiac penis with the urethra opening onto the perineum. {ECO:0000269|PubMed:10718838, ECO:0000269|PubMed:10999800, ECO:0000269|PubMed:1522235, ECO:0000269|PubMed:15528927, ECO:0000269|PubMed:15770495, ECO:0000269|PubMed:16098368, ECO:0000269|PubMed:16181229, ECO:0000269|PubMed:7554313, ECO:0000269|PubMed:8626825, ECO:0000269|PubMed:8768837, ECO:0000269|PubMed:9208814, ECO:0000269|PubMed:9745434, ECO:0000269|PubMed:9843052}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts testosterone (T) into 5-alpha- dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology. | 3-oxo-5-alpha-steroid 4-dehydrogenase 2 inhibitor: Azelaic Acid, Dutasteride, Finasteride | 16.04 | |
| dfaS6A12 | Sodium- and chloride-dependent betaine transporter | 4 | 51 | 99.91 | 99.30 | ND | 0.10 | 0.22 | 1.9 | Mammalian | Liver, heart, skeletal muscle, placenta, and a widespread distribution in the brain. | Electrochemical transporter | Transports betaine and GABA. May have a role in regulation of GABAergic transmission in the brain through the reuptake of GABA into presynaptic terminals, as well as in osmotic regulation. | 16.04 | ||||
| dfaSAHH | Adenosylhomocysteinase | 1 | 126 | 99.83 | 98.98 | ND | 0.45 | 0.35 | 0.7 | Mammalian | Enzyme | Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:613752]: A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy. {ECO:0000269|PubMed:15024124, ECO:0000269|PubMed:16736098, ECO:0000269|PubMed:19177456, ECO:0000269|PubMed:20852937}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Adenosylhomocysteine is a competitive inhibitor of S- adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine. {ECO:0000269|PubMed:12590576}. | 15.11 | ||||
| dfaSBK1 | Serine/threonine-protein kinase SBK1 | 2 | 58 | 81.20 | 86.67 | ND | 0.28 | 0.98 | 0.6 | Mammalian | Kinase | May be involved in signal-transduction pathways related to the control of brain development. {ECO:0000250}. | 16.04 | |||||
| dfaSC5A1 | Sodium/glucose cotransporter 1 | 3 | 290 | 94.51 | 96.33 | ND | 0.72 | 0.68 | 0.5 | Mammalian | Expressed mainly in intestine and kidney. | Electrochemical transporter | Congenital glucose/galactose malabsorption (GGM) [MIM:606824]: Intestinal monosaccharide transporter deficiency. It is an autosomal recessive disorder manifesting itself within the first weeks of life. It is characterized by severe diarrhea and dehydration which are usually fatal unless glucose and galactose are eliminated from the diet. {ECO:0000269|PubMed:10036327, ECO:0000269|PubMed:11406349, ECO:0000269|PubMed:2008213, ECO:0000269|PubMed:8195156}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Actively transports glucose into cells by Na(+) cotransport with a Na(+) to glucose coupling ratio of 2:1. Efficient substrate transport in mammalian kidney is provided by the concerted action of a low affinity high capacity and a high affinity low capacity Na(+)/glucose cotransporter arranged in series along kidney proximal tubules. | Sodium/glucose cotransporter 1 inhibitor: Canagliflozin | 16.04 | ||
| dfaSC5A2 | Sodium/glucose cotransporter 2 | 2 | 668 | 98.15 | 98.16 | ND | 0.66 | 0.62 | 0.6 | Mammalian | Electrochemical transporter | Renal glucosuria (GLYS) [MIM:233100]: A disorder characterized by persistent isolated glucosuria, normal fasting serum glucose concentration, decreased renal tubular resorption of glucose from the urine, and absence of any other signs of tubular dysfunction. {ECO:0000269|PubMed:14614622}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Sodium-dependent glucose transporter. Has a Na(+) to glucose coupling ratio of 1:1. Efficient substrate transport in mammalian kidney is provided by the concerted action of a low affinity high capacity and a high affinity low capacity Na(+)/glucose cotransporter arranged in series along kidney proximal tubules. | Sodium/glucose cotransporter 2 antagonist: Dapagliflozin, Empagliflozin Sodium/glucose cotransporter 2 inhibitor: Canagliflozin Sodium/glucose cotransporter 2 inhibitor, competitive: | 16.04 | |||
| dfaSC6A1 | Sodium- and chloride-dependent GABA transporter 1 | 1 | 265 | 99.56 | 97.92 | ND | 0.78 | 0.77 | 0.5 | Mammalian | Electrochemical transporter | Myoclonic-atonic epilepsy (MAE) [MIM:616421]: A form of epilepsy characterized by myoclonic-atonic and absence seizures, appearing in early childhood. Patients have delayed development before the onset of seizures and show varying degrees of intellectual disability following seizure onset. {ECO:0000269|PubMed:25865495}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Terminates the action of GABA by its high affinity sodium-dependent reuptake into presynaptic terminals. | Sodium- and chloride-dependent GABA transporter 1 Other: Clobazam Sodium- and chloride-dependent GABA transporter 1 inhibitor: Tiagabine | 16.04 | |||
| dfaSC6A2 | Sodium-dependent noradrenaline transporter | 4 | 2279 | 92.28 | 90.78 | ND | 0.49 | 0.55 | 0.6 | Nature11159 | Mammalian | Anticholinergic syndrome Blood glucose abnormal Conduction disorder Cycloplegia Dry mouth Ejaculation disorder Erectile dysfunction Hyperhidrosis Hypomania Insomnia Mania Orthostatic hypotension Palpitations Psychotic disorder Schizophrenia Sexual dysfunction Sleep disorder Tremor Weight decreased | Electrochemical transporter | Orthostatic intolerance (OI) [MIM:604715]: Syndrome characterized by lightheadedness, fatigue, altered mentation and syncope. It is associated with postural tachycardia. Plasma norepinephrine concentration is abnormally high. {ECO:0000269|PubMed:10684912}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals. {ECO:0000269|PubMed:2008212}. | Sodium-dependent noradrenaline transporter : Atomoxetine, Dextromethorphan, Dopamine, Ketamine, Pethidine Sodium-dependent noradrenaline transporter binder: Loxapine, Mirtazapine Sodium-dependent noradrenaline transporter inducer: Debrisoquin, Guanethidine Sodium-dependent noradrenaline transporter inhibitor: Amitriptyline, Amoxapine, Bupropion, Chlorphenamine, Clomipramine, Cocaine, Desipramine, Desvenlafaxine, Dexmethylphenidate, Diethylpropion, Doxepin, Duloxetine, Ergotamine, Escitalopram, Ginkgo biloba, Imipramine, Levomilnacipran, Levonordefrin, Maprotiline, Mazindol, Methylphenidate, Mianserin, Milnacipran, Nefazodone, Nortriptyline, Orphenadrine, Paroxetine, Phenmetrazine, Phentermine, Protriptyline, Pseudoephedrine, Reboxetine, Sibutramine, Tapentadol, Tramadol, Trimipramine, Venlafaxine Sodium-dependent noradrenaline transporter inverse agonist: Ephedrine Sodium-dependent noradrenaline transporter negative modulator: Dextroamphetamine, Ephedra, Methamphetamine, Phendimetrazine Sodium-dependent noradrenaline transporter partial agonist: Guanadrel Sodium-dependent noradrenaline transporter stimulator: Amphetamine Sodium-dependent noradrenaline transporter substrate: Citalopram, Droxidopa, Iobenguane, Norepinephrine | 16.04 | |
| dfaSC6A3 | Sodium-dependent dopamine transporter | 5 | 4363 | 93.50 | 89.50 | ND | 0.63 | 0.00 | 0.6 | Nature11159 | Mammalian | Highly expressed in substantia nigra. {ECO:0000269|PubMed:7637582}. | Dry mouth Ejaculation disorder Hyperhidrosis Insomnia Mydriasis Nervousness Palpitations Restlessness Tachycardia Tremor | Electrochemical transporter | Parkinsonism-dystonia infantile (PKDYS) [MIM:613135]: A neurodegenerative disorder characterized by infantile onset of parkinsonism and dystonia. Other neurologic features include global developmental delay, bradykinesia and pyramidal tract signs. {ECO:0000269|PubMed:19478460}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals. {ECO:0000269|PubMed:1406597, ECO:0000269|PubMed:15505207, ECO:0000269|PubMed:8302271}. | Sodium-dependent dopamine transporter : Imipramine, Ioflupane I 123, Pethidine Sodium-dependent dopamine transporter antagonist: Armodafinil Sodium-dependent dopamine transporter binder: Amoxapine, Atomoxetine, Loxapine, Mianserin, Mirtazapine Sodium-dependent dopamine transporter inducer: Dopamine Sodium-dependent dopamine transporter inhibitor: Benzatropine, Benzphetamine, Bupropion, Chloroprocaine, Chlorphenamine, Cocaine, Dexmethylphenidate, Diethylpropion, Diphenylpyraline, Duloxetine, Escitalopram, Fencamfamine, Lisdexamfetamine, Mazindol, Methylphenidate, Modafinil, Nefazodone, Phenmetrazine, Phentermine, Procaine, Pseudoephedrine, Sertraline, Sibutramine, Trimipramine, Venlafaxine Sodium-dependent dopamine transporter negative modulator: Amphetamine, Dextroamphetamine, Ephedra, Methamphetamine Sodium-dependent dopamine transporter substrate: Citalopram | 16.04 |
| dfaSC6A4 | Sodium-dependent serotonin transporter | 3 | 5824 | 92.07 | 88.98 | ND | 0.53 | 0.55 | 0.7 | Nature11159 | Mammalian | Expressed in platelets (at protein level). {ECO:0000269|PubMed:17506858}. | Anticholinergic syndrome Blood glucose abnormal Conduction disorder Cycloplegia Dependence Dry mouth Erectile dysfunction Extrapyramidal disorder Galactorrhoea Hyperhidrosis Hypomania Insomnia Libido disorder Mania Nervousness Orthostatic hypotension Palpitations Psychotic disorder Schizophrenia Sexual dysfunction Sleep disorder Tachycardia Tremor Urinary retention Weight decreased | Electrochemical transporter | Schizophrenia | Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner. {ECO:0000269|PubMed:17506858, ECO:0000269|PubMed:18227069, ECO:0000269|PubMed:19270731}. | Sodium-dependent serotonin transporter : Atomoxetine, Dopamine, Vilazodone Sodium-dependent serotonin transporter Inhibitor: Vortioxetine Sodium-dependent serotonin transporter antagonist: Butriptyline Sodium-dependent serotonin transporter binder: Amphetamine, Loxapine, Mirtazapine Sodium-dependent serotonin transporter binding: Pethidine Sodium-dependent serotonin transporter inhibitor: Amitriptyline, Amoxapine, Chlorphenamine, Citalopram, Clomipramine, Cocaine, Desipramine, Desvenlafaxine, Dexfenfluramine, Dexmethylphenidate, Dextromethorphan, Doxepin, Duloxetine, Escitalopram, Fluoxetine, Fluvoxamine, Imipramine, Levomilnacipran, Mazindol, Methylphenidate, Mianserin, Milnacipran, Minaprine, Nefazodone, Nortriptyline, Paroxetine, Phentermine, Protriptyline, Pseudoephedrine, Sertraline, Sibutramine, Tapentadol, Tramadol, Trazodone, Trimipramine, Venlafaxine Sodium-dependent serotonin transporter negative modulator: Ephedra, Methamphetamine Sodium-dependent serotonin transporter other/unknown: Verapamil Sodium-dependent serotonin transporter substrate: Citalopram | 16.04 |
| dfaSC6A5 | Sodium- and chloride-dependent glycine transporter 2 | 6 | 405 | 97.34 | 95.72 | ND | 0.77 | 0.80 | 0.3 | Mammalian | Expressed in medulla, and to a lesser extent in spinal cord and cerebellum. | Electrochemical transporter | Hyperekplexia 3 (HKPX3) [MIM:614618]: A neurologic disorder characterized by neonatal hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life- threatening neonatal apnea episodes. Notably, in some cases, symptoms resolved in the first year of life. {ECO:0000269|PubMed:16751771}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals. May be responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses. {ECO:0000269|PubMed:10381548, ECO:0000269|PubMed:10606742, ECO:0000269|PubMed:9845349}. | 16.04 | |||
| dfaSC6A9 | Sodium- and chloride-dependent glycine transporter 1 | 7 | 669 | 94.01 | 95.38 | ND | 0.56 | 0.57 | 0.6 | Mammalian | Isoform GlyT-1A and isoform GlyT-1B can be found in brain, kidney, pancreas, lung, placenta and liver but isoform GlyT-1C is only found in brain. | Electrochemical transporter | Disorders associated with NMDAR hypofunction | Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals. May play a role in regulation of glycine levels in NMDA receptor-mediated neurotransmission. | 16.04 | |||
| dfaSCN2A | Sodium channel protein type 2 subunit alpha | 4 | 154 | 98.09 | 96.94 | ND | 0.50 | 0.64 | 0.4 | Mammalian | Voltage-gated ion channel | Seizures, benign familial infantile 3 (BFIS3) [MIM:607745]: An autosomal dominant disorder in which afebrile seizures occur in clusters during the first year of life, without neurologic sequelae. {ECO:0000269|PubMed:11371648, ECO:0000269|PubMed:12243921, ECO:0000269|PubMed:15048894, ECO:0000269|PubMed:20371507, ECO:0000269|PubMed:22612257}. Note=The disease is caused by mutations affecting the gene represented in this entry. Epileptic encephalopathy, early infantile, 11 (EIEE11) [MIM:613721]: An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269|PubMed:19783390, ECO:0000269|PubMed:19786696, ECO:0000269|PubMed:20956790, ECO:0000269|PubMed:23550958, ECO:0000269|PubMed:23935176}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. {ECO:0000269|PubMed:1325650}. | Sodium channel protein type 2 subunit alpha inhibitor: Lamotrigine, Propofol, Zonisamide | 16.04 | |||
| dfaSCN4A | Sodium channel protein type 4 subunit alpha | 2 | 78 | 99.41 | 96.63 | ND | 0.91 | 0.92 | 0.2 | Mammalian | Apnoea Cardiac arrest Central nervous system stimulation Coma Convulsion Corneal disorder Death Dysarthria Foetal damage Hypoaesthesia oral Impaired healing Keratitis Loss of consciousness Methaemoglobinaemia Muscle twitching Myocardial depression Nervousness Presyncope Respiratory failure Sensitisation Tinnitus Vision blurred Visual pathway disorder | Voltage-gated ion channel | Paramyotonia congenita of von Eulenburg (PMC) [MIM:168300]: An autosomal dominant channelopathy characterized by myotonia, increased by exposure to cold, intermittent flaccid paresis, not necessarily dependent on cold or myotonia, lability of serum potassium, non-progressive nature and lack of atrophy or hypertrophy of muscles. In some patients, myotonia is not increased by cold exposure (paramyotonia without cold paralysis). Patients may have a combination phenotype of PMC and HYPP. {ECO:0000269|PubMed:10369308, ECO:0000269|PubMed:10727489, ECO:0000269|PubMed:1310898, ECO:0000269|PubMed:1316765, ECO:0000269|PubMed:1338909, ECO:0000269|PubMed:15318338, ECO:0000269|PubMed:15790667, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:18166706, ECO:0000269|PubMed:19077043, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:8242056, ECO:0000269|PubMed:8308722, ECO:0000269|PubMed:8388676, ECO:0000269|PubMed:8580427}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodic paralysis hypokalemic 2 (HOKPP2) [MIM:613345]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:10599760, ECO:0000269|PubMed:10851391, ECO:0000269|PubMed:10944223, ECO:0000269|PubMed:11558801, ECO:0000269|PubMed:11591859, ECO:0000269|PubMed:16890191, ECO:0000269|PubMed:17898326, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:20522878, ECO:0000269|PubMed:21043388, ECO:0000269|PubMed:24549961}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodic paralysis hyperkalemic (HYPP) [MIM:170500]: An autosomal dominant channelopathy characterized by episodic flaccid generalized muscle weakness associated with high levels of serum potassium. Concurrence of myotonia is found in HYPP patients. {ECO:0000269|PubMed:1659668, ECO:0000269|PubMed:1659948, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:7695243}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodic paralysis normokalemic (NKPP) [MIM:170500]: A disorder closely related to hyperkalemic periodic paralysis, but marked by a lack of alterations in potassium levels during attacks of muscle weakness. {ECO:0000269|PubMed:15596759, ECO:0000269|PubMed:18046642, ECO:0000269|PubMed:20522878}. Note=The disease is caused by mutations affecting the gene represented in this entry. Myotonia SCN4A-related (MYOSCN4A) [MIM:608390]: A phenotypically highly variable myotonia aggravated by potassium loading, and sometimes by cold. Myotonia is characterized by sustained muscle tensing that prevents muscles from relaxing normally. It causes muscle stiffness that can interfere with movement. In some people the stiffness is very mild, while in other cases it may be severe enough to interfere with walking, running, and other activities of daily life. Myotonia SCN4A- related includes myotonia permanens and myotonia fluctuans. In myotonia permanens, the myotonia is generalized and there is a hypertrophy of the muscle, particularly in the neck and the shoulder. Attacks of severe muscle stiffness of the thoracic muscles may be life threatening due to impaired ventilation. In myotonia fluctuans, the muscle stiffness may fluctuate from day to day, provoked by exercise. {ECO:0000269|PubMed:10218481, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:16832098, ECO:0000269|PubMed:17212350, ECO:0000269|PubMed:17998485, ECO:0000269|PubMed:18203179, ECO:0000269|PubMed:18337100, ECO:0000269|PubMed:19015483, ECO:0000269|PubMed:19347921, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:8058156, ECO:0000269|PubMed:9392583}. Note=The disease is caused by mutations affecting the gene represented in this entry. Myasthenic syndrome, congenital, 16 (CMS16) [MIM:614198]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS16 is characterized by fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth. The fatigable weakness involves lid-elevator, external ocular, facial, limb and truncal muscles and an decremental response of the compound muscle action potential on repetitive stimulation. {ECO:0000269|PubMed:12766226, ECO:0000269|PubMed:25707578, ECO:0000269|PubMed:26659129, ECO:0000269|PubMed:26700687}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle. | Sodium channel protein type 4 subunit alpha inhibitor: Diclofenac, Flecainide, Propofol, Zonisamide | 16.04 | ||
| dfaSCN5A | Sodium channel protein type 5 subunit alpha | 5 | 374 | 92.21 | 92.20 | ND | 0.83 | 0.75 | 0.3 | Nature11159 | Mammalian | Found in jejunal circular smooth muscle cells (at protein level). Expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. Isoform 4 is expressed in brain. {ECO:0000269|PubMed:12358675}. | Apnoea Cardiac arrest Central nervous system stimulation Coma Corneal disorder Death Diplopia Dysarthria Foetal damage Hypoaesthesia oral Impaired healing Keratitis Loss of consciousness Methaemoglobinaemia Muscle twitching Myocardial depression Nervousness Nystagmus Presyncope Respiratory failure Sensitisation Tinnitus Tremor Ventricular fibrillation Vision blurred | Voltage-gated ion channel | Progressive familial heart block 1A (PFHB1A) [MIM:113900]: A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His- Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death. {ECO:0000269|PubMed:12569159, ECO:0000269|PubMed:12574143, ECO:0000269|PubMed:19251209}. Note=The disease is caused by mutations affecting the gene represented in this entry. Long QT syndrome 3 (LQT3) [MIM:603830]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:10377081, ECO:0000269|PubMed:10508990, ECO:0000269|PubMed:10627139, ECO:0000269|PubMed:10911008, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:11304498, ECO:0000269|PubMed:11997281, ECO:0000269|PubMed:12209021, ECO:0000269|PubMed:12673799, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:16414944, ECO:0000269|PubMed:16922724, ECO:0000269|PubMed:18060054, ECO:0000269|PubMed:18708744, ECO:0000269|PubMed:18848812, ECO:0000269|PubMed:18929331, ECO:0000269|PubMed:19716085, ECO:0000269|PubMed:7651517, ECO:0000269|PubMed:7889574, ECO:0000269|PubMed:8541846, ECO:0000269|PubMed:9506831, ECO:0000269|PubMed:9686753, ECO:0000269|Ref.31}. Note=The disease is caused by mutations affecting the gene represented in this entry. Brugada syndrome 1 (BRGDA1) [MIM:601144]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:11748104, ECO:0000269|PubMed:11901046, ECO:0000269|PubMed:12051963, ECO:0000269|PubMed:12106943, ECO:0000269|PubMed:15023552, ECO:0000269|PubMed:15338453, ECO:0000269|PubMed:15579534, ECO:0000269|PubMed:15851320, ECO:0000269|PubMed:16266370, ECO:0000269|PubMed:16325048, ECO:0000269|PubMed:16616735, ECO:0000269|PubMed:17075016, ECO:0000269|PubMed:17081365, ECO:0000269|PubMed:17198989, ECO:0000269|PubMed:18252757, ECO:0000269|PubMed:18341814, ECO:0000269|PubMed:18451998, ECO:0000269|PubMed:18456723, ECO:0000269|PubMed:18616619, ECO:0000269|PubMed:19251209, ECO:0000269|PubMed:19272188, ECO:0000269|PubMed:20129283, ECO:0000269|PubMed:9521325}. Note=The disease is caused by mutations affecting the gene represented in this entry. Sick sinus syndrome 1 (SSS1) [MIM:608567]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS1 onset is in utero, infancy, or early childhood. {ECO:0000269|PubMed:14523039, ECO:0000269|PubMed:22795782}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial paroxysmal ventricular fibrillation 1 (VF1) [MIM:603829]: A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity. {ECO:0000269|PubMed:10940383}. Note=The disease is caused by mutations affecting the gene represented in this entry. Sudden infant death syndrome (SIDS) [MIM:272120]: SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. {ECO:0000269|PubMed:18596570, ECO:0000269|PubMed:19302788}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Atrial standstill 1 (ATRST1) [MIM:108770]: A rare arrhythmia characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. {ECO:0000269|PubMed:12522116}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry. A mutation in SCN5A has been detected in combination with a rare GJA5 genotype in a large family with atrial standstill. Cardiomyopathy, dilated 1E (CMD1E) [MIM:601154]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:15466643}. Note=The disease is caused by mutations affecting the gene represented in this entry. Atrial fibrillation, familial, 10 (ATFB10) [MIM:614022]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:18088563, ECO:0000269|PubMed:18378609}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels. {ECO:0000269|PubMed:19074138}. | Sodium channel protein type 5 subunit alpha antagonist: Benzonatate Sodium channel protein type 5 subunit alpha inhibitor: Ajmaline, Aprindine, Carbamazepine, Cinchocaine, Cocaine, Disopyramide, Encainide, Ethotoin, Flecainide, Fosphenytoin, Hexylcaine, Indecainide, Lidocaine, Mexiletine, Moricizine, Oxcarbazepine, Phenytoin, Prilocaine, Procainamide, Propafenone, Quinidine, Quinidine barbiturate, Ranolazine, Riluzole, Tocainide, Zonisamide Sodium channel protein type 5 subunit alpha other: Verapamil | 16.04 |
| dfaSCN9A | Sodium channel protein type 9 subunit alpha {ECO:0000305} | 4 | 1455 | 96.33 | 95.76 | ND | 0.57 | 0.00 | 0.6 | Mammalian | Expressed strongly in dorsal root ganglion, with only minor levels elsewhere in the body, smooth muscle cells, MTC cell line and C-cell carcinoma. Isoform 1 is expressed preferentially in the central and peripheral nervous system. Isoform 2 is expressed preferentially in the dorsal root ganglion. {ECO:0000269|PubMed:15178348, ECO:0000269|PubMed:15302875, ECO:0000269|PubMed:7720699, ECO:0000269|PubMed:9169448}. | Cardiac arrest Central nervous system stimulation Coma Convulsion Corneal disorder Dysarthria Foetal damage Hypoaesthesia oral Impaired healing Keratitis Loss of consciousness Methaemoglobinaemia Muscle twitching Myocardial depression Nervousness Presyncope Respiratory failure Sensitisation Tinnitus Vision blurred | Voltage-gated ion channel | Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands. {ECO:0000269|PubMed:14985375, ECO:0000269|PubMed:15955112, ECO:0000269|PubMed:15958509, ECO:0000269|PubMed:16216943, ECO:0000269|PubMed:16392115, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784}. Note=The disease is caused by mutations affecting the gene represented in this entry. Indifference to pain, congenital, autosomal recessive (CIP) [MIM:243000]: A disorder characterized by congenital inability to perceive any form of pain, in any part of the body. All other sensory modalities are preserved and the peripheral and central nervous systems are apparently intact. Patients perceive the sensations of touch, warm and cold temperature, proprioception, tickle and pressure, but not painful stimuli. There is no evidence of a motor or sensory neuropathy, either axonal or demyelinating. {ECO:0000269|PubMed:20635406}. Note=The disease is caused by mutations affecting the gene represented in this entry. Paroxysmal extreme pain disorder (PEPD) [MIM:167400]: Autosomal dominant paroxysmal disorder of pain and autonomic dysfunction. The distinctive features are paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic manifestations such as skin flushing. {ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:25285947}. Note=The disease is caused by mutations affecting the gene represented in this entry. Generalized epilepsy with febrile seizures plus 7 (GEFS+7) [MIM:613863]: A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity. {ECO:0000269|PubMed:19763161}. Note=The disease is caused by mutations affecting the gene represented in this entry. Febrile seizures, familial, 3B (FEB3B) [MIM:613863]: Seizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy. {ECO:0000269|PubMed:19763161}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784). {ECO:0000269|PubMed:15178348, ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:16988069, ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784, ECO:0000269|PubMed:25240195, ECO:0000269|PubMed:26680203, ECO:0000269|PubMed:7720699}. | Sodium channel protein type 9 subunit alpha {ECO:0000305} inhibitor: Lidocaine, Ranolazine, Zonisamide Sodium channel protein type 9 subunit alpha {ECO:0000305} modulator: Rufinamide | 16.04 | |
| dfaSCNAA | Sodium channel protein type 10 subunit alpha | 1 | 109 | 99.87 | 99.35 | ND | 0.43 | 0.46 | 0.7 | Mammalian | Expressed in the dorsal root ganglia and sciatic nerve. {ECO:0000269|PubMed:9839820}. | Agitation Apnoea Cardiac arrest Central nervous system stimulation Coma Convulsion Corneal disorder Death Dysarthria Encephalopathy Foetal damage Hypoaesthesia oral Impaired healing Keratitis Loss of consciousness Methaemoglobinaemia Muscle twitching Myocardial depression Nervousness Presyncope Respiratory disorder Respiratory failure Restlessness Sensitisation Tinnitus Tremor Vasodilatation Vision blurred | Voltage-gated ion channel | Episodic pain syndrome, familial, 2 (FEPS2) [MIM:615551]: An autosomal dominant neurologic disorder characterized by adult- onset of paroxysmal pain mainly affecting the distal lower extremities. {ECO:0000269|PubMed:23115331}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium- selective channel through which sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms. {ECO:0000269|PubMed:9839820}. | Sodium channel protein type 10 subunit alpha inhibitor: Benzocaine, Bupivacaine, Chloroprocaine, Cinchocaine, Cocaine, Dyclonine, Hexylcaine, Levobupivacaine, Lidocaine, Mepivacaine, Orphenadrine, Oxybuprocaine, Procaine, Proparacaine, Ropivacaine | 16.04 | |
| dfaSCRB1 | Scavenger receptor class B member 1 | 3 | 143 | 86.62 | 91.42 | ND | 0.60 | 0.77 | 0.9 | Mammalian | Widely expressed. | Atherosclerosis
Atherosclerotic cardiovascular disease Cardiovascular disease, unspecified Hypercholesterolemia Reproductive disorder | Receptor for different ligands such as phospholipids, cholesterol ester, lipoproteins, phosphatidylserine and apoptotic cells. Probable receptor for HDL, located in particular region of the plasma membrane, called caveolae. Facilitates the flux of free and esterified cholesterol between the cell surface and extracellular donors and acceptors, such as HDL and to a lesser extent, apoB-containing lipoproteins and modified lipoproteins. Probably involved in the phagocytosis of apoptotic cells, via its phosphatidylserine binding activity. Receptor for hepatitis C virus glycoprotein E2. Binding between SCARB1 and E2 was found to be independent of the genotype of the viral isolate. Plays an important role in the uptake of HDL cholesteryl ester (By similarity). {ECO:0000250}. (Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes. {ECO:0000269|PubMed:18000990}. | 16.04 | ||||
| dfaSENP6 | Sentrin-specific protease 6 | 2 | 558 | 81.83 | 86.94 | ND | 0.13 | 0.48 | 0.4 | Mammalian | Highly expressed in reproductive organs, such as testis, ovary and prostate. | Enzyme | Protease that deconjugates SUMO1, SUMO2 and SUMO3 from targeted proteins. Processes preferentially poly-SUMO2 and poly- SUMO3 chains, but does not efficiently process SUMO1, SUMO2 and SUMO3 precursors. Deconjugates SUMO1 from RXRA, leading to transcriptional activation. Involved in chromosome alignment and spindle assembly, by regulating the kinetochore CENPH-CENPI-CENPK complex. Desumoylates PML and CENPI, protecting them from degradation by the ubiquitin ligase RNF4, which targets polysumoylated proteins for proteasomal degradation. Desumoylates also RPA1, thus preventing recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination. {ECO:0000269|PubMed:16912044, ECO:0000269|PubMed:17000875, ECO:0000269|PubMed:18799455, ECO:0000269|PubMed:20212317, ECO:0000269|PubMed:20705237, ECO:0000269|PubMed:21148299}. | 16.04 | ||||
| dfaSENP7 | Sentrin-specific protease 7 | 1 | 644 | 80.50 | 89.96 | ND | 0.24 | 0.18 | 0.3 | Mammalian | Enzyme | Protease that deconjugates SUMO2 and SUMO3 from targeted proteins, but not SUMO1. Catalyzes the deconjugation of poly-SUMO2 and poly-SUMO3 chains. Has very low efficiency in processing full- length SUMO proteins to their mature forms. {ECO:0000269|PubMed:18799455}. | 16.04 | |||||
| dfaSEPR | Prolyl endopeptidase FAP {ECO:0000305} | 2 | 442 | 99.31 | 97.96 | ND | 0.68 | 0.64 | 0.6 | Mammalian | Expressed in adipose tissue. Expressed in the dermal fibroblasts in the fetal skin. Expressed in the granulation tissue of healing wounds and on reactive stromal fibroblast in epithelial cancers. Expressed in activated fibroblast-like synoviocytes from inflamed synovial tissues. Expressed in activated hepatic stellate cells (HSC) and myofibroblasts from cirrhotic liver, but not detected in normal liver. Expressed in glioma cells (at protein level). Expressed in glioblastomas and glioma cells. Isoform 1 and isoform 2 are expressed in melanoma, carcinoma and fibroblast cell lines. {ECO:0000269|PubMed:10347120, ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:10644713, ECO:0000269|PubMed:16175601, ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:20707604, ECO:0000269|PubMed:24371721, ECO:0000269|PubMed:7911242}. | Protease | Atherogenesis
Inflammatory diseases Thrombosis | Cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth. Both plasma membrane and soluble forms exhibit post-proline cleaving endopeptidase activity, with a marked preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2 (PubMed:14751930, PubMed:16223769, PubMed:16480718, PubMed:16410248, PubMed:17381073, PubMed:18095711, PubMed:21288888, PubMed:24371721). Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vibronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219, PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769, PubMed:16651416, PubMed:18095711). Have also dipeptidyl peptidase activity, exhibiting the ability to hydrolyze the prolyl bond two residues from the N-terminus of synthetic dipeptide substrates provided that the penultimate residue is proline, with a preference for Ala-Pro, Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro (PubMed:10347120, PubMed:10593948, PubMed:16175601, PubMed:16223769, PubMed:16651416, PubMed:16410248, PubMed:17381073, PubMed:21314817, PubMed:24371721, PubMed:24717288). Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB) (PubMed:21314817). The plasma membrane form, in association with either DPP4, PLAUR or integrins, is involved in the pericellular proteolysis of the extracellular matrix (ECM), and hence promotes cell adhesion, migration and invasion through the ECM. Plays a role in tissue remodeling during development and wound healing. Participates in the cell invasiveness towards the ECM in malignant melanoma cancers. Enhances tumor growth progression by increasing angiogenesis, collagen fiber degradation and apoptosis and by reducing antitumor response of the immune system. Promotes glioma cell invasion through the brain parenchyma by degrading the proteoglycan brevican. Acts as a tumor suppressor in melanocytic cells through regulation of cell proliferation and survival in a serine protease activity-independent manner. {ECO:0000250|UniProtKB:P97321, ECO:0000269|PubMed:10347120, ECO:0000269|PubMed:10455171, ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:12376466, ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16175601, ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:16480718, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:17381073, ECO:0000269|PubMed:18095711, ECO:0000269|PubMed:20707604, ECO:0000269|PubMed:21288888, ECO:0000269|PubMed:21314817, ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:24371721, ECO:0000269|PubMed:24717288, ECO:0000269|PubMed:7923219, ECO:0000269|PubMed:9065413}. | 16.04 | |||
| dfaSFRP1 | Secreted frizzled-related protein 1 | 1 | 58 | 100.00 | 100.00 | ND | 0.41 | 0.60 | 0.2 | Mammalian | Widely expressed. Absent from lung, liver and peripheral blood leukocytes. Highest levels in heart and fetal kidney. Also expressed in testis, ovary, fetal brain and lung, leiomyomal cells, myometrial cells and vascular smooth muscle cells. Expressed in foreskin fibroblasts and in keratinocytes. {ECO:0000269|PubMed:9391078}. | Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP1 decreases intracellular beta-catenin levels (By similarity). Has antiproliferative effects on vascular cells, in vitro and in vivo, and can induce, in vivo, an angiogenic response. In vascular cell cycle, delays the G1 phase and entry into the S phase (By similarity). In kidney development, inhibits tubule formation and bud growth in metanephroi (By similarity). Inhibits WNT1/WNT4-mediated TCF-dependent transcription. {ECO:0000250}. | 16.04 | |||||
| dfaSGK1 | Serine/threonine-protein kinase Sgk1 | 4 | 117 | 91.95 | 98.29 | ND | 0.96 | 0.91 | 0.2 | Mammalian | Expressed in most tissues with highest levels in the pancreas, followed by placenta, kidney and lung. Isoform 2 is strongly expressed in brain and pancreas, weaker in heart, placenta, lung, liver and skeletal muscle. {ECO:0000269|PubMed:10548550, ECO:0000269|PubMed:18753299}. | Kinase | Leukemia, Myeloid
Myelodysplastic Syndrome Solid tumors | Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cellular enzymes, transcription factors, neuronal excitability, cell growth, proliferation, survival, migration and apoptosis. Plays an important role in cellular stress response. Contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Up-regulates Na(+) channels: SCNN1A/ENAC, SCN5A and ASIC1/ACCN2, K(+) channels: KCNJ1/ROMK1, KCNA1-5, KCNQ1-5 and KCNE1, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channels: BSND, CLCN2 and CFTR, glutamate transporters: SLC1A3/EAAT1, SLC1A2 /EAAT2, SLC1A1/EAAT3, SLC1A6/EAAT4 and SLC1A7/EAAT5, amino acid transporters: SLC1A5/ASCT2, SLC38A1/SN1 and SLC6A19, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, glutamate receptor: GRIK2/GLUR6. Up-regulates carriers: SLC9A3/NHE3, SLC12A1/NKCC2, SLC12A3/NCC, SLC5A3/SMIT, SLC2A1/GLUT1, SLC5A1/SGLT1 and SLC15A2/PEPT2. Regulates enzymes: GSK3A/B, PMM2 and Na(+)/K(+) ATPase, and transcription factors: CTNNB1 and nuclear factor NF-kappa-B. Stimulates sodium transport into epithelial cells by enhancing the stability and expression of SCNN1A/ENAC. This is achieved by phosphorylating the NEDD4L ubiquitin E3 ligase, promoting its interaction with 14-3-3 proteins, thereby preventing it from binding to SCNN1A/ENAC and targeting it for degradation. Regulates store-operated Ca(+2) entry (SOCE) by stimulating ORAI1 and STIM1. Regulates KCNJ1/ROMK1 directly via its phosphorylation or indirectly via increased interaction with SLC9A3R2/NHERF2. Phosphorylates MDM2 and activates MDM2-dependent ubiquitination of p53/TP53. Phosphorylates MAPT/TAU and mediates microtubule depolymerization and neurite formation in hippocampal neurons. Phosphorylates SLC2A4/GLUT4 and up-regulates its activity. Phosphorylates APBB1/FE65 and promotes its localization to the nucleus. Phosphorylates MAPK1/ERK2 and activates it by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Phosphorylates FBXW7 and plays an inhibitory role in the NOTCH1 signaling. Phosphorylates FOXO1 resulting in its relocalization from the nucleus to the cytoplasm. Phosphorylates FOXO3, promoting its exit from the nucleus and interference with FOXO3-dependent transcription. Phosphorylates BRAF and MAP3K3/MEKK3 and inhibits their activity. Phosphorylates SLC9A3/NHE3 in response to dexamethasone, resulting in its activation and increased localization at the cell membrane. Phosphorylates CREB1. Necessary for vascular remodeling during angiogenesis. Sustained high levels and activity may contribute to conditions such as hypertension and diabetic nephropathy. Isoform 2 exhibited a greater effect on cell plasma membrane expression of SCNN1A/ENAC and Na(+) transport than isoform 1. {ECO:0000269|PubMed:11154281, ECO:0000269|PubMed:11410590, ECO:0000269|PubMed:11696533, ECO:0000269|PubMed:12397388, ECO:0000269|PubMed:12590200, ECO:0000269|PubMed:12634932, ECO:0000269|PubMed:12650886, ECO:0000269|PubMed:12761204, ECO:0000269|PubMed:12911626, ECO:0000269|PubMed:14623317, ECO:0000269|PubMed:14706641, ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:15044175, ECO:0000269|PubMed:15234985, ECO:0000269|PubMed:15319523, ECO:0000269|PubMed:15496163, ECO:0000269|PubMed:15733869, ECO:0000269|PubMed:15737648, ECO:0000269|PubMed:15845389, ECO:0000269|PubMed:15888551, ECO:0000269|PubMed:16036218, ECO:0000269|PubMed:16443776, ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:17382906, ECO:0000269|PubMed:18005662, ECO:0000269|PubMed:18304449, ECO:0000269|PubMed:18753299, ECO:0000269|PubMed:19447520, ECO:0000269|PubMed:19756449, ECO:0000269|PubMed:20511718, ECO:0000269|PubMed:20730100, ECO:0000269|PubMed:21865597}. | 15.11 | |||
| dfaSGK2 | Serine/threonine-protein kinase Sgk2 | 5 | 202 | 84.98 | 88.46 | ND | 0.01 | 0.74 | 0.7 | Mammalian | Highly expressed in liver, kidney and pancreas, and at lower levels in brain. {ECO:0000269|PubMed:10548550}. | Kinase | Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, survival and proliferation. Up- regulates Na(+) channels: SCNN1A/ENAC, K(+) channels: KCNA3/Kv1.3, KCNE1 and KCNQ1, amino acid transporter: SLC6A19, glutamate transporter: SLC1A6/EAAT4, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase. {ECO:0000269|PubMed:12397388, ECO:0000269|PubMed:12590200, ECO:0000269|PubMed:12632189, ECO:0000269|PubMed:12634932, ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:20511718, ECO:0000269|PubMed:21865597}. | 16.04 | ||||
| dfaSGK3 | Serine/threonine-protein kinase Sgk3 | 3 | 59 | 99.47 | 94.92 | ND | 0.53 | 1.00 | 1.0 | Mammalian | Expressed in most tissues with highest levels in pancreas, kidney liver, heart and brain and lower levels in lung, placenta and skeletal muscle. Expression is higher in ER- positive breast tumors than ER-negative breast tumors. {ECO:0000269|PubMed:21084382}. | Kinase | Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, proliferation, survival and migration. Up-regulates Na(+) channels: SCNN1A/ENAC and SCN5A, K(+) channels: KCNA3/KV1.3, KCNE1, KCNQ1 and KCNH2/HERG, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channel: BSND, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, amino acid transporters: SLC1A5/ASCT2 and SLC6A19, glutamate transporters: SLC1A3/EAAT1, SLC1A6/EAAT4 and SLC1A7/EAAT5, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase. Plays a role in the regulation of renal tubular phosphate transport and bone density. Phosphorylates NEDD4L and GSK3B. Positively regulates ER transcription activity through phosphorylation of FLII. Negatively regulates the function of ITCH/AIP4 via its phosphorylation and thereby prevents CXCR4 from being efficiently sorted to lysosomes. {ECO:0000269|PubMed:12054501, ECO:0000269|PubMed:12397388, ECO:0000269|PubMed:12590200, ECO:0000269|PubMed:12632189, ECO:0000269|PubMed:12634932, ECO:0000269|PubMed:12650886, ECO:0000269|PubMed:12911626, ECO:0000269|PubMed:14706641, ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:15044175, ECO:0000269|PubMed:15319523, ECO:0000269|PubMed:15496163, ECO:0000269|PubMed:15737648, ECO:0000269|PubMed:15845389, ECO:0000269|PubMed:16036218, ECO:0000269|PubMed:16888620, ECO:0000269|PubMed:17167223, ECO:0000269|PubMed:18005662, ECO:0000269|PubMed:19293151, ECO:0000269|PubMed:20511718, ECO:0000269|PubMed:21865597}. | 16.04 | ||||
| dfaSGMR1 | Sigma non-opioid intracellular receptor 1 | 3 | 3109 | 91.29 | 85.76 | ND | 0.55 | 0.56 | 0.7 | Mammalian | Widely expressed with higher expression in liver, colon, prostate, placenta, small intestine, heart and pancreas. Expressed in the retina by retinal pigment epithelial cells. Expressed in alpha-motor neurons (PubMed:23314020). {ECO:0000269|PubMed:11687279, ECO:0000269|PubMed:23314020, ECO:0000269|PubMed:8954936, ECO:0000269|PubMed:9341151}. | Biliary colic Bladder disorder Cerebrovascular disorder Dependence Dermatitis contact Drug tolerance Dry mouth Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Miosis Mood altered Oliguria Respiratory depression Shock Ureteral spasm Withdrawal syndrome | Membrane receptor | Amyotrophic lateral sclerosis 16, juvenile (ALS16) [MIM:614373]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. {ECO:0000269|PubMed:21842496}. Note=The disease is caused by mutations affecting the gene represented in this entry. Distal spinal muscular atrophy, autosomal recessive, 2 (DSMA2) [MIM:605726]: An autosomal recessive neuromuscular disorder characterized by onset of distal muscle weakness and wasting affecting the lower and upper limbs in the first decade. There is no sensory involvement. {ECO:0000269|PubMed:26078401}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration (PubMed:16472803, PubMed:9341151). Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria (By similarity). {ECO:0000250|UniProtKB:O55242, ECO:0000269|PubMed:16472803, ECO:0000269|PubMed:9341151}. | Sigma non-opioid intracellular receptor 1 agonist: Amitriptyline, Captodiame, Dextromethorphan, Pentazocine Sigma non-opioid intracellular receptor 1 antagonist: Remoxipride | 16.04 | |
| dfaSHBG | Sex hormone-binding globulin | 1 | 96 | 91.31 | 88.01 | ND | 0.74 | 0.34 | 0.6 | Mammalian | Isoform 1 and isoform 2 are present in liver and testis. | Secreted protein | Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol. Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentration. | Sex hormone-binding globulin : Danazol, Drostanolone, Estradiol, Estropipate, Fluoxymesterone, Hydrocortisone, Methyltestosterone, Mitotane, Oxymetholone, transdermal testosterone gel Sex hormone-binding globulin binder: Spironolactone Sex hormone-binding globulin other/unknown: Testosterone Sex hormone-binding globulin substrate: Norethindrone | 15.11 | |||
| dfaSHH | Sonic hedgehog protein | 6 | 164 | 94.28 | 91.94 | ND | 0.76 | 0.69 | 0.5 | Mammalian | Expressed in fetal intestine, liver, lung, and kidney. Not expressed in adult tissues. | Microphthalmia, isolated, with coloboma, 5 (MCOPCB5) [MIM:611638]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:12503095}. Note=The disease is caused by mutations affecting the gene represented in this entry. Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. {ECO:0000269|PubMed:10441331, ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728, ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953, ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572, ECO:0000269|PubMed:9302262}. Note=The disease is caused by mutations affecting the gene represented in this entry. Solitary median maxillary central incisor (SMMCI) [MIM:147250]: Rare dental anomaly characterized by the congenital absence of one maxillary central incisor. {ECO:0000269|PubMed:11471164, ECO:0000269|PubMed:15103725}. Note=The disease is caused by mutations affecting the gene represented in this entry. Triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]: Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. {ECO:0000269|PubMed:12837695, ECO:0000269|PubMed:18417549}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH expression. Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. {ECO:0000269|PubMed:12837695}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences (PubMed:12837695). {ECO:0000269|PubMed:12837695}. Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740]: An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. {ECO:0000269|PubMed:19847792, ECO:0000269|PubMed:24965254}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences. {ECO:0000303|PubMed:19847792, ECO:0000303|PubMed:24965254}. Laurin-Sandrow syndrome (LSS) [MIM:135750]: A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome). {ECO:0000269|PubMed:24456159}. Note=The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5 (PubMed:24456159). | Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior- posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction. Activates the transcription of target genes by interacting with its receptor PTCH1 to prevent normal inhibition by PTCH1 on the constitutive signaling activity of SMO (By similarity). {ECO:0000250, ECO:0000269|PubMed:10753901}. | 16.04 | ||||
| dfaSIK1 | Serine/threonine-protein kinase SIK1 | 6 | 69 | 87.14 | 92.28 | ND | 0.53 | 0.86 | 0.5 | Mammalian | Kinase | Epileptic encephalopathy, early infantile, 30 (EIEE30) [MIM:616341]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:25839329}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Defects in SIK1 may be associated with some cancers, such as breast cancers. Loss of SIK1 correlates with poor patient outcome in breast cancers (PubMed:19622832). {ECO:0000269|PubMed:19622832}. | Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, CRTC1/TORC1 and CRTC2/TORC2. Acts as a tumor suppressor and plays a key role in p53/TP53-dependent anoikis, a type of apoptosis triggered by cell detachment: required for phosphorylation of p53/TP53 in response to loss of adhesion and is able to suppress metastasis. Part of a sodium-sensing signaling network, probably by mediating phosphorylation of PPME1: following increases in intracellular sodium, SIK1 is activated by CaMK1 and phosphorylates PPME1 subunit of protein phosphatase 2A (PP2A), leading to dephosphorylation of sodium/potassium-transporting ATPase ATP1A1 and subsequent increase activity of ATP1A1. Acts as a regulator of muscle cells by phosphorylating and inhibiting class II histone deacetylases HDAC4 and HDAC5, leading to promote expression of MEF2 target genes in myocytes. Also required during cardiomyogenesis by regulating the exit of cardiomyoblasts from the cell cycle via down-regulation of CDKN1C/p57Kip2. Acts as a regulator of hepatic gluconeogenesis by phosphorylating and repressing the CREB-specific coactivators CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB activity. Also regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. In concert with CRTC1/TORC1, regulates the light-induced entrainment of the circadian clock by attenuating PER1 induction; represses CREB-mediated transcription of PER1 by phosphorylating and deactivating CRTC1/TORC1 (By similarity). {ECO:0000250|UniProtKB:Q60670, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:16306228, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:19622832}. | Serine/threonine-protein kinase SIK1 inhibitor: Dabrafenib | 16.04 | |||
| dfaSIK2 | Serine/threonine-protein kinase SIK2 | 5 | 74 | 92.07 | 93.78 | ND | 0.81 | 0.92 | 0.4 | Mammalian | Kinase | Phosphorylates 'Ser-794' of IRS1 in insulin-stimulated adipocytes, potentially modulating the efficiency of insulin signal transduction. Inhibits CREB activity by phosphorylating and repressing TORCs, the CREB-specific coactivators. {ECO:0000269|PubMed:15454081}. | 16.04 | |||||
| dfaSIK3 | Serine/threonine-protein kinase SIK3 | 3 | 60 | 99.82 | 97.88 | ND | 0.89 | 0.82 | 0.2 | Mammalian | Kinase | 16.04 | ||||||
| dfaSIR1 | NAD-dependent protein deacetylase sirtuin-1 | 7 | 262 | 96.05 | 97.82 | ND | 0.86 | 0.70 | 0.4 | Mammalian | Widely expressed. {ECO:0000269|PubMed:10381378}. | Eraser | Diabetes Mellitus Type 2
Neurologic Disorders | NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A- mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insulin-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys-542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1- dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transactivation and contributes to its stability. Deacteylates MECOM/EVI1. Deacetylates PML at 'Lys-487' and this deacetylation promotes PML control of PER2 nuclear localization. During the neurogenic transition, repress selective NOTCH1-target genes through histone deacetylation in a BCL6-dependent manner and leading to neuronal differentiation. Regulates the circadian expression of several core clock genes, including ARNTL/BMAL1, RORC, PER2 and CRY1 and plays a critical role in maintaining a controlled rhythmicity in histone acetylation, thereby contributing to circadian chromatin remodeling. Deacetylates ARNTL/BMAL1 and histones at the circadian gene promoters in order to facilitate repression by inhibitory components of the circadian oscillator. Deacetylates PER2, facilitating its ubiquitination and degradation by the proteosome. Protects cardiomyocytes against palmitate-induced apoptosis (PubMed:11672523, PubMed:12006491, PubMed:14976264, PubMed:14980222, PubMed:15126506, PubMed:15152190, PubMed:15205477, PubMed:15469825, PubMed:15692560, PubMed:16079181, PubMed:16166628, PubMed:16892051, PubMed:16998810, PubMed:17283066, PubMed:17334224, PubMed:17505061, PubMed:17612497, PubMed:17620057, PubMed:17936707, PubMed:18203716, PubMed:18296641, PubMed:18662546, PubMed:18687677, PubMed:19188449, PubMed:19220062, PubMed:19364925, PubMed:19690166, PubMed:19934257, PubMed:20097625, PubMed:20100829, PubMed:20203304, PubMed:20375098, PubMed:20620956, PubMed:20670893, PubMed:20817729, PubMed:21149730, PubMed:21245319, PubMed:21471201, PubMed:21504832, PubMed:21555002, PubMed:21698133, PubMed:21701047, PubMed:21775285, PubMed:21807113, PubMed:21841822, PubMed:21890893, PubMed:21909281, PubMed:21947282, PubMed:22274616). Deacetylates XBP1 isoform 2; deacetylation decreases protein stability of XBP1 isoform 2 and inhibits its transcriptional activity (PubMed:20955178). Involved in the CCAR2- mediated regulation of PCK1 and NR1D1 (PubMed:24415752). Deacetylates CTNB1 at 'Lys-49' (PubMed:24824780). In POMC (pro- opiomelanocortin) neurons, required for leptin-induced activation of PI3K signaling (By similarity). {ECO:0000250|UniProtKB:Q923E4, ECO:0000269|PubMed:11672523, ECO:0000269|PubMed:12006491, ECO:0000269|PubMed:14976264, ECO:0000269|PubMed:14980222, ECO:0000269|PubMed:15126506, ECO:0000269|PubMed:15152190, ECO:0000269|PubMed:15205477, ECO:0000269|PubMed:15469825, ECO:0000269|PubMed:15692560, ECO:0000269|PubMed:16079181, ECO:0000269|PubMed:16166628, ECO:0000269|PubMed:16892051, ECO:0000269|PubMed:16998810, ECO:0000269|PubMed:17283066, ECO:0000269|PubMed:17290224, ECO:0000269|PubMed:17334224, ECO:0000269|PubMed:17505061, ECO:0000269|PubMed:17612497, ECO:0000269|PubMed:17620057, ECO:0000269|PubMed:17936707, ECO:0000269|PubMed:18203716, ECO:0000269|PubMed:18296641, ECO:0000269|PubMed:18662546, ECO:0000269|PubMed:18687677, ECO:0000269|PubMed:19188449, ECO:0000269|PubMed:19220062, ECO:0000269|PubMed:19364925, ECO:0000269|PubMed:19690166, ECO:0000269|PubMed:19934257, ECO:0000269|PubMed:20097625, ECO:0000269|PubMed:20100829, ECO:0000269|PubMed:20203304, ECO:0000269|PubMed:20375098, ECO:0000269|PubMed:20620956, ECO:0000269|PubMed:20670893, ECO:0000269|PubMed:20817729, ECO:0000269|PubMed:20955178, ECO:0000269|PubMed:21149730, ECO:0000269|PubMed:21245319, ECO:0000269|PubMed:21471201, ECO:0000269|PubMed:21504832, ECO:0000269|PubMed:21555002, ECO:0000269|PubMed:21698133, ECO:0000269|PubMed:21701047, ECO:0000269|PubMed:21775285, ECO:0000269|PubMed:21807113, ECO:0000269|PubMed:21841822, ECO:0000269|PubMed:21890893, ECO:0000269|PubMed:21909281, ECO:0000269|PubMed:21947282, ECO:0000269|PubMed:22274616, ECO:0000269|PubMed:24415752, ECO:0000269|PubMed:24824780}. Isoform 2: Isoform 2 is shown to deacetylate 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop. {ECO:0000269|PubMed:20975832}. (Microbial infection) In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. The viral Tat protein inhibits SIRT1 deacetylation activity toward RELA/NF- kappa-B p65, thereby potentiates its transcriptional activity and SIRT1 is proposed to contribute to T-cell hyperactivation during infection. {ECO:0000269|PubMed:18329615}. SirtT1 75 kDa fragment: catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly. {ECO:0000269|PubMed:21987377}. | 15.11 | |||
| dfaSIR2 | NAD-dependent protein deacetylase sirtuin-2 | 3 | 269 | 96.77 | 81.69 | ND | 0.82 | 0.83 | 0.4 | Mammalian | Isoform 1 is expressed in heart, liver and skeletal muscle, weakly expressed in the cortex. Isoform 2 is strongly expressed in the cortex, weakly expressed in heart and liver. Weakly expressed in several malignancies including breast, liver, brain, kidney and prostate cancers compared to normal tissues. Weakly expressed in glioma cell lines compared to normal brain tissues (at protein level). Widely expressed. Highly expressed in heart, brain and skeletal muscle, while it is weakly expressed in placenta and lung. Down-regulated in many gliomas suggesting that it may act as a tumor suppressor gene in human gliomas possibly through the regulation of microtubule network. {ECO:0000269|PubMed:10381378, ECO:0000269|PubMed:10393250, ECO:0000269|PubMed:12963026, ECO:0000269|PubMed:16909107, ECO:0000269|PubMed:21791548, ECO:0000269|PubMed:22014574}. | Eraser | NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors. Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes. Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis. Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by KMT5A leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression. Deacetylates KMT5A modulating KMT5A chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys- 57' (H3K56ac) during the mitotic G2/M transition. Upon bacterium Listeria monocytogenes infection, deacetylates 'Lys-18' of histone H3 in a receptor tyrosine kinase MET- and PI3K/Akt-dependent manner, thereby inhibiting transcriptional activity and promoting late stages of listeria infection. During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function. Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1- mediated autophagy. Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation. Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia. Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation. Inhibits transcriptional activation by deacetylating p53/TP53 and EP300. Deacetylates also EIF5A. Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions. Plays a role as tumor suppressor. Isoform 1: Deacetylates EP300, alpha-tubulin and histone H3 and H4. Isoform 2: Deacetylates EP300, alpha-tubulin and histone H3 and H4. Isoform 5: Lacks deacetylation activity. | 16.04 | ||||
| dfaSIR3 | NAD-dependent protein deacetylase sirtuin-3, mitochondrial | 1 | 51 | 99.61 | 99.98 | ND | 0.66 | 0.67 | 0.9 | Mammalian | Widely expressed. {ECO:0000269|PubMed:10381378, ECO:0000269|PubMed:12374852}. | Eraser | NAD-dependent protein deacetylase. Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues. Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5O. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels. {ECO:0000269|PubMed:16788062, ECO:0000269|PubMed:18680753, ECO:0000269|PubMed:18794531, ECO:0000269|PubMed:19535340, ECO:0000269|PubMed:24121500, ECO:0000269|PubMed:24252090}. | 16.04 | ||||
| dfaSL9A1 | Sodium/hydrogen exchanger 1 | 4 | 309 | 96.55 | 99.83 | ND | 0.77 | 0.74 | 0.5 | Mammalian | Kidney and intestine. | Electrochemical transporter | Lichtenstein-Knorr syndrome (LIKNS) [MIM:616291]: An autosomal recessive neurologic disorder characterized by progressive cerebellar ataxia and severe progressive sensorineural hearing loss. {ECO:0000269|PubMed:25205112}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction. {ECO:0000269|PubMed:11350981, ECO:0000269|PubMed:15035633, ECO:0000269|PubMed:8901634}. | Sodium/hydrogen exchanger 1 inhibitor: Amiloride | 16.04 | ||
| dfaSLK | STE20-like serine/threonine-protein kinase | 3 | 300 | 86.85 | 88.70 | ND | 0.45 | 0.60 | 0.5 | Mammalian | Ubiquitously expressed. Highest expression is found in heart and in skeletal muscle. {ECO:0000269|PubMed:10699464}. | Kinase | Mediates apoptosis and actin stress fiber dissolution. {ECO:0000250}. | 15.11 | ||||
| dfaSMO | Smoothened homolog | 4 | 400 | 97.28 | 98.06 | ND | 0.47 | 0.71 | 0.7 | Mammalian | Frizzled family G protein-coupled receptor | Cancers | G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia. {ECO:0000269|PubMed:19592253}. | Smoothened homolog agonist: Fluocinonide Smoothened homolog antagonist: Sonidegib, Vismodegib | 15.11 | |||
| dfaSO1B1 | Solute carrier organic anion transporter family member 1B1 | 4 | 111 | 91.51 | 92.25 | ND | 0.68 | 0.49 | 0.1 | Mammalian | Highly expressed in liver, at the basolateral membranes of centrilobular hepatocytes. Not detected in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocyte. {ECO:0000269|PubMed:10358072, ECO:0000269|PubMed:10601278, ECO:0000269|PubMed:22232210}. | Electrochemical transporter | Hyperbilirubinemia, Rotor type (HBLRR) [MIM:237450]: An autosomal recessive form of primary conjugated hyperbilirubinemia. Affected individuals develop mild jaundice not associated with hemolysis shortly after birth or in childhood. They have delayed plasma clearance of the unconjugated anionic dye bromsulphthalein and prominent urinary excretion of coproporphyrin I. Hepatic pigmentation is normal. {ECO:0000269|PubMed:22232210}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver. {ECO:0000269|PubMed:10358072, ECO:0000269|PubMed:10601278, ECO:0000269|PubMed:12196548, ECO:0000269|PubMed:22232210}. | Solute carrier organic anion transporter family member 1B1 : Clarithromycin, Dextrothyroxine, Fexofenadine, Fluvastatin, Levothyroxine, Rifampicin Solute carrier organic anion transporter family member 1B1 inducer: Solute carrier organic anion transporter family member 1B1 inhibitor: Acetylcysteine, Aminohippurate, Bezafibrate, Cabazitaxel, Caspofungin, Cyclosporine, Dabrafenib, Daclatasvir, Eltrombopag, Estradiol, Estrone, Gemfibrozil, Idelalisib, Indinavir, Irinotecan, L-Carnitine, Lovastatin, Nelfinavir, Pantoprazole, Pazopanib, Pioglitazone, Quinidine, Rifampicin, Rilpivirine, Ritonavir, Rosiglitazone, Sacubitril, Saquinavir, Sirolimus, Verapamil Solute carrier organic anion transporter family member 1B1 substrate: Ambrisentan, Atorvastatin, Axitinib, Benzylpenicillin, Cholic Acid, Cobimetinib, Conjugated Estrogens, Digoxin, Dinoprostone, Eluxadoline, Ezetimibe, Gadoxetate, Liothyronine, Liotrix, Methotrexate, Mycophenolate mofetil, Olmesartan, Ouabain, Penicillamine, Pitavastatin, Pravastatin, Repaglinide, Rosuvastatin, Selexipag, Simeprevir, Simvastatin, Sumatriptan, Valsartan Solute carrier organic anion transporter family member 1B1 weak inhibitor: | 16.04 | ||
| dfaSOAT1 | Sterol O-acyltransferase 1 | 7 | 729 | 96.23 | 97.38 | ND | 0.69 | 0.75 | 0.5 | Mammalian | Enzyme | Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol. Plays a role in lipoprotein assembly and dietary cholesterol absorption. In addition to its acyltransferase activity, it may act as a ligase. | Sterol O-acyltransferase 1 inhibitor: Ezetimibe, Hesperetin | 16.04 | ||||
| dfaSOAT2 | Sterol O-acyltransferase 2 | 1 | 85 | 98.25 | 97.78 | ND | 0.75 | 0.75 | 0.8 | Mammalian | Expression seems confined in hepatocytes and enterocytes. {ECO:0000269|PubMed:16331323}. | Enzyme | Not Available | Plays a role in lipoprotein assembly and dietary cholesterol absorption. In addition to its acyltransferase activity, it may act as a ligase. May provide cholesteryl esters for lipoprotein secretion from hepatocytes and intestinal mucosa. | Sterol O-acyltransferase 2 inhibitor: Hesperetin | 16.04 | ||
| dfaSPHK1 | Sphingosine kinase 1 | 2 | 132 | 99.04 | 97.93 | ND | 0.76 | 0.63 | 0.5 | Mammalian | Widely expressed with highest levels in adult liver, kidney, heart and skeletal muscle. {ECO:0000269|PubMed:10802064}. | Enzyme | Late-Stage Ovarian cancer
Prostate cancer | Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol. {ECO:0000269|PubMed:20577214, ECO:0000269|PubMed:23602659}. | Sphingosine kinase 1 substrate: Fingolimod | 15.11 | ||
| dfaSPHK2 | Sphingosine kinase 2 | 2 | 84 | 99.63 | 99.61 | ND | 0.60 | 0.80 | 0.4 | Mammalian | Enzyme | Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro- dihydrosphingosine, D-erythro-sphingosine and L-threo- dihydrosphingosine. Binds phosphoinositides. {ECO:0000269|PubMed:19168031}. | 16.04 | |||||
| dfaSRC | Proto-oncogene tyrosine-protein kinase Src | 4 | 2502 | 96.36 | 94.92 | ND | 0.65 | 0.66 | 0.7 | Mammalian | Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues. | Diarrhoea | Kinase | Note=SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells. | Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein- coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin- 43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1. Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors. Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation. Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr- 1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of ADRBK1, leading to beta- arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor. Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus. Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase. Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr- 128'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Required for podosome formation (By similarity). {ECO:0000250|UniProtKB:P05480, ECO:0000269|PubMed:11389730, ECO:0000269|PubMed:12615910, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:16186108, ECO:0000269|PubMed:18586953, ECO:0000269|PubMed:19419966, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20525694, ECO:0000269|PubMed:21309750, ECO:0000269|PubMed:21411625, ECO:0000269|PubMed:22710723, ECO:0000269|PubMed:2498394, ECO:0000269|PubMed:3093483, ECO:0000269|PubMed:7853507, ECO:0000269|PubMed:8755529, ECO:0000269|PubMed:8759729}. | Proto-oncogene tyrosine-protein kinase Src Inhibitor: Nintedanib Proto-oncogene tyrosine-protein kinase Src inhibitor: Bosutinib, Ponatinib Proto-oncogene tyrosine-protein kinase Src multitarget: Dasatinib | 15.11 | |
| dfaSRMS | Tyrosine-protein kinase Srms | 8 | 100 | 90.29 | 86.31 | ND | 0.61 | 0.86 | 0.4 | Mammalian | Highly expressed in most breast cancers (at protein level). | Kinase | Non-receptor tyrosine-protein kinase which phosphorylates DOK1 on tyrosine residues. May be involved in proliferation or differentiation of keratinocytes in the skin. {ECO:0000269|PubMed:23822091}. | 16.04 | ||||
| dfaSRPK1 | SRSF protein kinase 1 | 4 | 220 | 82.72 | 88.21 | ND | 0.43 | 0.65 | 0.5 | Mammalian | Isoform 2 is predominantly expressed in the testis but is also present at lower levels in heart, ovary, small intestine, liver, kidney, pancreas and skeletal muscle. Isoform 1 is only seen in the testis, at lower levels than isoform 2. Highly expressed in different erythroid and lymphoid cell lines, with isoform 2 being far more abundant than isoform 1. {ECO:0000269|PubMed:10390541, ECO:0000269|PubMed:11509566, ECO:0000269|PubMed:20708644}. | Kinase | Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation. {ECO:0000269|PubMed:10049757, ECO:0000269|PubMed:10390541, ECO:0000269|PubMed:11509566, ECO:0000269|PubMed:12134018, ECO:0000269|PubMed:14555757, ECO:0000269|PubMed:15034300, ECO:0000269|PubMed:16122776, ECO:0000269|PubMed:16209947, ECO:0000269|PubMed:18155240, ECO:0000269|PubMed:18687337, ECO:0000269|PubMed:19240134, ECO:0000269|PubMed:19477182, ECO:0000269|PubMed:19886675, ECO:0000269|PubMed:20708644, ECO:0000269|PubMed:8208298, ECO:0000269|PubMed:9237760}. | 15.11 | ||||
| dfaSRPK2 | SRSF protein kinase 2 | 3 | 67 | 99.43 | 99.39 | ND | 0.37 | 0.88 | 0.4 | Mammalian | Highly expressed in brain, moderately expressed in heart and skeletal muscle and at low levels in lung, liver, and kidney. {ECO:0000269|PubMed:9472028}. | Kinase | Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Promotes neuronal apoptosis by up-regulating cyclin-D1 (CCND1) expression. This is done by the phosphorylation of SRSF2, leading to the suppression of p53/TP53 phosphorylation thereby relieving the repressive effect of p53/TP53 on cyclin-D1 (CCND1) expression. Phosphorylates ACIN1, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not cyclin A2 up- regulation. Plays an essential role in spliceosomal B complex formation via the phosphorylation of DDX23/PRP28. Can mediate hepatitis B virus (HBV) core protein phosphorylation. Plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. {ECO:0000269|PubMed:12134018, ECO:0000269|PubMed:16122776, ECO:0000269|PubMed:18425142, ECO:0000269|PubMed:18559500, ECO:0000269|PubMed:19592491, ECO:0000269|PubMed:21056976, ECO:0000269|PubMed:21157427, ECO:0000269|PubMed:9472028}. | 15.11 | ||||
| dfaSSR1 | Somatostatin receptor type 1 | 2 | 196 | 97.93 | 98.27 | ND | 0.57 | 0.66 | 0.8 | Mammalian | Fetal kidney, fetal liver, and adult pancreas, brain, lung, jejunum and stomach. | Family A G protein-coupled receptor | Cushing's disease
Neuroblastoma Refractory Renal Cell Carcinoma | Receptor for somatostatin with higher affinity for somatostatin-14 than -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and Na(+)/H(+) exchanger via pertussis toxin insensitive G proteins. | Somatostatin receptor type 1 : Octreotide, Pasireotide | 16.04 | ||
| dfaSSR2 | Somatostatin receptor type 2 | 1 | 273 | 96.09 | 95.54 | ND | 0.80 | 0.90 | 0.6 | Mammalian | Expressed in both pancreatic alpha- and beta- cells (at protein level). Expressed at higher levels in the pancreas than other somatostatin receptors. Also expressed in the cerebrum and kidney and, in lesser amounts, in the jejunum, colon and liver. In the developing nervous system, expressed in the cortex where it is located in the preplate at early stages and is enriched in the outer part of the germinal zone at later stages. In the cerebellum, expressed in the deep part of the external granular layer at gestational week 19. This pattern persists until birth but disappears at adulthood. {ECO:0000269|PubMed:19434240, ECO:0000269|PubMed:22932785}. | Family A G protein-coupled receptor | Cancer, unspecified
Cushing's disease Neuroblastoma | Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization. {ECO:0000269|PubMed:15231824, ECO:0000269|PubMed:18653781, ECO:0000269|PubMed:19434240, ECO:0000269|PubMed:22495673, ECO:0000269|PubMed:22932785}. | Somatostatin receptor type 2 : Pasireotide Somatostatin receptor type 2 agonist: Lanreotide Somatostatin receptor type 2 binder: Octreotide Somatostatin receptor type 2 inducer: Vapreotide | 16.04 | ||
| dfaSSR3 | Somatostatin receptor type 3 | 3 | 213 | 98.68 | 98.84 | ND | 0.70 | 0.76 | 0.7 | Mammalian | Brain, pituitary and pancreas. {ECO:0000269|PubMed:1337145}. | Family A G protein-coupled receptor | Cushing's disease | Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. {ECO:0000269|PubMed:1337145}. | 16.04 | |||
| dfaSSR4 | Somatostatin receptor type 4 | 3 | 148 | 98.43 | 99.14 | ND | 0.86 | 0.84 | 0.5 | Mammalian | Specifically expressed in fetal and adult brain, lung tissue, stomach, and in lesser quantities in the kidney, pituitary and adrenals. | Family A G protein-coupled receptor | Solid tumors | Receptor for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. It is functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade. Mediates antiproliferative action of somatostatin in tumor cells. | 16.04 | |||
| dfaSSR5 | Somatostatin receptor type 5 | 2 | 172 | 98.69 | 99.56 | ND | 0.80 | 0.85 | 0.5 | Mammalian | Adult pituitary gland, heart, small intestine, adrenal gland, cerebellum and fetal hypothalamus. No expression in fetal or adult kidney, liver, pancreas, uterus, spleen, lung, thyroid or ovary. {ECO:0000269|PubMed:12072395, ECO:0000269|PubMed:7908405, ECO:0000269|PubMed:8078491}. | Family A G protein-coupled receptor | Cushing's disease | Receptor for somatostatin 28 and to a lesser extent for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. Increases cell growth inhibition activity of SSTR2 following heterodimerization. {ECO:0000269|PubMed:12072395, ECO:0000269|PubMed:7908405, ECO:0000269|PubMed:8078491, ECO:0000269|PubMed:8373420}. | Somatostatin receptor type 5 : Octreotide, Pasireotide Somatostatin receptor type 5 agonist: Lanreotide, Vapreotide | 16.04 | ||
| dfaST14 | Suppressor of tumorigenicity 14 protein | 1 | 145 | 99.93 | 98.56 | ND | 0.47 | 0.50 | 0.5 | Mammalian | Protease | Ichthyosis, congenital, autosomal recessive 11 (ARCI11) [MIM:602400]: A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. {ECO:0000269|PubMed:17273967, ECO:0000269|PubMed:18843291}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Degrades extracellular matrix. Proposed to play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Involved in the terminal differentiation of keratinocytes through prostasin (PRSS8) activation and filaggrin (FLG) processing. {ECO:0000269|PubMed:18843291}. | 15.11 | ||||
| dfaST17A | Serine/threonine-protein kinase 17A | 3 | 275 | 88.43 | 91.84 | ND | 0.73 | 0.71 | 0.4 | Mammalian | Highly expressed in placenta. Lower levels in heart, lung, skeletal muscle, kidney and pancreas. {ECO:0000269|PubMed:9786912}. | Kinase | Acts as a positive regulator of apoptosis. Also acts as a regulator of cellular reactive oxygen species. {ECO:0000269|PubMed:21489989, ECO:0000269|PubMed:9786912}. | 16.04 | ||||
| dfaST17B | Serine/threonine-protein kinase 17B | 3 | 67 | 85.54 | 94.15 | ND | 0.91 | 0.93 | 0.3 | Mammalian | Highly expressed in placenta, lung, pancreas. Lower levels in heart, brain, liver, skeletal muscle and kidney. {ECO:0000269|PubMed:9786912}. | Kinase | Phosphorylates myosin light chains (By similarity). Acts as a positive regulator of apoptosis. {ECO:0000250, ECO:0000269|PubMed:9786912}. | 15.11 | ||||
| dfaST38L | Serine/threonine-protein kinase 38-like | 2 | 64 | 96.98 | 91.74 | ND | 0.28 | 0.84 | 0.3 | Mammalian | Ubiquitously expressed with highest levels observed in the thymus. {ECO:0000269|PubMed:15067004}. | Kinase | Involved in the regulation of structural processes in differentiating and mature neuronal cells. {ECO:0000250, ECO:0000269|PubMed:15037617, ECO:0000269|PubMed:15067004}. | 16.04 | ||||
| dfaSTAT3 | Signal transducer and activator of transcription 3 {ECO:0000312|HGNC:HGNC:11364} | 7 | 324 | 85.65 | 84.92 | ND | 0.16 | 0.57 | 0.8 | Mammalian | Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. | Transcription factor | Hyperimmunoglobulin E recurrent infection syndrome, autosomal dominant (AD-HIES) [MIM:147060]: A rare disorder of immunity and connective tissue characterized by immunodeficiency, chronic eczema, recurrent Staphylococcal infections, increased serum IgE, eosinophilia, distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures. {ECO:0000269|PubMed:17676033, ECO:0000269|PubMed:17881745, ECO:0000269|PubMed:23342295, ECO:0000269|PubMed:26293184}. Note=The disease is caused by mutations affecting the gene represented in this entry. Autoimmune disease, multisystem, infantile-onset (ADMIO) [MIM:615952]: A disorder characterized by early childhood onset of a spectrum of autoimmune manifestations affecting multiple organs, including insulin-dependent diabetes mellitus and autoimmune enteropathy or celiac disease. Other features include short stature, non-specific dermatitis, hypothyroidism, autoimmune arthritis, and delayed puberty. {ECO:0000269|PubMed:25038750}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors. Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:17344214). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Binds to the interleukin-6 (IL-6)- responsive elements identified in the promoters of various acute- phase protein genes. Activated by IL31 through IL31RA. Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity. {ECO:0000250|UniProtKB:P42227, ECO:0000269|PubMed:10688651, ECO:0000269|PubMed:12359225, ECO:0000269|PubMed:12873986, ECO:0000269|PubMed:15194700, ECO:0000269|PubMed:17344214, ECO:0000269|PubMed:18242580, ECO:0000269|PubMed:23084476}. | 16.04 | |||
| dfaSTAT6 | Signal transducer and activator of transcription 6 | 1 | 93 | 90.53 | 93.84 | ND | 0.45 | 0.70 | 0.7 | Mammalian | Carries out a dual function: signal transduction and activation of transcription. Involved in IL4/interleukin-4- and IL3/interleukin-3-mediated signaling. {ECO:0000269|PubMed:17210636}. | 16.04 | ||||||
| dfaSTF1 | Steroidogenic factor 1 | 6 | 194 | 88.38 | 82.45 | ND | 0.47 | 0.69 | 0.4 | Mammalian | Nuclear receptor | 46,XY sex reversal 3 (SRXY3) [MIM:612965]: A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. {ECO:0000269|PubMed:10369247, ECO:0000269|PubMed:11932325, ECO:0000269|PubMed:17200175, ECO:0000269|PubMed:17694559}. Note=The disease is caused by mutations affecting the gene represented in this entry. Adrenocortical insufficiency, without ovarian defect (ACIWOD) [MIM:184757]: A disorder that is characterized by severe 'slackness,' muscular hypotonia. There is decreased sodium, increased potassium and elevated ACTH. {ECO:0000269|PubMed:11038323}. Note=The disease is caused by mutations affecting the gene represented in this entry. Premature ovarian failure 7 (POF7) [MIM:612964]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:19246354}. Note=The disease is caused by mutations affecting the gene represented in this entry. Spermatogenic failure 8 (SPGF8) [MIM:613957]: An infertility disorder characterized by spermatogenesis failure and severe oligozoospermia. {ECO:0000269|PubMed:20887963}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transcriptional activator. Seems to be essential for sexual differentiation and formation of the primary steroidogenic tissues. Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1. The SFPQ-NONO- NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional avtivity. Binds phosphatidylcholine (By similarity). Binds phospholipids with a phosphatidylinositol (PI) headgroup, in particular PI(3,4)P2 and PI(3,4,5)P3. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. {ECO:0000250, ECO:0000269|PubMed:17210646}. | 16.04 | ||||
| dfaSTK10 | Serine/threonine-protein kinase 10 | 6 | 66 | 92.19 | 94.09 | ND | 0.73 | 0.82 | 0.4 | Mammalian | Highly expressed in rapidly proliferating tissues (spleen, placenta, and peripheral blood leukocytes). Also expressed in brain, heart, skeletal muscle, colon, thymus, kidney, liver, small intestine and lung. {ECO:0000269|PubMed:12639966}. | Kinase | Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:16175573}. Note=The disease may be caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase involved in regulation of lymphocyte migration. Phosphorylates MSN, and possibly PLK1. Involved in regulation of lymphocyte migration by mediating phosphorylation of ERM proteins such as MSN. Acts as a negative regulator of MAP3K1/MEKK1. May also act as a cell cycle regulator by acting as a polo kinase kinase: mediates phosphorylation of PLK1 in vitro; however such data require additional evidences in vivo. {ECO:0000269|PubMed:11903060, ECO:0000269|PubMed:12639966, ECO:0000269|PubMed:19255442}. | 15.11 | |||
| dfaSTK11 | Serine/threonine-protein kinase STK11 | 5 | 67 | 99.93 | 95.75 | ND | 0.59 | 0.86 | 0.2 | Mammalian | Ubiquitously expressed. Strongest expression in testis and fetal liver. | Kinase | Peutz-Jeghers syndrome (PJS) [MIM:175200]: An autosomal dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer. {ECO:0000269|PubMed:10408777, ECO:0000269|PubMed:12372054, ECO:0000269|PubMed:21411391, ECO:0000269|PubMed:9425897, ECO:0000269|PubMed:9428765, ECO:0000269|PubMed:9760200, ECO:0000269|PubMed:9837816}. Note=The disease is caused by mutations affecting the gene represented in this entry. Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:9605748}. Note=The gene represented in this entry may be involved in disease pathogenesis. Note=Defects in STK11 are associated with some sporadic cancers, especially lung cancers. Frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Defects promote lung cancerigenesis process, especially lung cancer progression and metastasis. Confers lung adenocarcinoma the ability to trans- differentiate into squamous cell carcinoma. Also able to promotes lung cancer metastasis, via both cancer-cell autonomous and non- cancer-cell autonomous mechanisms. | Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, thus promoting their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non- AMPK family proteins such as STRADA, PTEN and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2 and thereby regulates processes including: inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, and B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neuron polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1. Also acts as a mediator of p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to the mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways. In vein endothelial cells, inhibits PI3K/Akt signaling activity and thus induces apoptosis in response to the oxidant peroxynitrite (in vitro). Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with NUAK1, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair (PubMed:25329316). {ECO:0000269|PubMed:11430832, ECO:0000269|PubMed:12805220, ECO:0000269|PubMed:14517248, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15016379, ECO:0000269|PubMed:15733851, ECO:0000269|PubMed:15987703, ECO:0000269|PubMed:17108107, ECO:0000269|PubMed:18321849, ECO:0000269|PubMed:21317932, ECO:0000269|PubMed:25329316}. Isoform 2: Has a role in spermiogenesis. {ECO:0000250}. | 16.04 | |||
| dfaSTK16 | Serine/threonine-protein kinase 16 | 2 | 68 | 88.82 | 94.10 | ND | 0.68 | 0.91 | 0.4 | Mammalian | Ubiquitously expressed at very low levels. {ECO:0000269|PubMed:10364453}. | Kinase | Membrane-associated protein kinase that phosphorylates on serine and threonine residues. In vitro substrates include DRG1, ENO1 and EIF4EBP1. Also autophosphorylates. May be involved in secretory vesicle trafficking or intracellular signaling. May have a role in regulating stromal-epithelial interactions that occur during ductal morphogenesis in the mammary gland. May be involved in TGF-beta signaling. Able to autophosphorylate on Tyr residue; it is however unclear whether it has tyrosine-protein kinase toward other proteins. {ECO:0000269|PubMed:10364453}. | 15.11 | ||||
| dfaSTK24 | Serine/threonine-protein kinase 24 | 7 | 64 | 99.17 | 98.65 | ND | 0.44 | 0.75 | 0.4 | Mammalian | Isoform A is ubiquitous. Isoform B is expressed in brain with high expression in hippocampus and cerebral cortex. | Kinase | Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress- induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase- independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve. {ECO:0000269|PubMed:16314523, ECO:0000269|PubMed:17046825, ECO:0000269|PubMed:19604147, ECO:0000269|PubMed:19782762, ECO:0000269|PubMed:19855390}. | 15.11 | ||||
| dfaSTK25 | Serine/threonine-protein kinase 25 | 4 | 64 | 84.09 | 87.72 | ND | 0.58 | 0.69 | 0.3 | Mammalian | Ubiquitously expressed. Highest levels are found in testis, large intestine, brain and stomach followed by heart and lung. | Kinase | Oxidant stress-activated serine/threonine kinase that may play a role in the response to environmental stress. Targets to the Golgi apparatus where it appears to regulate protein transport events, cell adhesion, and polarity complexes important for cell migration. {ECO:0000269|PubMed:15037601}. | 15.11 | ||||
| dfaSTK26 | Serine/threonine-protein kinase 26 {ECO:0000305} | 4 | 83 | 98.28 | 92.31 | ND | 0.43 | 0.91 | 0.8 | Mammalian | Kinase | Mediator of cell growth. Modulates apoptosis. {ECO:0000269|PubMed:11641781, ECO:0000269|PubMed:17360971}. | 15.11 | |||||
| dfaSTK3 | Serine/threonine-protein kinase 3 | 6 | 354 | 88.02 | 88.71 | ND | 0.51 | 0.69 | 0.5 | Mammalian | Expressed at high levels in adult kidney, skeletal and placenta tissues and at very low levels in adult heart, lung and brain tissues. {ECO:0000269|PubMed:8566796}. | Kinase | Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38. {ECO:0000250, ECO:0000269|PubMed:15688006, ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:18328708, ECO:0000269|PubMed:18362890, ECO:0000269|PubMed:19525978, ECO:0000269|PubMed:20212043, ECO:0000269|PubMed:21076410, ECO:0000269|PubMed:21104395, ECO:0000269|PubMed:8566796, ECO:0000269|PubMed:8816758}. | 16.04 | ||||
| dfaSTK33 | Serine/threonine-protein kinase 33 | 4 | 92 | 87.01 | 93.80 | ND | 0.55 | 0.82 | 0.5 | Mammalian | Highly expressed in testis, fetal lung and heart, followed by pituitary gland, kidney, interventricular septum, pancreas, heart, trachea, thyroid gland and uterus. Weak hybridization signals were observed in the following tissues: amygdala, aorta, esophagus, colon ascending, colon transverse, skeletal muscle, spleen, peripheral blood leukocyte, lymph node, bone marrow, placenta, prostate, liver, salivary gland, mammary gland, some tumor cell lines, fetal brain, fetal liver, fetal spleen and fetal thymus. No signal at all was detectable in RNA from tissues of the nervous system. {ECO:0000269|PubMed:11738831, ECO:0000269|PubMed:16176263}. | Kinase | Serine/threonine protein kinase which phosphorylates VIME. May play a specific role in the dynamic behavior of the intermediate filament cytoskeleton by phosphorylation of VIME (By similarity). Not essential for the survival of KRAS-dependent AML cell lines. {ECO:0000250, ECO:0000269|PubMed:21742770}. | 16.04 | ||||
| dfaSTK35 | Serine/threonine-protein kinase 35 | 5 | 59 | 84.72 | 85.81 | ND | 0.90 | 0.81 | 0.2 | Mammalian | Expressed in testis. | Kinase | 16.04 | |||||
| dfaSTK39 | STE20/SPS1-related proline-alanine-rich protein kinase | 2 | 59 | 99.91 | 96.73 | ND | 0.42 | 0.92 | 0.6 | Mammalian | Predominantly expressed in brain and pancreas followed by heart, lung, kidney, skeletal muscle, liver, placenta and testis. | Kinase | May act as a mediator of stress-activated signals. Mediates the inhibiton of SLC4A4, SLC26A6 as well as CFTR activities by the WNK scaffolds, probably through phosphorylation. {ECO:0000250|UniProtKB:Q9Z1W9}. | 16.04 | ||||
| dfaSTK4 | Serine/threonine-protein kinase 4 | 3 | 68 | 99.17 | 97.19 | ND | 0.88 | 0.93 | 0.2 | Mammalian | Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Ubiquitously expressed. {ECO:0000269|PubMed:17932490}. | Kinase | T-cell immunodeficiency, recurrent infections, and autoimmunity with or without cardiac malformations (TIIAC) [MIM:614868]: A primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T-cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect. {ECO:0000269|PubMed:22294732}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation (By similarity). Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes. {ECO:0000250, ECO:0000269|PubMed:11278283, ECO:0000269|PubMed:11517310, ECO:0000269|PubMed:12757711, ECO:0000269|PubMed:15109305, ECO:0000269|PubMed:16510573, ECO:0000269|PubMed:16751106, ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:17932490, ECO:0000269|PubMed:18328708, ECO:0000269|PubMed:18986304, ECO:0000269|PubMed:19525978, ECO:0000269|PubMed:21212262, ECO:0000269|PubMed:21245099, ECO:0000269|PubMed:21512132, ECO:0000269|PubMed:8702870, ECO:0000269|PubMed:8816758}. | 16.04 | |||
| dfaSTS | Steryl-sulfatase | 6 | 281 | 96.99 | 96.18 | ND | 0.71 | 0.70 | 0.7 | Mammalian | Enzyme | Ichthyosis, X-linked (IXL) [MIM:308100]: A keratinization disorder manifesting with mild erythroderma and generalized exfoliation of the skin within a few weeks after birth. Affected boys later develop large, polygonal, dark brown scales, especially on the neck, extremities, trunk, and buttocks. {ECO:0000269|PubMed:10679952, ECO:0000269|PubMed:10844566, ECO:0000269|PubMed:1539590, ECO:0000269|PubMed:9252398}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Conversion of sulfated steroid precursors to estrogens during pregnancy. | Steryl-sulfatase inhibitor: Norelgestromin | 16.04 | |||
| dfaSUIS | Sucrase-isomaltase, intestinal | 3 | 120 | 94.98 | 99.10 | ND | 0.54 | 0.62 | 0.7 | Mammalian | Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon. {ECO:0000269|PubMed:1677636}. | Enzyme | Congenital sucrase-isomaltase deficiency (CSID) [MIM:222900]: Autosomal recessive intestinal disorder that is clinically characterized by fermentative diarrhea, abdominal pain, and cramps upon ingestion of sugar. The symptoms are the consequence of absent or drastically reduced enzymatic activities of sucrase and isomaltase. The prevalence of CSID is 0.02 % in individuals of European descent and appears to be much higher in Greenland, Alaskan, and Canadian native people. CSID arises due to post-translational perturbations in the intracellular transport, polarized sorting, aberrant processing, and defective function of SI. {ECO:0000269|PubMed:10903344, ECO:0000269|PubMed:11340066, ECO:0000269|PubMed:14724820, ECO:0000269|PubMed:16329100, ECO:0000269|PubMed:8609217}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays an important role in the final stage of carbohydrate digestion. Isomaltase activity is specific for both alpha-1,4- and alpha-1,6-oligosaccharides. {ECO:0000269|PubMed:20356844}. | Sucrase-isomaltase, intestinal inhibitor: Acarbose, Scopolamine | 15.11 | ||
| dfaSYK | Lysine--tRNA ligase | 4 | 111 | 95.05 | 93.70 | ND | 0.66 | 0.59 | 0.6 | Mammalian | Enzyme | Charcot-Marie-Tooth disease, recessive, intermediate type, B (CMTRIB) [MIM:613641]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:20920668}. Note=The disease is caused by mutations affecting the gene represented in this entry. Deafness, autosomal recessive, 89 (DFNB89) [MIM:613916]: A form of non-syndromic deafness characterized by bilateral, prelingual, moderate to severe hearing loss affecting all frequencies. {ECO:0000269|PubMed:23768514}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages. Catalyzes the synthesis of diadenosine oligophosphate (Ap4A), a signaling molecule involved in the activation of MITF transcriptional activity. Interacts with HIV-1 virus GAG protein, facilitating the selective packaging of tRNA(3)(Lys), the primer for reverse transcription initiation. {ECO:0000269|PubMed:15851690, ECO:0000269|PubMed:5338216}. | 15.11 | ||||
| dfaSYMC | Methionine--tRNA ligase, cytoplasmic | 4 | 70 | 99.21 | 98.45 | ND | 0.81 | 0.80 | 0.4 | Mammalian | Enzyme | Interstitial lung and liver disease (ILLD) [MIM:615486]: An autosomal recessive, life-threatening disorder characterized by respiratory insufficiency and progressive liver disease with onset in infancy or early childhood. Clinical features include failure to thrive, hypotonia, intermittent lactic acidosis, aminoaciduria, hypothyroidism, interstitial lung disease, pulmonary alveolar proteinosis, anemia, and liver canalicular cholestasis, steatosis, and iron deposition. {ECO:0000269|PubMed:24103465, ECO:0000269|PubMed:25913036}. Note=The disease is caused by mutations affecting the gene represented in this entry. Charcot-Marie-Tooth disease 2U (CMT2U) [MIM:616280]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2U is a slowly progressive, autosomal dominant form characterized by late-adult onset. {ECO:0000269|PubMed:23729695, ECO:0000269|PubMed:24354524}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Methionine--tRNA ligase, cytoplasmic substrate: L-Methionine | 15.11 | ||||
| dfaT23O | Tryptophan 2,3-dioxygenase {ECO:0000255|HAMAP-Rule:MF_03020} | 3 | 72 | 99.11 | 94.28 | ND | 0.33 | 0.28 | 1.2 | Mammalian | Enzyme | Incorporates oxygen into the indole moiety of tryptophan. Has a broad specificity towards tryptamine and derivatives including D- and L-tryptophan, 5-hydroxytryptophan and serotonin (By similarity). {ECO:0000250}. | Tryptophan 2,3-dioxygenase {ECO:0000255|HAMAP-Rule:MF_03020} inhibitor: Nalidixic Acid, Tolmetin Tryptophan 2,3-dioxygenase {ECO:0000255|HAMAP-Rule:MF_03020} substrate: L-Tryptophan | 16.04 | ||||
| dfaTA2R | Thromboxane A2 receptor | 5 | 941 | 95.16 | 98.06 | ND | 0.73 | 0.73 | 0.6 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Bleeding disorder, platelet-type 13 (BDPLT13) [MIM:614009]: A disorder characterized by reduced platelet aggregation and a tendency to mild mucocutaneous bleeding. {ECO:0000269|PubMed:7929844}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C. Isoform 1 activates adenylyl cyclase. Isoform 2 inhibits adenylyl cyclase. {ECO:0000269|PubMed:8613548}. | Thromboxane A2 receptor antagonist: Ridogrel | 16.04 | ||
| dfaTAAR1 | Trace amine-associated receptor 1 | 4 | 531 | 84.49 | 81.92 | ND | 0.62 | 0.66 | 0.4 | Mammalian | Detected in low levels in discrete regions within the central nervous system and in several peripheral tissues. Moderately expressed in stomach. Low levels in amygdala, kidney, and lung, and small intestine. Trace amounts in cerebellum, dorsal root ganglia, hippocampus, hypothalamus, liver, medulla, pancreas, pituitary, pontine reticular formation, prostate, skeletal muscle and spleen. | Family A G protein-coupled receptor | Receptor for trace amines, including beta- phenylethylamine (b-PEA), p-tyramine (p-TYR), octopamine and tryptamine, with highest affinity for b-PEA and p-TYR. Unresponsive to classical biogenic amines, such as epinephrine and histamine and only partially activated by dopamine and serotonine. Trace amines are biogenic amines present in very low levels in mammalian tissues. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood. The signal transduced by this receptor is mediated by the G(s)-class of G-proteins which activate adenylate cyclase. {ECO:0000269|PubMed:15718104}. | Trace amine-associated receptor 1 agonist: Amphetamine, Dextroamphetamine, Methamphetamine, Propylhexedrine | 16.04 | |||
| dfaTAOK1 | Serine/threonine-protein kinase TAO1 | 4 | 343 | 88.70 | 91.75 | ND | 0.50 | 0.65 | 0.4 | Mammalian | Highly expressed in the testis, and to a lower extent also expressed in brain, placenta, colon and skeletal muscle. {ECO:0000269|PubMed:13679851, ECO:0000269|PubMed:9786855}. | Kinase | Serine/threonine-protein kinase involved in various processes such as p38/MAPK14 stress-activated MAPK cascade, DNA damage response and regulation of cytoskeleton stability. Phosphorylates MAP2K3, MAP2K6 and MARK2. Acts as an activator of the p38/MAPK14 stress-activated MAPK cascade by mediating phosphorylation and subsequent activation of the upstream MAP2K3 and MAP2K6 kinases. Involved in G-protein coupled receptor signaling to p38/MAPK14. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of MAP2K3 and MAP2K6. Acts as a regulator of cytoskeleton stability by phosphorylating 'Thr-208' of MARK2, leading to activate MARK2 kinase activity and subsequent phosphorylation and detachment of MAPT/TAU from microtubules. Also acts as a regulator of apoptosis: regulates apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation via activation of the MAPK8/JNK cascade. {ECO:0000269|PubMed:12665513, ECO:0000269|PubMed:13679851, ECO:0000269|PubMed:16407310, ECO:0000269|PubMed:17396146, ECO:0000269|PubMed:17900936}. | 16.04 | ||||
| dfaTAOK2 | Serine/threonine-protein kinase TAO2 | 2 | 60 | 89.00 | 89.78 | ND | 0.75 | 0.94 | 0.4 | Mammalian | Ubiquitously expressed, with a higher level of expression in testis and brain. {ECO:0000269|PubMed:10660600, ECO:0000269|PubMed:13679851}. | Kinase | Serine/threonine-protein kinase involved in different processes such as membrane blebbing and apoptotic bodies formation DNA damage response and MAPK14/p38 MAPK stress-activated MAPK cascade. Phosphorylates itself, MBP, activated MAPK8, MAP2K3, MAP2K6 and tubulins. Activates the MAPK14/p38 MAPK signaling pathway through the specific activation and phosphorylation of the upstream MAP2K3 and MAP2K6 kinases. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of upstream MAP2K3 and MAP2K6 kinases. Isoform 1, but not isoform 2, plays a role in apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation. This function, which requires the activation of MAPK8/JNK and nuclear localization of C-terminally truncated isoform 1, may be linked to the mitochondrial CASP9-associated death pathway. Isoform 1 binds to microtubules and affects their organization and stability independently of its kinase activity. Prevents MAP3K7-mediated activation of CHUK, and thus NF-kappa-B activation, but not that of MAPK8/JNK. May play a role in the osmotic stress-MAPK8 pathway. Isoform 2, but not isoform 1, is required for PCDH8 endocytosis. Following homophilic interactions between PCDH8 extracellular domains, isoform 2 phosphorylates and activates MAPK14/p38 MAPK which in turn phosphorylates isoform 2. This process leads to PCDH8 endocytosis and CDH2 cointernalization. Both isoforms are involved in MAPK14 phosphorylation. {ECO:0000269|PubMed:10660600, ECO:0000269|PubMed:11279118, ECO:0000269|PubMed:12639963, ECO:0000269|PubMed:12665513, ECO:0000269|PubMed:13679851, ECO:0000269|PubMed:16893890, ECO:0000269|PubMed:17158878, ECO:0000269|PubMed:17396146}. | 16.04 | ||||
| dfaTBA1A | Tubulin alpha-1A chain | 2 | 205 | 92.11 | 90.72 | ND | 0.62 | 0.85 | 0.4 | Mammalian | Expressed at a high level in fetal brain. {ECO:0000269|PubMed:17584854}. | Structural protein | Lissencephaly 3 (LIS3) [MIM:611603]: A classic type lissencephaly associated with psychomotor retardation and seizures. Features include agyria or pachygyria or laminar heterotopia, severe mental retardation, motor delay, variable presence of seizures, and abnormalities of corpus callosum, hippocampus, cerebellar vermis and brainstem. {ECO:0000269|PubMed:17584854}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. | Tubulin alpha-1A chain adduct: Vinblastine Tubulin alpha-1A chain inhibitor: Albendazole, Mebendazole | 16.04 | ||
| dfaTBB1 | Tubulin beta-1 chain | 2 | 65 | 99.49 | 97.21 | ND | 0.48 | 0.36 | 0.4 | Mammalian | Hematopoietic cell-specific. Major isotype in leukocytes, where it represents 50% of all beta-tubulins. {ECO:0000269|PubMed:20191564}. | Structural protein | Macrothrombocytopenia, autosomal dominant, TUBB1-related (MAD-TUBB1) [MIM:613112]: A congenital blood disorder characterized by increased platelet size and decreased number of circulating platelets. {ECO:0000269|PubMed:18849486}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity). {ECO:0000250}. | Tubulin beta-1 chain : Docetaxel Tubulin beta-1 chain binder: Cabazitaxel Tubulin beta-1 chain inhibitor: Colchicine, Paclitaxel, Vindesine | 16.04 | ||
| dfaTBB2B | Tubulin beta-2B chain | 3 | 192 | 96.97 | 93.87 | ND | 0.54 | 0.66 | 0.3 | Mammalian | High expression in brain. {ECO:0000269|PubMed:20191564}. | Structural protein | Polymicrogyria, symmetric or asymmetric (PMGYSA) [MIM:610031]: A malformation of the cortex in which the brain surface is irregular and characterized by an excessive number of small gyri with abnormal lamination. Polymicrogyria is a heterogeneous disorder, considered to be the result of postmigratory abnormal cortical organization. {ECO:0000269|PubMed:19465910}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity). TUBB2B is implicated in neuronal migration. {ECO:0000250, ECO:0000269|PubMed:19465910}. | 16.04 | |||
| dfaTBK1 | Serine/threonine-protein kinase TBK1 | 4 | 226 | 95.14 | 93.24 | ND | 0.58 | 0.72 | 0.6 | Mammalian | Ubiquitous with higher expression in testis. Expressed in the ganglion cells, nerve fiber layer and microvasculature of the retina. {ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:21447600}. | Kinase | Glaucoma 1, open angle, P (GLC1P) [MIM:177700]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1P is characterized by early onset, thin central corneas and low intraocular pressure. {ECO:0000269|PubMed:21447600, ECO:0000269|PubMed:22306015}. Note=The disease may be caused by mutations affecting the gene represented in this entry. A copy number variation on chromosome 12q14 consisting of a 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been found in individuals affected by glaucoma. TBK1 is the most likely candidate for the disorder (PubMed:21447600). {ECO:0000269|PubMed:21447600}. Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (FTDALS4) [MIM:616439]: A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. {ECO:0000269|PubMed:25803835, ECO:0000269|PubMed:25943890}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser- 177', thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates and activates AKT1. Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates Borna disease virus (BDV) P protein. {ECO:0000269|PubMed:10581243, ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:11839743, ECO:0000269|PubMed:12692549, ECO:0000269|PubMed:12702806, ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:15485837, ECO:0000269|PubMed:15489227, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:21931631, ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23453972, ECO:0000269|PubMed:23746807}. | 15.11 | |||
| dfaTERA | Transitional endoplasmic reticulum ATPase | 2 | 117 | 99.85 | 99.93 | ND | 0.77 | 0.70 | 0.3 | Mammalian | Primary active transporter | Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]: An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance. {ECO:0000269|PubMed:15034582, ECO:0000269|PubMed:15732117, ECO:0000269|PubMed:16247064}. Note=The disease is caused by mutations affecting the gene represented in this entry. Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia (ALS14) [MIM:613954]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS14 may develop frontotemporal dementia. {ECO:0000269|PubMed:21145000}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1L, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1L-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage. Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation. {ECO:0000250|UniProtKB:P46462, ECO:0000269|PubMed:15456787, ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:21118995, ECO:0000269|PubMed:22020440, ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22607976, ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607}. | 16.04 | ||||
| dfaTERT | Telomerase reverse transcriptase | 4 | 397 | 96.24 | 90.21 | ND | 0.68 | 0.67 | 0.5 | Mammalian | Expressed at a high level in thymocyte subpopulations, at an intermediate level in tonsil T-lymphocytes, and at a low to undetectable level in peripheral blood T- lymphocytes. {ECO:0000269|PubMed:8676067, ECO:0000269|PubMed:9389643}. | Enzyme | Note=Activation of telomerase has been implicated in cell immortalization and cancer cell pathogenesis. Aplastic anemia (AA) [MIM:609135]: A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements. It is characterized by peripheral pancytopenia and marrow hypoplasia. {ECO:0000269|PubMed:15885610, ECO:0000269|PubMed:16627250, ECO:0000269|PubMed:16990594, ECO:0000269|PubMed:19760749}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Genetic variations in TERT are associated with coronary artery disease (CAD). Dyskeratosis congenita, autosomal dominant, 2 (DKCA2) [MIM:613989]: A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. {ECO:0000269|PubMed:15885610, ECO:0000269|PubMed:16247010}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pulmonary fibrosis, and/or bone marrow failure, telomere- related, 1 (PFBMFT1) [MIM:614742]: A disease associated with shortened telomeres. Pulmonary fibrosis is the most common manifestation. Other manifestations include aplastic anemia due to bone marrow failure, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome and acute myeloid leukemia. Phenotype, age at onset, and severity are determined by telomere length. {ECO:0000269|PubMed:15814878, ECO:0000269|PubMed:17460043, ECO:0000269|PubMed:21436073, ECO:0000269|PubMed:21483807, ECO:0000269|PubMed:22512499}. Note=The disease is caused by mutations affecting the gene represented in this entry. Dyskeratosis congenita, autosomal recessive, 4 (DKCB4) [MIM:613989]: A severe form of dyskeratosis congenita, a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. {ECO:0000269|PubMed:16332973, ECO:0000269|PubMed:17785587, ECO:0000269|PubMed:18042801}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pulmonary fibrosis, idiopathic (IPF) [MIM:178500]: A lung disease characterized by shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees of inflammation and fibrosis on biopsy. In some cases, the disorder can be rapidly progressive and characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Melanoma, cutaneous malignant 9 (CMM9) [MIM:615134]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:23348503}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA- dependent extension of 3'-chromosomal termini with the 6- nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis. {ECO:0000269|PubMed:14963003, ECO:0000269|PubMed:15082768, ECO:0000269|PubMed:15857955, ECO:0000269|PubMed:17026956, ECO:0000269|PubMed:17264120, ECO:0000269|PubMed:17296728, ECO:0000269|PubMed:17548608, ECO:0000269|PubMed:19188162, ECO:0000269|PubMed:19567472, ECO:0000269|PubMed:19571879, ECO:0000269|PubMed:19777057, ECO:0000269|PubMed:9389643}. | Telomerase reverse transcriptase inhibitor: Zidovudine | 16.04 | ||
| dfaTF | Tissue factor | 3 | 74 | 98.06 | 93.85 | ND | 0.86 | 0.85 | 0.6 | Mammalian | Lung, placenta and pancreas. {ECO:0000269|PubMed:12652293}. | Membrane receptor | Atherosclerosis
Coronary syndromes Disseminated intravascular coagulation Gliomas Over-expression of TF Sepsis Thrombotic disease | Initiates blood coagulation by forming a complex with circulating factor VII or VIIa. The [TF:VIIa] complex activates factors IX or X by specific limited protolysis. TF plays a role in normal hemostasis by initiating the cell-surface assembly and propagation of the coagulation protease cascade. {ECO:0000269|PubMed:12652293}. | 16.04 | |||
| dfaTF65 | Transcription factor p65 | 1 | 88 | 93.99 | 91.18 | ND | 0.80 | 0.73 | 0.2 | Mammalian | Transcription factor | Note=A chromosomal aberration involving C11orf95 is found in more than two-thirds of supratentorial ependymomas. Translocation with C11orf95 produces a C11orf95-RELA fusion protein. C11orf95-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF- kappa-B transcription program (PubMed:24553141). {ECO:0000269|PubMed:24553141}. | NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). {ECO:0000269|PubMed:10928981, ECO:0000269|PubMed:12748188, ECO:0000269|PubMed:15790681, ECO:0000269|PubMed:17000776, ECO:0000269|PubMed:17620405, ECO:0000269|PubMed:19058135, ECO:0000269|PubMed:19103749, ECO:0000269|PubMed:20547752}. | 16.04 | ||||
| dfaTGFR1 | TGF-beta receptor type-1 | 1 | 642 | 98.42 | 97.75 | ND | 0.72 | 0.70 | 0.5 | Mammalian | Found in all tissues examined, most abundant in placenta and least abundant in brain and heart. Expressed in a variety of cancer cell lines (PubMed:25893292). {ECO:0000269|PubMed:25893292}. | Kinase | Loeys-Dietz syndrome 1 (LDS1) [MIM:609192]: An aortic aneurysm syndrome with widespread systemic involvement, characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. Some patients have craniosynostosis, exotropy, micrognathia and retrognathia, structural brain abnormalities, and intellectual deficit. {ECO:0000269|PubMed:15731757, ECO:0000269|PubMed:16596670, ECO:0000269|PubMed:16791849, ECO:0000269|PubMed:16928994, ECO:0000269|PubMed:19883511, ECO:0000269|PubMed:22113417}. Note=The disease is caused by mutations affecting the gene represented in this entry. TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS1 by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS1 by the OMIM resource. {ECO:0000269|PubMed:16791849}. Multiple self-healing squamous epithelioma (MSSE) [MIM:132800]: A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars. {ECO:0000269|PubMed:21358634}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non- canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation. {ECO:0000269|PubMed:15761148, ECO:0000269|PubMed:16754747, ECO:0000269|PubMed:18758450, ECO:0000269|PubMed:7774578, ECO:0000269|PubMed:8752209, ECO:0000269|PubMed:8980228, ECO:0000269|PubMed:9346908}. | 15.11 | |||
| dfaTGFR2 | TGF-beta receptor type-2 | 5 | 125 | 83.75 | 89.16 | ND | 0.57 | 0.84 | 0.6 | Mammalian | Kinase | Hereditary non-polyposis colorectal cancer 6 (HNPCC6) [MIM:614331]: An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. {ECO:0000269|PubMed:9590282}. Note=The disease is caused by mutations affecting the gene represented in this entry. Esophageal cancer (ESCR) [MIM:133239]: A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage. {ECO:0000269|PubMed:10789724}. Note=The disease is caused by mutations affecting the gene represented in this entry. Loeys-Dietz syndrome 2 (LDS2) [MIM:610168]: An aortic aneurysm syndrome with widespread systemic involvement, characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. Some patients have craniosynostosis, exotropy, micrognathia and retrognathia, structural brain abnormalities, and intellectual deficit. {ECO:0000269|PubMed:15235604, ECO:0000269|PubMed:15731757, ECO:0000269|PubMed:16027248, ECO:0000269|PubMed:16251899, ECO:0000269|PubMed:19883511, ECO:0000269|PubMed:20101701, ECO:0000269|PubMed:20358619, ECO:0000269|PubMed:21949523, ECO:0000269|PubMed:22113417}. Note=The disease is caused by mutations affecting the gene represented in this entry. TGFBR2 mutations Cys-460 and His-460 have been reported to be associated with thoracic aortic aneurysms and dissection (TAAD). This phenotype, also known as thoracic aortic aneurysms type 3 (AAT3), is distinguised from LDS2 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit descending aortic disease and aneurysms of other arteries (PubMed:16027248), they have been considered as LDS2 by the OMIM resource. {ECO:0000269|PubMed:16027248}. | Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non- promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFRB1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non- canonical, SMAD-independent TGF-beta signaling pathways. {ECO:0000269|PubMed:7774578}. | 15.11 | ||||
| dfaTGM1 | Protein-glutamine gamma-glutamyltransferase K | 1 | 71 | 99.76 | 99.93 | ND | 0.41 | 0.47 | 0.2 | Mammalian | Enzyme | Ichthyosis, congenital, autosomal recessive 1 (ARCI1) [MIM:242300]: A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. {ECO:0000269|PubMed:11251583, ECO:0000269|PubMed:11511296, ECO:0000269|PubMed:19890349, ECO:0000269|PubMed:26220141, ECO:0000269|PubMed:7773290, ECO:0000269|PubMed:7824952, ECO:0000269|PubMed:9326318}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Responsible for cross- linking epidermal proteins during formation of the stratum corneum. Involved in cell proliferation (PubMed:26220141). {ECO:0000269|PubMed:26220141}. | Protein-glutamine gamma-glutamyltransferase K substrate: L-Glutamine | 16.04 | |||
| dfaTGM2 | Protein-glutamine gamma-glutamyltransferase 2 | 6 | 241 | 95.65 | 97.12 | ND | 0.51 | 0.70 | 0.5 | Mammalian | Enzyme | Burns and Burn Infections
Coeliac disease Fibrosis Neurodegenerative diseases Renal fibrosis Scar Tissue | Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. | Protein-glutamine gamma-glutamyltransferase 2 substrate: L-Glutamine | 15.11 | |||
| dfaTHA | Thyroid hormone receptor alpha | 3 | 376 | 98.19 | 99.04 | ND | 0.80 | 0.82 | 0.6 | VirtualToxLab | Mammalian | Nuclear receptor | Hypothyroidism, congenital, non-goitrous, 6 (CHNG6) [MIM:614450]: A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance. {ECO:0000269|PubMed:22168587, ECO:0000269|PubMed:24969835, ECO:0000269|PubMed:25670821, ECO:0000269|PubMed:26037512}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Isoform Alpha-1: Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:19926848}. Isoform Alpha-2: Does not bind thyroid hormone and functions as a weak dominant negative inhibitor of thyroid hormone action. {ECO:0000269|PubMed:8910441}. | Thyroid hormone receptor alpha agonist: Dextrothyroxine, Levothyroxine, Liothyronine, Liotrix | 15.11 | ||
| dfaTHAS | Thromboxane-A synthase | 4 | 793 | 92.69 | 93.14 | ND | 0.45 | 0.46 | 0.5 | Mammalian | Platelets, lung, kidney, spleen, macrophages and lung fibroblasts. | Cytochrome P450 | Ghosal hematodiaphyseal dysplasia (GHDD) [MIM:231095]: Rare autosomal recessive disorder characterized by increased bone density with predominant diaphyseal involvement and aregenerative corticosteroid-sensitive anemia. Aregenerative anemia is characterized by bone marrow failure, so that functional marrow cells are regenerated slowly or not at all. {ECO:0000269|PubMed:18264100}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Thromboxane synthetase deficiency has been detected in some patients with a bleeding disorder due to platelet dysfunction. {ECO:0000269|PubMed:6101498}. | Thromboxane-A synthase antagonist: Sulfasalazine Thromboxane-A synthase inhibitor: Ridogrel | 16.04 | |||
| dfaTHB | Thyroid hormone receptor beta | 5 | 1254 | 89.13 | 87.88 | ND | 0.72 | 0.75 | 0.8 | VirtualToxLab | Mammalian | Nuclear receptor | Generalized thyroid hormone resistance (GTHR) [MIM:188570]: A disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). {ECO:0000269|PubMed:10660344, ECO:0000269|PubMed:1314846, ECO:0000269|PubMed:1324420, ECO:0000269|PubMed:1563081, ECO:0000269|PubMed:1587388, ECO:0000269|PubMed:1619012, ECO:0000269|PubMed:1661299, ECO:0000269|PubMed:16804041, ECO:0000269|PubMed:1846005, ECO:0000269|PubMed:19268523, ECO:0000269|PubMed:2153155, ECO:0000269|PubMed:2510172, ECO:0000269|PubMed:7833659, ECO:0000269|PubMed:8175986, ECO:0000269|PubMed:8514853, ECO:0000269|PubMed:8664910, ECO:0000269|PubMed:8889584}. Note=The disease is caused by mutations affecting the gene represented in this entry. Generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:274300]: An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. {ECO:0000269|PubMed:1653889}. Note=The disease is caused by mutations affecting the gene represented in this entry. Selective pituitary thyroid hormone resistance (PRTH) [MIM:145650]: Variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established. {ECO:0000269|PubMed:7528740, ECO:0000269|PubMed:8381821}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, ECO:0000269|PubMed:16781732, ECO:0000269|PubMed:17418816, ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:18798561, ECO:0000269|PubMed:19926848}. | Thyroid hormone receptor beta agonist: Dextrothyroxine, Levothyroxine, Liothyronine, Liotrix | 15.11 | ||
| dfaTHRB | Prothrombin | 2 | 4674 | 94.59 | 89.15 | ND | 0.59 | 0.00 | 0.9 | Mammalian | Expressed by the liver and secreted in plasma. | Protease | Coagulative disorders
Coronary atherosclerosis Gliomas Heparin-induced thrombocytopenia type II Multiple organ failure Thromboembolic disorders Thrombosis Thrombotic disease | Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing (By similarity). {ECO:0000250}. | Thrombin inhibitor: Argatroban, Bivalirudin, Dabigatran Etexilate, Desirudin, Lepirudin | 15.11 | ||
| dfaTIE2 | Angiopoietin-1 receptor | 1 | 669 | 96.87 | 96.53 | ND | 0.72 | 0.70 | 0.6 | Mammalian | Detected in umbilical vein endothelial cells. Proteolytic processing gives rise to a soluble extracellular domain that is detected in blood plasma (at protein level). Predominantly expressed in endothelial cells and their progenitors, the angioblasts. Has been directly found in placenta and lung, with a lower level in umbilical vein endothelial cells, brain and kidney. {ECO:0000269|PubMed:11806244, ECO:0000269|PubMed:8382358}. | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Mental disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Dominantly inherited venous malformations (VMCM) [MIM:600195]: An error of vascular morphogenesis characterized by dilated, serpiginous channels. {ECO:0000269|PubMed:10369874, ECO:0000269|PubMed:19888299, ECO:0000269|PubMed:8980225}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation. | Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post- natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1. {ECO:0000269|PubMed:12816861, ECO:0000269|PubMed:14665640, ECO:0000269|PubMed:15284220, ECO:0000269|PubMed:15851516, ECO:0000269|PubMed:18366015, ECO:0000269|PubMed:18425119, ECO:0000269|PubMed:18425120, ECO:0000269|PubMed:19223473, ECO:0000269|PubMed:20651738, ECO:0000269|PubMed:9204896}. | Angiopoietin-1 receptor : Ampicillin Angiopoietin-1 receptor inhibitor: Ponatinib, Regorafenib, Vandetanib | 15.11 | |
| dfaTKT | Transketolase | 1 | 48 | 94.73 | 96.28 | ND | 0.34 | 0.63 | 0.4 | Mammalian | Enzyme | Thiamine deficiency | Catalyzes the transfer of a two-carbon ketol group from a ketose donor to an aldose acceptor, via a covalent intermediate with the cofactor thiamine pyrophosphate. | 15.11 | ||||
| dfaTLK1 | Serine/threonine-protein kinase tousled-like 1 | 3 | 64 | 99.76 | 99.50 | ND | 0.31 | 0.91 | 0.2 | Mammalian | Widely expressed. Present in fetal placenta, liver, kidney and pancreas but not heart or skeletal muscle. Also found in adult cell lines. Isoform 3 is ubiquitously expressed in all tissues examined. {ECO:0000269|PubMed:10588641, ECO:0000269|PubMed:9427565}. | Kinase | Rapidly and transiently inhibited by phosphorylation following the generation of DNA double-stranded breaks during S- phase. This is cell cycle checkpoint and ATM-pathway dependent and appears to regulate processes involved in chromatin assembly. Isoform 3 phosphorylates and enhances the stability of the t-SNARE SNAP23, augmenting its assembly with syntaxin. Isoform 3 protects the cells from the ionizing radiation by facilitating the repair of DSBs. In vitro, phosphorylates histone H3 at 'Ser-10'. {ECO:0000269|PubMed:10523312, ECO:0000269|PubMed:10588641, ECO:0000269|PubMed:11314006, ECO:0000269|PubMed:11470414, ECO:0000269|PubMed:12660173, ECO:0000269|PubMed:9427565}. | 16.04 | ||||
| dfaTLR4 | Toll-like receptor 4 | 3 | 94 | 94.22 | 95.68 | ND | 0.90 | 0.70 | 0.2 | Mammalian | Highly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes, macrophages, dendritic cells and several types of T-cells. {ECO:0000269|PubMed:9237759, ECO:0000269|PubMed:9435236}. | Membrane receptor | Macular degeneration, age-related, 10 (ARMD10) [MIM:611488]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). {ECO:0000269|PubMed:10835634, ECO:0000269|PubMed:17478729, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20711192, ECO:0000269|PubMed:23880187, ECO:0000269|PubMed:9237759}. | Toll-like receptor 4 inhibitor: Naloxone | 16.04 | ||
| dfaTLR7 | Toll-like receptor 7 | 2 | 139 | 99.65 | 99.63 | ND | 0.73 | 0.69 | 0.6 | Mammalian | Detected in brain, placenta, spleen, stomach, small intestine, lung and in plasmacytoid pre-dendritic cells. | Toll-like and Il-1 receptors | Basal cell carcinoma
Hepatitis C Skin cancer | Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR7 is a nucleotide-sensing TLR which is activated by single-stranded RNA. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity). {ECO:0000250, ECO:0000269|PubMed:18250417}. | Toll-like receptor 7 agonist: Imiquimod Toll-like receptor 7 antagonist: Hydroxychloroquine | 16.04 | ||
| dfaTMIG3 | Transmembrane domain-containing protein TMIGD3 {ECO:0000305} | 7 | 2846 | 94.24 | 91.84 | ND | 0.71 | 0.00 | 0.6 | Mammalian | Family A G protein-coupled receptor | 16.04 | ||||||
| dfaTNFA | Tumor necrosis factor | 6 | 259 | 88.36 | 85.04 | ND | 0.84 | 0.82 | 0.4 | Mammalian | Secreted protein | Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). {ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918). {ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:22517918, ECO:0000269|PubMed:23396208}. The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. {ECO:0000269|PubMed:16829952}. | Tumor necrosis factor : Apremilast, Chloroquine, Glucosamine, Isopropyl Alcohol, Pseudoephedrine Tumor necrosis factor antagonist: Epinephrine Tumor necrosis factor antibody: Adalimumab, Etanercept, golimumab Tumor necrosis factor inhibitor: Amrinone, Infliximab, Pomalidomide, Thalidomide Tumor necrosis factor neutralizer: Certolizumab pegol Tumor necrosis factor other/unknown: Clenbuterol, Pranlukast | 16.04 | |||
| dfaTNI3K | Serine/threonine-protein kinase TNNI3K | 7 | 64 | 99.35 | 93.68 | ND | 0.63 | 0.95 | 0.3 | Mammalian | Highly expressed in both adult and fetal heart. {ECO:0000269|PubMed:12721663}. | Kinase | Cardiac conduction disease with or without dilated cardiomyopathy (CCDD) [MIM:616117]: A cardiac disorder characterized by atrial tachyarrhythmia and conduction system disease. Some patients have dilated cardiomyopathy. {ECO:0000269|PubMed:24925317}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May play a role in cardiac physiology. {ECO:0000303|PubMed:12721663}. | 15.11 | |||
| dfaTNIK | TRAF2 and NCK-interacting protein kinase | 4 | 78 | 96.74 | 97.10 | ND | 0.45 | 0.89 | 0.8 | Mammalian | Expressed ubiquitously. Highest levels observed in heart, brain and skeletal muscle. Expressed in normal colonic epithelia and colorectal cancer tissues. {ECO:0000269|PubMed:10521462, ECO:0000269|PubMed:19816403}. | Kinase | Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway. Recruited to promoters of Wnt target genes and required to activate their expression. May act by phosphorylating TCF4/TCF7L2. Appears to act upstream of the JUN N-terminal pathway. May play a role in the response to environmental stress. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it may play a role in cytoskeletal rearrangements and regulate cell spreading. Phosphorylates SMAD1 on Thr-322. {ECO:0000269|PubMed:10521462, ECO:0000269|PubMed:15342639, ECO:0000269|PubMed:19061864, ECO:0000269|PubMed:19816403, ECO:0000269|PubMed:20159449, ECO:0000269|PubMed:21690388}. | 15.11 | ||||
| dfaTNKS1 | Tankyrase-1 | 3 | 130 | 96.35 | 95.48 | ND | 0.55 | 0.76 | 0.7 | Mammalian | Ubiquitous; highest levels in testis. | Enzyme | Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1. Stimulates 26S proteasome activity. {ECO:0000269|PubMed:10988299, ECO:0000269|PubMed:11739745, ECO:0000269|PubMed:16076287, ECO:0000269|PubMed:19759537, ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:22864114, ECO:0000269|PubMed:23622245}. | 15.11 | ||||
| dfaTNKS2 | Tankyrase-2 | 5 | 147 | 92.47 | 88.86 | ND | 0.59 | 0.66 | 0.6 | Mammalian | Highly expressed in placenta, skeletal muscle, liver, brain, kidney, heart, thymus, spinal cord, lung, peripheral blood leukocytes, pancreas, lymph nodes, spleen, prostate, testis, ovary, small intestine, colon, mammary gland, breast and breast carcinoma, and in common-type meningioma. Highly expressed in fetal liver, heart and brain. | Enzyme | Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP- ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. Stimulates 26S proteasome activity. {ECO:0000269|PubMed:11739745, ECO:0000269|PubMed:11802774, ECO:0000269|PubMed:19759537, ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:23622245}. | 15.11 | ||||
| dfaTNR1A | Tumor necrosis factor receptor superfamily member 1A | 4 | 95 | 98.57 | 99.88 | ND | 0.45 | 0.60 | 0.3 | Mammalian | Membrane receptor | Familial hibernian fever (FHF) [MIM:142680]: A hereditary periodic fever syndrome characterized by recurrent fever, abdominal pain, localized tender skin lesions and myalgia. Reactive amyloidosis is the main complication and occurs in 25% of cases. {ECO:0000269|PubMed:10199409, ECO:0000269|PubMed:10902757, ECO:0000269|PubMed:11443543, ECO:0000269|PubMed:13130484, ECO:0000269|PubMed:14610673}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple sclerosis 5 (MS5) [MIM:614810]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. {ECO:0000269|PubMed:22801493}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. An intronic mutation affecting alternative splicing and skipping of exon 6 directs increased expression of isoform 4 a transcript encoding a C-terminally truncated protein which is secreted and may function as a TNF antagonist. | Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate- specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase. | 16.04 | ||||
| dfaTOP1 | DNA topoisomerase 1 | 3 | 295 | 99.72 | 99.74 | ND | 0.68 | 0.68 | 0.5 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Isomerase | Note=A chromosomal aberration involving TOP1 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with NUP98. {ECO:0000269|PubMed:10556215}. | Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component ARNTL/BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the ARNTL/BMAL1 promoter. {ECO:0000250|UniProtKB:Q13472, ECO:0000269|PubMed:14594810, ECO:0000269|PubMed:16033260, ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:22904072, ECO:0000269|PubMed:2833744}. | DNA topoisomerase 1 inhibitor: Irinotecan, Lucanthone, Sodium stibogluconate, Topotecan | 15.11 | ||
| dfaTOP2B | DNA topoisomerase 2-beta | 3 | 47 | 99.93 | 99.56 | ND | 0.88 | 0.74 | 0.3 | Mammalian | Alopecia Anaemia Bone marrow failure Haemorrhagic diathesis Mucosal inflammation Stomatitis | Isomerase | Cancer, unspecific | Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. {ECO:0000269|PubMed:10684600}. | DNA topoisomerase 2-beta : Dexrazoxane DNA topoisomerase 2-beta inhibitor: Daunorubicin, Etoposide | 15.11 | ||
| dfaTOPK | Lymphokine-activated killer T-cell-originated protein kinase | 4 | 96 | 86.60 | 87.53 | ND | 0.59 | 0.78 | 0.3 | Mammalian | Expressed in the testis and placenta. In the testis, restrictedly expressed in outer cell layer of seminiferous tubules. {ECO:0000269|PubMed:10781613, ECO:0000269|PubMed:11378444}. | Kinase | Phosphorylates MAP kinase p38. Seems to be active only in mitosis. May also play a role in the activation of lymphoid cells. When phosphorylated, forms a complex with TP53, leading to TP53 destabilization and attenuation of G2/M checkpoint during doxorubicin-induced DNA damage. {ECO:0000269|PubMed:10781613, ECO:0000269|PubMed:17482142}. | 16.04 | ||||
| dfaTPA | Tissue-type plasminogen activator | 5 | 401 | 95.03 | 94.96 | ND | 0.65 | 0.69 | 0.5 | Mammalian | Synthesized in numerous tissues (including tumors) and secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, and milk. | Protease | Note=Increased activity of TPA results in increased fibrinolysis of fibrin blood clots that is associated with excessive bleeding. Defective release of TPA results in hypofibrinolysis that can lead to thrombosis or embolism. {ECO:0000269|PubMed:1762144}. | Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. Plays a direct role in facilitating neuronal migration. | Tissue-type plasminogen activator : Urokinase Tissue-type plasminogen activator antagonist: Aminocaproic Acid Tissue-type plasminogen activator negative modulator: Ibuprofen Tissue-type plasminogen activator other/unknown: Iloprost | 15.11 | ||
| dfaTPH1 | Tryptophan 5-hydroxylase 1 | 1 | 47 | 99.96 | 100.00 | ND | 0.19 | 0.14 | 0.2 | Mammalian | Isoform 2 seems to be less widely expressed than isoform 1. | Enzyme | Tryptophan 5-hydroxylase 1 cofactor: Tetrahydrobiopterin Tryptophan 5-hydroxylase 1 substrate: L-Tryptophan | 15.11 | ||||
| dfaTPOR | Thrombopoietin receptor | 4 | 232 | 98.77 | 99.75 | ND | 0.48 | 0.59 | 0.5 | Mammalian | Expressed at a low level in a large number of cells of hematopoietic origin. Isoform 1 and isoform 2 are always found to be coexpressed. | Membrane receptor | Congenital amegakaryocytic thrombocytopenia (CAMT) [MIM:604498]: Disease characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies. {ECO:0000269|PubMed:16470591}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thrombocythemia 2 (THCYT2) [MIM:601977]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. {ECO:0000269|PubMed:14764528, ECO:0000269|PubMed:23441089, ECO:0000269|PubMed:25538044}. Note=The disease is caused by mutations affecting the gene represented in this entry. Myelofibrosis with myeloid metaplasia (MMM) [MIM:254450]: A chronic myeloproliferative disorder characterized by replacement of the bone marrow by fibrous tissue, extramedullary hematopoiesis, anemia, leukoerythroblastosis and hepatosplenomegaly. {ECO:0000269|PubMed:16834459, ECO:0000269|PubMed:16868251}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for thrombopoietin. May represent a regulatory molecule specific for TPO-R-dependent immune responses. | Thrombopoietin receptor agonist: Eltrombopag, Romiplostim | 16.04 | ||
| dfaTPP2 | Tripeptidyl-peptidase 2 | 2 | 78 | 99.81 | 99.81 | ND | 0.46 | 0.66 | 0.9 | Mammalian | Protease | Eating disorders
Obesity Psychiatric illness | Component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. May be able to complement the 26S proteasome function to some extent under conditions in which the latter is inhibited. Stimulates adipogenesis (By similarity). {ECO:0000250}. | 16.04 | ||||
| dfaTRPA1 | Transient receptor potential cation channel subfamily A member 1 | 8 | 419 | 90.87 | 80.37 | ND | 0.71 | 0.73 | 0.7 | Mammalian | Expressed at very low level. Expressed at very low level in human fibroblasts and at a moderate level in liposarcoma cells. {ECO:0000269|PubMed:10066796}. | Voltage-gated ion channel | Episodic pain syndrome, familial, 1 (FEPS1) [MIM:615040]: An autosomal dominant neurologic disorder characterized by onset in infancy of episodic debilitating upper body pain triggered by fasting, cold, and physical stress. The period of intense pain is accompanied by breathing difficulties, tachycardia, sweating, generalized pallor, peribuccal cyanosis, and stiffness of the abdominal wall. Affected individuals do not manifest altered pain sensitivity outside the episodes. {ECO:0000269|PubMed:20547126}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as a ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity). {ECO:0000250|UniProtKB:Q8BLA8, ECO:0000269|PubMed:20547126, ECO:0000269|PubMed:25389312, ECO:0000269|PubMed:25855297}. | Transient receptor potential cation channel subfamily A member 1 inducer: Menthol | 16.04 | ||
| dfaTRPM8 | Transient receptor potential cation channel subfamily M member 8 | 5 | 184 | 93.87 | 90.37 | ND | 0.76 | 0.65 | 0.5 | Mammalian | Expressed in prostate. Also expressed in prostate tumors and in non-prostatic primary tumors such as colon, lung, breast and skin tumors. {ECO:0000269|PubMed:11325849, ECO:0000269|PubMed:12858355, ECO:0000269|PubMed:16174775, ECO:0000269|PubMed:22128173}. | Voltage-gated ion channel | Analgesics
Irritation Pain | Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonist menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration (PubMed:25559186). Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel. {ECO:0000269|PubMed:15306801, ECO:0000269|PubMed:16174775, ECO:0000269|PubMed:22128173, ECO:0000269|PubMed:25559186}. | Transient receptor potential cation channel subfamily M member 8 inducer: Menthol | 16.04 | ||
| dfaTRPV1 | Transient receptor potential cation channel subfamily V member 1 | 4 | 1913 | 94.58 | 94.59 | ND | 0.61 | 0.00 | 0.7 | Mammalian | Widely expressed at low levels. Expression is elevated in dorsal root ganglia. In skin, expressed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands (at protein level). {ECO:0000269|PubMed:11050376, ECO:0000269|PubMed:11243859, ECO:0000269|PubMed:14987252}. | Voltage-gated ion channel | Acute migraine
Analgesics Chronic pathological pain Osteoarthritis pain Pain, Acute or Chronic Urinary incontinence | Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Can be activated by endogenous compounds, including 12- hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis (By similarity). Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. {ECO:0000250, ECO:0000269|PubMed:11050376, ECO:0000269|PubMed:11226139, ECO:0000269|PubMed:11243859, ECO:0000269|PubMed:12077606}. | Transient receptor potential cation channel subfamily V member 1 : Alpha-Linolenic Acid Transient receptor potential cation channel subfamily V member 1 agonist: Capsaicin Transient receptor potential cation channel subfamily V member 1 inducer: Aspartame, Icosapent | 16.04 | ||
| dfaTRY1 | Cationic trypsin | 2 | 1445 | 98.52 | 97.58 | ND | 0.60 | 0.60 | 0.7 | Mammalian | Synthesized in the acinar cells of the pancreas. | Protease | 15.11 | |||||
| dfaTRY2 | Trypsin-2 | 1 | 170 | 97.80 | 99.50 | ND | 0.62 | 0.47 | 0.5 | Mammalian | Expressed in Paneth cells, at the base of small intestinal crypts. {ECO:0000269|PubMed:12021776}. | Protease | In the ileum, may be involved in defensin processing, including DEFA5. {ECO:0000269|PubMed:12021776}. | 16.04 | ||||
| dfaTRYB1 | Tryptase alpha/beta-1 | 2 | 107 | 99.38 | 99.41 | ND | 0.58 | 0.75 | 0.6 | Mammalian | Isoform 1 and isoform 2 are expressed in lung, stomach, spleen, heart and skin; in these tissues, isoform 1 is predominant. Isoform 2 is expressed in aorta, spleen, and breast tumor, with highest levels in the endothelial cells of some blood vessels surrounding the aorta, as well as those surrounding the tumor and low levels, if any, in mast cells (at protein level). {ECO:0000269|PubMed:18854315}. | Protease | Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type. May play a role in innate immunity. Isoform 2 cleaves large substrates, such as fibronectin, more efficiently than isoform 1, but seems less efficient toward small substrates (PubMed:18854315). {ECO:0000250, ECO:0000250|UniProtKB:P21845, ECO:0000269|PubMed:18854315}. | 15.11 | ||||
| dfaTSPO | Translocator protein 2 | 6 | 718 | 97.58 | 94.32 | ND | 0.54 | 0.65 | 0.8 | Mammalian | Binds cholesterol and mediates its redistribution during erythropoiesis which may play a role in erythrocyte maturation. {ECO:0000269|PubMed:19729679}. | 16.04 | ||||||
| dfaTSSK1 | Testis-specific serine/threonine-protein kinase 1 | 4 | 115 | 87.24 | 95.03 | ND | 0.69 | 0.85 | 0.5 | Mammalian | Testis-specific. Present in sperm (at protein level). {ECO:0000269|PubMed:15044604, ECO:0000269|PubMed:20729278}. | Kinase | Testis-specific serine/threonine-protein kinase required during spermatid development. Phosphorylates 'Ser-288' of TSKS. Involved in the late stages of spermatogenesis, during the reconstruction of the cytoplasm. During spermatogenesis, required for the transformation of a ring-shaped structure around the base of the flagellum originating from the chromatoid body. {ECO:0000269|PubMed:15733851, ECO:0000269|PubMed:19530700}. | 16.04 | ||||
| dfaTSSK2 | Testis-specific serine/threonine-protein kinase 2 | 2 | 43 | 82.07 | 80.60 | ND | 0.00 | 0.97 | 0.8 | Mammalian | Testis-specific. Present in mature spermatozoa (at protein level). {ECO:0000269|PubMed:15044604, ECO:0000269|PubMed:18533145, ECO:0000269|PubMed:20729278}. | Kinase | Testis-specific serine/threonine-protein kinase required during spermatid development. Phosphorylates TSKS at 'Ser-288' and SPAG16. Involved in the late stages of spermatogenesis, during the reconstruction of the cytoplasm. During spermatogenesis, required for the transformation of a ring-shaped structure around the base of the flagellum originating from the chromatoid body. {ECO:0000269|PubMed:15044604, ECO:0000269|PubMed:18533145, ECO:0000269|PubMed:20729278}. | 16.04 | ||||
| dfaTTK | Dual specificity protein kinase TTK | 3 | 188 | 96.10 | 98.11 | ND | 0.80 | 0.78 | 0.5 | Mammalian | Present in rapidly proliferating cell lines. | Kinase | Cancer, unspecific | Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint. {ECO:0000269|PubMed:18243099}. | 15.11 | |||
| dfaTXK | Tyrosine-protein kinase TXK | 7 | 81 | 98.82 | 99.48 | ND | 0.89 | 0.81 | 0.3 | Mammalian | Expressed in T-cells and some myeloid cell lines. Expressed in Th1/Th0 cells with IFN-gamma-producing potential. {ECO:0000269|PubMed:10523612, ECO:0000269|PubMed:7951233}. | Kinase | Non-receptor tyrosine kinase that plays a redundant role with ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T- cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of TXK to the cell membrane, where it is phosphorylated at Tyr-420. Phosphorylation leads to TXK full activation. Contributes also to signaling from many receptors and participates in multiple downstream pathways, including regulation of the actin cytoskeleton. Like ITK, can phosphorylate PLCG1, leading to its localization in lipid rafts and activation, followed by subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. With PARP1 and EEF1A1, TXK forms a complex that acts as a T-helper 1 (Th1) cell- specific transcription factor and binds the promoter of IFNG to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Phosphorylates both PARP1 and EEF1A1. Phosphorylates also key sites in LCP2 leading to the up-regulation of Th1 preferred cytokine IL-2. Phosphorylates 'Tyr- 201' of CTLA4 which leads to the association of PI-3 kinase with the CTLA4 receptor. {ECO:0000269|PubMed:10523612, ECO:0000269|PubMed:11564877, ECO:0000269|PubMed:11859127, ECO:0000269|PubMed:17177976, ECO:0000269|PubMed:9813138}. | 16.04 | ||||
| dfaTYDP2 | Tyrosyl-DNA phosphodiesterase 2 | 2 | 68 | 95.05 | 95.18 | ND | 0.87 | 0.80 | 0.3 | Mammalian | Widely expressed. {ECO:0000269|PubMed:10764746}. | Enzyme | DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'- phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'- tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'- tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl- RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF- beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non- canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress. {ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:21030584, ECO:0000269|PubMed:21921940, ECO:0000269|PubMed:21980489, ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062, ECO:0000269|PubMed:22908287}. | 16.04 | ||||
| dfaTYK2 | Non-receptor tyrosine-protein kinase TYK2 | 6 | 375 | 95.06 | 95.70 | ND | 0.66 | 0.71 | 0.6 | Mammalian | Observed in all cell lines analyzed. Expressed in a variety of lymphoid and non-lymphoid cell lines. {ECO:0000269|PubMed:2156206}. | Kinase | Immunodeficiency 35 (IMD35) [MIM:611521]: A primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE. {ECO:0000269|PubMed:17088085}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. {ECO:0000269|PubMed:7526154}. | 15.11 | |||
| dfaTYPH | Thymidine phosphorylase | 3 | 143 | 94.88 | 85.97 | ND | 0.68 | 0.84 | 0.5 | Mammalian | Enzyme | Mitochondrial DNA depletion syndrome 1, MNGIE type (MTDPS1) [MIM:603041]: A multisystem disease associated with mitochondrial dysfunction. It is clinically characterized by onset between the second and fifth decades of life, ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), diffuse leukoencephalopathy, cachexia, peripheral neuropathy, and myopathy. {ECO:0000269|PubMed:12177387, ECO:0000269|PubMed:9924029}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro. {ECO:0000269|PubMed:1590793}. Catalyzes the reversible phosphorolysis of thymidine. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis. {ECO:0000269|PubMed:1590793}. | Thymidine phosphorylase inhibitor: Cidofovir Thymidine phosphorylase substrate: Capecitabine, Floxuridine, Fluorouracil, Trifluridine | 16.04 | |||
| dfaTYRO3 | Tyrosine-protein kinase receptor TYRO3 | 5 | 397 | 92.25 | 92.86 | ND | 0.63 | 0.72 | 0.5 | Mammalian | Abundant in the brain and lower levels in other tissues. | Kinase | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:20546121}. (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:25277499, PubMed:22156524, PubMed:22673088). Acts as a receptor for ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:17005688). {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:22156524, ECO:0000269|PubMed:22673088, ECO:0000269|PubMed:25277499}. | 15.11 | ||||
| dfaTYSY | Thymidylate synthase | 1 | 707 | 97.43 | 93.24 | ND | 0.58 | 0.73 | 0.6 | Mammalian | Transferase | Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. {ECO:0000269|PubMed:21876188}. | Thymidylate synthase : Floxuridine Thymidylate synthase inhibitor: Capecitabine, Gemcitabine, Leucovorin, Pemetrexed, Pralatrexate, Raltitrexed, Trifluridine, Trimethoprim Thymidylate synthase other/unknown: Fluorouracil Thymidylate synthase substrate: Fluorouracil, Methotrexate | 15.11 | ||||
| dfaUD2B7 | UDP-glucuronosyltransferase 2B7 | 1 | 69 | 99.99 | 99.84 | ND | 0.28 | 0.87 | 0.6 | Mammalian | Enzyme | UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. {ECO:0000269|PubMed:17442341}. Its unique specificity for 3,4-catechol estrogens and estriol suggests it may play an important role in regulating the level and activity of these potent and active estrogen metabolites. Is also active with androsterone, hyodeoxycholic acid and tetrachlorocatechol (in vitro). {ECO:0000269|PubMed:17442341}. | UDP-glucuronosyltransferase 2B7 : Dabigatran etexilate UDP-glucuronosyltransferase 2B7 inhibitor: Chenodeoxycholic acid, Flunitrazepam UDP-glucuronosyltransferase 2B7 substrate: Ambrisentan, Atorvastatin, Carbamazepine, Codeine, Dapagliflozin, Diclofenac, Epirubicin, Etodolac, Ezetimibe, Flurbiprofen, Fluvastatin, Ibuprofen, Indomethacin, Losartan, Lovastatin, Mitiglinide, Morphine, Mycophenolate mofetil, Mycophenolic acid, Naproxen, Oxazepam, Pitavastatin, Silodosin, Simvastatin, Suprofen, Tapentadol, Valproic Acid, Zidovudine | 16.04 | ||||
| dfaUFO | Tyrosine-protein kinase receptor UFO | 4 | 372 | 91.49 | 92.21 | ND | 0.62 | 0.70 | 0.6 | Mammalian | Highly expressed in metastatic colon tumors. Expressed in primary colon tumors. Weakly expressed in normal colon tissue. {ECO:0000269|PubMed:7896447}. | Kinase | Note=AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer. | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, ALX binds and induces tyrosine phosphorylation of PI3- kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TNS2. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. {ECO:0000269|PubMed:10403904, ECO:0000269|PubMed:11484958, ECO:0000269|PubMed:12364394, ECO:0000269|PubMed:12490074, ECO:0000269|PubMed:15507525, ECO:0000269|PubMed:15733062, ECO:0000269|PubMed:1656220, ECO:0000269|PubMed:18840707}. (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:22156524, PubMed:22673088, PubMed:25277499, PubMed:21501828). Acts as a receptor for ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:17005688). {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:21501828, ECO:0000269|PubMed:22156524, ECO:0000269|PubMed:22673088, ECO:0000269|PubMed:25277499}. | 16.04 | |||
| dfaULK1 | Serine/threonine-protein kinase ULK1 | 7 | 60 | 99.66 | 97.42 | ND | 0.32 | 0.82 | 0.6 | Mammalian | Ubiquitously expressed. Detected in the following adult tissues: skeletal muscle, heart, pancreas, brain, placenta, liver, kidney, and lung. | Kinase | Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3- kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 and PRKAG1, leading to negatively regulate AMPK activity. May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences. Plays a role early in neuronal differentiation and is required for granule cell axon formation. {ECO:0000269|PubMed:18936157, ECO:0000269|PubMed:21460634, ECO:0000269|PubMed:21795849}. | 15.11 | ||||
| dfaULK3 | Serine/threonine-protein kinase ULK3 | 5 | 61 | 87.08 | 85.55 | ND | 0.59 | 0.90 | 0.5 | Mammalian | Widely expressed. Highest levels observed in fetal brain. In adult tissues, high levels in brain, liver and kidney, moderate levels in testis and adrenal gland and low levels in heart, lung, stomach, thymus, prostate and placenta. In the brain, highest expression in the hippocampus, high levels also detected in the cerebellum, olfactory bulb and optic nerve. In the central nervous system, lowest levels in the spinal cord. {ECO:0000269|PubMed:19878745}. | Kinase | Serine/threonine protein kinase that acts as a regulator of Sonic hedgehog (SHH) signaling and autophagy. Acts as a negative regulator of SHH signaling in the absence of SHH ligand: interacts with SUFU, thereby inactivating the protein kinase activity and preventing phosphorylation of GLI proteins (GLI1, GLI2 and/or GLI3). Positively regulates SHH signaling in the presence of SHH: dissociates from SUFU, autophosphorylates and mediates phosphorylation of GLI2, activating it and promoting its nuclear translocation. Phosphorylates in vitro GLI2, as well as GLI1 and GLI3, although less efficiently. Also acts as a regulator of autophagy: following cellular senescence, able to induce autophagy. {ECO:0000269|PubMed:19279323, ECO:0000269|PubMed:19878745, ECO:0000269|PubMed:20643644}. | 16.04 | ||||
| dfaUPP1 | Uridine phosphorylase 1 | 2 | 46 | 95.86 | 82.82 | ND | 0.86 | 0.81 | 0.3 | Mammalian | Enzyme | Catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1- phosphate (PubMed:7488099). The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis. {ECO:0000269|PubMed:7488099, ECO:0000305}. | Uridine phosphorylase 1 substrate: Fluorouracil | 15.11 | ||||
| dfaUR2R | Urotensin-2 receptor | 5 | 163 | 96.96 | 98.80 | ND | 0.39 | 0.73 | 0.7 | Mammalian | Most abundant expression in the heart and pancreas. | Family A G protein-coupled receptor | Congestive heart failure
Myocardial infarction | High affinity receptor for urotensin-2 and urotensin-2B. The activity of this receptor is mediated by a G-protein that activate a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:14550283}. | 16.04 | |||
| dfaUROK | Urokinase-type plasminogen activator | 3 | 823 | 97.30 | 97.26 | ND | 0.69 | 0.71 | 0.6 | Mammalian | Expressed in the prostate gland and prostate cancers. {ECO:0000269|PubMed:15988036}. | Protease | Quebec platelet disorder (QPD) [MIM:601709]: An autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. {ECO:0000269|PubMed:20007542}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. | Urokinase-type plasminogen activator : Urokinase Urokinase-type plasminogen activator inhibitor: Amiloride | 15.11 | ||
| dfaUTS2 | Urotensin-2 | 3 | 51 | 99.36 | 99.95 | ND | 0.63 | 0.78 | 0.2 | Mammalian | Brain specific. | Cardiorenal disease
Cardiovascular disease, unspecified | Highly potent vasoconstrictor. | 16.04 | ||||
| dfaV1AR | Vasopressin V1a receptor | 5 | 679 | 93.46 | 96.78 | ND | 0.65 | 0.67 | 0.6 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Congestive heart failure
Dysmenorrhea, unspecified Hypertension Raynaud's syndrome Renal diseases Vasoconstriction Water-retaining diseases | Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl- inositol-calcium second messenger system. Has been involved in social behaviors, including affiliation and attachment. {ECO:0000269|PubMed:12082568}. | Vasopressin V1a receptor : Desmopressin, Vasopressin Vasopressin V1a receptor agonist: Felypressin Vasopressin V1a receptor antagonist: Conivaptan, Tolvaptan Vasopressin V1a receptor stimulator: Terlipressin | 16.04 | ||
| dfaV1BR | Vasopressin V1b receptor | 3 | 374 | 93.45 | 93.76 | ND | 0.76 | 0.78 | 0.6 | Mammalian | Family A G protein-coupled receptor | Adrenocorticotrophic hormone-secreting tumors
Emotional diseases Stress-related disorders | Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl- inositol-calcium second messenger system. | Vasopressin V1b receptor : Desmopressin, Terlipressin, Vasopressin | 16.04 | |||
| dfaV2R | Vasopressin V2 receptor | 1 | 729 | 98.16 | 97.31 | ND | 0.82 | 0.79 | 0.5 | Nature11159 | Mammalian | Kidney. | Family A G protein-coupled receptor | Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) [MIM:300539]: Characterized by an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypoosmolarity, and natriuresis. {ECO:0000269|PubMed:15872203}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes insipidus, nephrogenic, X-linked (XNDI) [MIM:304800]: A disorder caused by the inability of the renal collecting ducts to absorb water in response to arginine vasopressin. Characterized by excessive water drinking (polydipsia), excessive urine excretion (polyuria), persistent hypotonic urine, and hypokalemia. {ECO:0000269|PubMed:10694923, ECO:0000269|PubMed:10770218, ECO:0000269|PubMed:11232028, ECO:0000269|PubMed:11916004, ECO:0000269|PubMed:1303257, ECO:0000269|PubMed:1303271, ECO:0000269|PubMed:1356229, ECO:0000269|PubMed:16845277, ECO:0000269|PubMed:7560098, ECO:0000269|PubMed:7833930, ECO:0000269|PubMed:7984150, ECO:0000269|PubMed:7987330, ECO:0000269|PubMed:7999078, ECO:0000269|PubMed:8037205, ECO:0000269|PubMed:8045948, ECO:0000269|PubMed:8078903, ECO:0000269|PubMed:8267567, ECO:0000269|PubMed:8479490, ECO:0000269|PubMed:8514744, ECO:0000269|PubMed:9402087, ECO:0000269|PubMed:9452109, ECO:0000269|PubMed:9711877}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption. {ECO:0000269|PubMed:19440390}. | Vasopressin V2 receptor agonist: Desmopressin, Terlipressin, Vasopressin Vasopressin V2 receptor antagonist: Conivaptan, Tolvaptan | 16.04 | |
| dfaVACHT | Vesicular acetylcholine transporter | 1 | 200 | 97.62 | 98.83 | ND | 0.57 | 0.58 | 0.6 | Mammalian | Peripheral and central cholinergic nervous systems. {ECO:0000269|PubMed:8071310}. | Electrochemical transporter | Involved in acetylcholine transport into synaptic vesicles. {ECO:0000269|PubMed:8071310}. | 16.04 | ||||
| dfaVCAM1 | Vascular cell adhesion protein 1 | 2 | 148 | 93.40 | 86.32 | ND | 0.55 | 0.37 | 0.5 | Mammalian | Expressed on inflammed vascular endothelium, as well as on macrophage-like and dendritic cell types in both normal and inflammed tissue. | Adhesion | Not Available | Important in cell-cell recognition. Appears to function in leukocyte-endothelial cell adhesion. Interacts with integrin alpha-4/beta-1 (ITGA4/ITGB1) on leukocytes, and mediates both adhesion and signal transduction. The VCAM1/ITGA4/ITGB1 interaction may play a pathophysiologic role both in immune responses and in leukocyte emigration to sites of inflammation. | Vascular cell adhesion protein 1 : Ethanol Vascular cell adhesion protein 1 inhibitor: Carvedilol | 16.04 | ||
| dfaVGFR1 | Vascular endothelial growth factor receptor 1 | 4 | 1048 | 92.19 | 93.36 | ND | 0.68 | 0.76 | 0.7 | Mammalian | Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform 2 is strongly expressed in placenta. Isoform 3 is expressed in corneal epithelial cells (at protein level). Isoform 3 is expressed in vascular smooth muscle cells (VSMC). {ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:20512933}. | Kinase | Note=Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages. Note=Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia. | Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion. {ECO:0000269|PubMed:11141500, ECO:0000269|PubMed:11312102, ECO:0000269|PubMed:11811792, ECO:0000269|PubMed:12796773, ECO:0000269|PubMed:14633857, ECO:0000269|PubMed:15735759, ECO:0000269|PubMed:16685275, ECO:0000269|PubMed:18079407, ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:18583712, ECO:0000269|PubMed:18593464, ECO:0000269|PubMed:20512933, ECO:0000269|PubMed:20551949, ECO:0000269|PubMed:21752276, ECO:0000269|PubMed:7824266, ECO:0000269|PubMed:8248162, ECO:0000269|PubMed:8605350, ECO:0000269|PubMed:9299537}. | Vascular endothelial growth factor receptor 1 Inhibitor: Lenvatinib, Nintedanib Vascular endothelial growth factor receptor 1 antagonist: Sunitinib Vascular endothelial growth factor receptor 1 inhibitor: Axitinib, Pazopanib, Regorafenib, Sorafenib | 15.11 | ||
| dfaVGFR2 | Vascular endothelial growth factor receptor 2 | 6 | 4578 | 95.71 | 92.66 | ND | 0.58 | 0.62 | 0.7 | Mammalian | Detected in cornea (at protein level). Widely expressed. {ECO:0000269|PubMed:19668192}. | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Hemangioma, capillary infantile (HCI) [MIM:602089]: A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. {ECO:0000269|PubMed:11807987, ECO:0000269|PubMed:18931684}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. | Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC. {ECO:0000269|PubMed:10102632, ECO:0000269|PubMed:10368301, ECO:0000269|PubMed:10600473, ECO:0000269|PubMed:11387210, ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:1417831, ECO:0000269|PubMed:15026417, ECO:0000269|PubMed:15215251, ECO:0000269|PubMed:15962004, ECO:0000269|PubMed:16966330, ECO:0000269|PubMed:17303569, ECO:0000269|PubMed:18529047, ECO:0000269|PubMed:19668192, ECO:0000269|PubMed:19834490, ECO:0000269|PubMed:20080685, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20705758, ECO:0000269|PubMed:21893193, ECO:0000269|PubMed:7929439, ECO:0000269|PubMed:9160888, ECO:0000269|PubMed:9804796, ECO:0000269|PubMed:9837777}. | Vascular endothelial growth factor receptor 2 Inhibitor: Lenvatinib, Nintedanib Vascular endothelial growth factor receptor 2 antagonist: Cabozantinib, Ramucirumab, Sorafenib Vascular endothelial growth factor receptor 2 inhibitor: Axitinib, Pazopanib, Ponatinib, Regorafenib Vascular endothelial growth factor receptor 2 multitarget: Sunitinib | 15.11 | |
| dfaVGFR3 | Vascular endothelial growth factor receptor 3 | 4 | 525 | 89.33 | 88.56 | ND | 0.52 | 0.71 | 0.9 | Mammalian | Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney. {ECO:0000269|PubMed:1327515, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:7675451}. | Kinase | Lymphedema, hereditary, 1A (LMPH1A) [MIM:153100]: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment. {ECO:0000269|PubMed:10835628, ECO:0000269|PubMed:10856194, ECO:0000269|PubMed:16924388, ECO:0000269|PubMed:16965327, ECO:0000269|PubMed:17458866, ECO:0000269|PubMed:19289394, ECO:0000269|PubMed:26091405, ECO:0000269|PubMed:9817924}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hemangioma, capillary infantile (HCI) [MIM:602089]: A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. {ECO:0000269|PubMed:11807987}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases. | Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3- kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr- 185', and of AKT1 at 'Ser-473'. {ECO:0000269|PubMed:11532940, ECO:0000269|PubMed:15102829, ECO:0000269|PubMed:15474514, ECO:0000269|PubMed:16076871, ECO:0000269|PubMed:16452200, ECO:0000269|PubMed:17210781, ECO:0000269|PubMed:19610651, ECO:0000269|PubMed:19779139, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20431062, ECO:0000269|PubMed:20445537, ECO:0000269|PubMed:21273538, ECO:0000269|PubMed:7675451, ECO:0000269|PubMed:8700872, ECO:0000269|PubMed:9435229}. | Vascular endothelial growth factor receptor 3 : Pazopanib Vascular endothelial growth factor receptor 3 Inhibitor: Lenvatinib, Nintedanib Vascular endothelial growth factor receptor 3 antagonist: Sorafenib, Sunitinib Vascular endothelial growth factor receptor 3 inhibitor: Axitinib, Regorafenib | 16.04 | ||
| dfaVMAT2 | Synaptic vesicular amine transporter | 2 | 191 | 97.94 | 98.48 | ND | 0.58 | 0.47 | 0.6 | Mammalian | Electrochemical transporter | Cocaine dependence
Neurodegenerative diseases | Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Requisite for vesicular amine storage prior to secretion via exocytosis. | Synaptic vesicular amine transporter binder: Norepinephrine Synaptic vesicular amine transporter inducer: Benzphetamine, Dextroamphetamine Synaptic vesicular amine transporter inhibitor: Amphetamine, Deserpidine, Ephedra, Ephedrine, Isometheptene, Methamphetamine, Reserpine, Tetrabenazine | 16.04 | |||
| dfaWEE1 | Wee1-like protein kinase | 3 | 315 | 98.73 | 98.50 | ND | 0.78 | 0.65 | 0.5 | Mammalian | Kinase | Cancer | Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation. | 15.11 | ||||
| dfaWNT3 | Proto-oncogene Wnt-3 | 2 | 65 | 99.76 | 99.85 | ND | 0.67 | 0.82 | 0.4 | Mammalian | Tetraamelia syndrome, autosomal recessive (TETAMS) [MIM:273395]: A rare human genetic disorder characterized by complete absence of all four limbs and other anomalies such as craniofacial, nervous system, pulmonary, skeletal and urogenital defects. {ECO:0000269|PubMed:14872406}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ligand for members of the frizzled family of seven transmembrane receptors. Wnt-3 and Wnt-3a play distinct roles in cell-cell signaling during morphogenesis of the developing neural tube (By similarity). {ECO:0000250}. | 16.04 | |||||
| dfaXDH | Xanthine dehydrogenase/oxidase | 8 | 441 | 94.36 | 82.05 | ND | 0.83 | 0.75 | 0.5 | Mammalian | Detected in milk (at protein level). {ECO:0000269|PubMed:11005854, ECO:0000269|PubMed:12421831, ECO:0000269|PubMed:15148401}. | Enzyme | Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. | 15.11 | ||||
| dfaXIAP | E3 ubiquitin-protein ligase XIAP | 1 | 381 | 99.88 | 99.10 | ND | 0.73 | 0.64 | 0.5 | Mammalian | Ubiquitous, except peripheral blood leukocytes. | Other cytosolic protein | Lymphoproliferative syndrome, X-linked, 2 (XLP2) [MIM:300635]: A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma. {ECO:0000269|PubMed:17080092}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta- catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program. {ECO:0000269|PubMed:11447297, ECO:0000269|PubMed:12121969, ECO:0000269|PubMed:14645242, ECO:0000269|PubMed:14685266, ECO:0000269|PubMed:17560374, ECO:0000269|PubMed:17967870, ECO:0000269|PubMed:19473982, ECO:0000269|PubMed:20154138, ECO:0000269|PubMed:21145488, ECO:0000269|PubMed:22103349, ECO:0000269|PubMed:22304967, ECO:0000269|PubMed:9230442}. | 15.11 | |||
| dfaYES | Tyrosine-protein kinase Yes | 7 | 121 | 87.63 | 92.67 | ND | 0.48 | 0.82 | 0.9 | Mammalian | Expressed in the epithelial cells of renal proximal tubules and stomach as well as hematopoietic cells in the bone marrow and spleen in the fetal tissues. In adult, expressed in epithelial cells of the renal proximal tubules and present in keratinocytes in the basal epidermal layer of epidermis. {ECO:0000269|PubMed:2021534, ECO:0000269|PubMed:2067846}. | Kinase | Philadelphia-positive leukemia | Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGRF, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin-dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis. {ECO:0000269|PubMed:11901164, ECO:0000269|PubMed:18479465, ECO:0000269|PubMed:19276087, ECO:0000269|PubMed:21566460, ECO:0000269|PubMed:21713032}. | Tyrosine-protein kinase Yes inhibitor: Dasatinib | 16.04 | ||
| dfaZAP70 | Tyrosine-protein kinase ZAP-70 | 4 | 282 | 98.78 | 97.83 | ND | 0.45 | 0.70 | 0.7 | Mammalian | Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells. {ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:16467082, ECO:0000269|PubMed:9378960}. | Kinase | Selective T-cell defect (STCD) [MIM:269840]: A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T-cells. {ECO:0000269|PubMed:11123350, ECO:0000269|PubMed:11412303, ECO:0000269|PubMed:18509675, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8202713}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). {ECO:0000269|PubMed:11353765, ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:20135127, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8702662, ECO:0000269|PubMed:9489702}. | 15.11 | |||
| dpc5HT1B | 5-hydroxytryptamine receptor 1B | 0 | 1185 | 82.55 | ND | 95.19 | 0.58 | ND | 0.9 | Mammalian | Detected in cerebral artery smooth muscle cells (at protein level). Detected in brain cortex, striatum, amygdala, medulla, hippocampus, caudate nucleus and putamen. {ECO:0000269|PubMed:1348246, ECO:0000269|PubMed:1351684, ECO:0000269|PubMed:15853772}. | Family A G protein-coupled receptor | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries. {ECO:0000269|PubMed:10452531, ECO:0000269|PubMed:1315531, ECO:0000269|PubMed:1328844, ECO:0000269|PubMed:1348246, ECO:0000269|PubMed:1351684, ECO:0000269|PubMed:1559993, ECO:0000269|PubMed:1565658, ECO:0000269|PubMed:15853772, ECO:0000269|PubMed:1610347, ECO:0000269|PubMed:23519210, ECO:0000269|PubMed:23519215, ECO:0000269|PubMed:8218242}. | 15.11 | ||||
| dpc5HT2B | 5-hydroxytryptamine receptor 2B | 0 | 993 | 70.50 | ND | 84.86 | 0.29 | ND | 0.8 | Nature11159 | Mammalian | Ubiquitous. Detected in liver, kidney, heart, pulmonary artery, and intestine. Detected at lower levels in blood, placenta and brain, especially in cerebellum, occipital cortex and frontal cortex. {ECO:0000269|PubMed:21179162, ECO:0000269|PubMed:7926008, ECO:0000269|PubMed:8078486, ECO:0000269|PubMed:8143856, ECO:0000269|PubMed:8882600}. | Family A G protein-coupled receptor | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down- stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of dopamine and 5-hydroxytryptamine release, 5-hydroxytryptamine uptake and in the regulation of extracellular dopamine and 5- hydroxytryptamine levels, and thereby affects neural activity. May play a role in the perception of pain. Plays a role in the regulation of behavior, including impulsive behavior. Required for normal proliferation of embryonic cardiac myocytes and normal heart development. Protects cardiomyocytes against apoptosis. Plays a role in the adaptation of pulmonary arteries to chronic hypoxia. Plays a role in vasoconstriction. Required for normal osteoblast function and proliferation, and for maintaining normal bone density. Required for normal proliferation of the interstitial cells of Cajal in the intestine. {ECO:0000269|PubMed:12970106, ECO:0000269|PubMed:18703043, ECO:0000269|PubMed:23519210, ECO:0000269|PubMed:23519215, ECO:0000269|PubMed:7926008, ECO:0000269|PubMed:8078486, ECO:0000269|PubMed:8143856, ECO:0000269|PubMed:8882600}. | 15.11 | |||
| dpc5NTD | 5'-nucleotidase | 0 | 44 | 82.61 | ND | 96.94 | 0.21 | ND | 0.4 | Mammalian | Enzyme | Calcification of joints and arteries (CALJA) [MIM:211800]: A condition characterized by adult-onset calcification of the lower extremity arteries, including the iliac, femoral and tibial arteries, and hand and foot capsule joints. Age of onset has been reported as early as the second decade of life, usually involving intense joint pain or calcification in the hands. {ECO:0000269|PubMed:21288095}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Hydrolyzes extracellular nucleotides into membrane permeable nucleosides. Exhibits AMP-, NAD-, and NMN-nucleosidase activities. {ECO:0000269|PubMed:21933152}. | 15.11 | ||||
| dpcAA2AR | Adenosine receptor A2a | 0 | 4634 | 82.35 | ND | 95.46 | 0.58 | ND | 0.7 | Nature11159 | Mammalian | Angina pectoris Flushing Palpitations | Family A G protein-coupled receptor | Analgesics
Brain injury Depression Dyskinesia Inflammation Ischemia reperfusion injuries Neurodegenerative diseases Neuropsychiatric disorders Oxygen-induced retinopathy Pain Parkinson's disease Renal diseases | Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. | Adenosine receptor A2a agonist: Adenosine, Regadenoson Adenosine receptor A2a antagonist: Dyphylline, Mefloquine, Oxtriphylline, Pentoxifylline, Theobromine, Theophylline Adenosine receptor A2a antagonist;multitarget: Caffeine Adenosine receptor A2a unknown: Enprofylline | 15.11 | |
| dpcAAK1 | AP2-associated protein kinase 1 | 0 | 67 | 84.26 | ND | 84.06 | 0.23 | ND | 0.9 | Mammalian | Detected in brain, heart and liver. Isoform 1 is the predominant isoform in brain. {ECO:0000269|PubMed:17494869}. | Kinase | Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity. {ECO:0000269|PubMed:12952931, ECO:0000269|PubMed:17494869, ECO:0000269|PubMed:18657069, ECO:0000269|PubMed:21464124}. | 15.11 | ||||
| dpcAAPK1 | 5'-AMP-activated protein kinase catalytic subunit alpha-1 | 0 | 307 | 81.92 | ND | 84.59 | 0.23 | ND | 0.8 | Mammalian | Kinase | Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. {ECO:0000269|PubMed:11518699, ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:18439900, ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641}. | 5'-AMP-activated protein kinase catalytic subunit alpha-1 activator: Acetylsalicylic acid, Adenosine monophosphate, Phenformin 5'-AMP-activated protein kinase catalytic subunit alpha-1 unknown: Adenosine triphosphate | 15.11 | ||||
| dpcABL1 | Tyrosine-protein kinase ABL1 | 0 | 1065 | 88.28 | ND | 93.95 | 0.54 | ND | 0.8 | Mammalian | Widely expressed. | Kinase | Leukemia, chronic myeloid (CML) [MIM:608232]: A clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B-lymphoid, and sometimes T-lymphoid cells, but not marrow fibroblasts. Note=The gene represented in this entry is involved in disease pathogenesis. Note=A chromosomal aberration involving ABL1 has been found in patients with chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). | Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage- induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin- associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. {ECO:0000269|PubMed:10391250, ECO:0000269|PubMed:11971963, ECO:0000269|PubMed:12379650, ECO:0000269|PubMed:12531427, ECO:0000269|PubMed:12672821, ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:15556646, ECO:0000269|PubMed:15657060, ECO:0000269|PubMed:15886098, ECO:0000269|PubMed:16424036, ECO:0000269|PubMed:16678104, ECO:0000269|PubMed:16943190, ECO:0000269|PubMed:17306540, ECO:0000269|PubMed:17623672, ECO:0000269|PubMed:18328268, ECO:0000269|PubMed:18945674, ECO:0000269|PubMed:19891780, ECO:0000269|PubMed:20357770, ECO:0000269|PubMed:20417104, ECO:0000269|PubMed:9037071, ECO:0000269|PubMed:9144171, ECO:0000269|PubMed:9461559}. | Tyrosine-protein kinase ABL1 inhibitor: Adenosine triphosphate, Bosutinib, Imatinib, Nilotinib, Ponatinib, Regorafenib Tyrosine-protein kinase ABL1 multitarget: Dasatinib | 15.11 | ||
| dpcABL2 | Abelson tyrosine-protein kinase 2 | 0 | 81 | 91.23 | ND | 87.78 | 0.43 | ND | 0.9 | Mammalian | Widely expressed. | Kinase | Non-receptor tyrosine-protein kinase that plays an ABL1- overlapping role in key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion and receptor endocytosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like MYH10 (involved in movement); CTTN (involved in signaling); or TUBA1 and TUBB (microtubule subunits). Binds directly F-actin and regulates actin cytoskeletal structure through its F-actin- bundling activity. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as CRK, CRKL, DOK1 or ARHGAP35. Adhesion-dependent phosphorylation of ARHGAP35 promotes its association with RASA1, resulting in recruitment of ARHGAP35 to the cell periphery where it inhibits RHO. Phosphorylates multiple receptor tyrosine kinases like PDGFRB and other substrates which are involved in endocytosis regulation such as RIN1. In brain, may regulate neurotransmission by phosphorylating proteins at the synapse. ABL2 acts also as a regulator of multiple pathological signaling cascades during infection. Pathogens can highjack ABL2 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. {ECO:0000269|PubMed:15735735, ECO:0000269|PubMed:15886098, ECO:0000269|PubMed:16678104, ECO:0000269|PubMed:17306540, ECO:0000269|PubMed:18945674}. | Abelson tyrosine-protein kinase 2 inhibitor: Adenosine triphosphate Abelson tyrosine-protein kinase 2 multitarget: Dasatinib | 15.11 | |||
| dpcACACB | Acetyl-CoA carboxylase 2 | 0 | 307 | 91.03 | ND | 99.26 | 0.30 | ND | 0.6 | Mammalian | Widely expressed with highest levels in heart, skeletal muscle, liver, adipose tissue, mammary gland, adrenal gland and colon (PubMed:9099716). Isoform 3 is expressed in skeletal muscle, adipose tissue and liver (at protein level) (PubMed:19190759). Isoform 3 is detected at high levels in adipose tissue with lower levels in heart, liver, skeletal muscle and testis (PubMed:19190759). {ECO:0000269|PubMed:19190759, ECO:0000269|PubMed:9099716}. | Enzyme | Obesity | Catalyzes the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA. Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. Involved in inhibition of fatty acid and glucose oxidation and enhancement of fat storage (By similarity). May play a role in regulation of mitochondrial fatty acid oxidation through malonyl- CoA-dependent inhibition of carnitine palmitoyltransferase 1 (By similarity). {ECO:0000250|UniProtKB:E9Q4Z2, ECO:0000269|PubMed:20952656}. | Acetyl-CoA carboxylase 2 unknown: Adenine, Biotin | 15.11 | ||
| dpcACE | Angiotensin-converting enzyme | 0 | 1219 | 83.27 | ND | 96.46 | 0.34 | ND | 0.9 | Mammalian | Ubiquitously expressed, with highest levels in lung, kidney, heart, gastrointestinal system and prostate. Isoform Testis-specific is expressed in spermatocytes and adult testis. {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:12459472, ECO:0000269|PubMed:15671045}. | Angioedema Cough Dysgeusia Palpitations Pancreatitis | Protease | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry. Microvascular complications of diabetes 3 (MVCD3) [MIM:612624]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end- stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Intracerebral hemorrhage (ICH) [MIM:614519]: A pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke. {ECO:0000269|PubMed:15277638}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. | Angiotensin-converting enzyme inhibitor: Benazepril, Candoxatril, Captopril, Cilazapril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Rescinnamine, Spirapril, Trandolapril | 15.11 | |
| dpcACES | Acetylcholinesterase | 0 | 3484 | 73.06 | ND | 90.64 | 0.55 | ND | 0.9 | Mammalian | Isoform H is highly expressed in erythrocytes. {ECO:0000269|PubMed:2714437}. | Diarrhoea Nausea Salivary hypersecretion | Hydrolase | Alzheimer's disease
Cognitive deficits Hypoxic-ischemic encephalopathy Motor neurone disease Parkinson's disease | Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis. {ECO:0000269|PubMed:11985878, ECO:0000269|PubMed:1517212, ECO:0000269|PubMed:1748670, ECO:0000269|PubMed:2714437}. | Acetylcholinesterase activator: Pralidoxime Acetylcholinesterase antagonist: Dimetacrine Acetylcholinesterase antagonist;inhibitor: Pyridostigmine Acetylcholinesterase inhibitor: Ambenonium, Decamethonium, Demecarium, Donepezil, Edrophonium, Galantamine, Gallamine Triethiodide, Isoflurophate, Mefloquine, Minaprine, Neostigmine, Physostigmine, Rivastigmine, Tubocurarine Acetylcholinesterase product of: Choline Acetylcholinesterase unknown: Dipivefrin, Ephedrine | 15.11 | |
| dpcACK1 | Activated CDC42 kinase 1 | 0 | 288 | 93.80 | ND | 93.80 | 0.50 | ND | 0.7 | Mammalian | The Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. It also shows a significant increase in expression in prostate cancers during the progressive stages. {ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20623637}. | Kinase | Non-receptor tyrosine-protein and serine/threonine- protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr- 287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. {ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:11278436, ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:18262180, ECO:0000269|PubMed:18435854, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20383201}. | Activated CDC42 kinase 1 unknown: Adenosine triphosphate | 15.11 | |||
| dpcACVR1 | Activin receptor type-1 | 0 | 188 | 88.23 | ND | 90.45 | 0.49 | ND | 0.6 | Mammalian | Expressed in normal parenchymal cells, endothelial cells, fibroblasts and tumor-derived epithelial cells. | Kinase | Fibrodysplasia ossificans progressiva (FOP) [MIM:135100]: A rare autosomal dominant connective tissue disorder resulting in skeletal malformations and progressive extraskeletal ossification. Heterotopic ossification begins in childhood and can be induced by trauma or may occur without warning. Bone formation is episodic and progressive, leading to a debilitating ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible. {ECO:0000269|PubMed:16642017, ECO:0000269|PubMed:19085907, ECO:0000269|PubMed:19330033}. Note=The disease is caused by mutations affecting the gene represented in this entry. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin. May be involved for left-right pattern formation during embryogenesis (By similarity). {ECO:0000250}. | Activin receptor type-1 unknown: Adenosine triphosphate | 15.11 | ||
| dpcADA17 | Disintegrin and metalloproteinase domain-containing protein 17 | 0 | 1423 | 86.63 | ND | 98.58 | 0.70 | ND | 0.6 | Mammalian | Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney. | Protease | Inflammatory skin and bowel disease, neonatal, 1 (NISBD1) [MIM:614328]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269|PubMed:22010916}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2. {ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:24226769, ECO:0000269|PubMed:24227843}. | 15.11 | |||
| dpcADK | Adenosine kinase | 0 | 436 | 76.79 | ND | 96.72 | 0.67 | ND | 0.7 | Mammalian | Widely expressed. Highest level in placenta, liver, muscle and kidney. | Enzyme | Hypermethioninemia due to adenosine kinase deficiency (HMAKD) [MIM:614300]: A metabolic disorder characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S- adenosylmethionine and S-adenosylhomocysteine. Homocysteine levels are typically normal. {ECO:0000269|PubMed:21963049}. Note=The disease is caused by mutations affecting the gene represented in this entry. | ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives. Serves as a potential regulator of concentrations of extracellular adenosine and intracellular adenine nucleotides. | Adenosine kinase activator: Ribavirin Adenosine kinase product of: Adenosine monophosphate Adenosine kinase substrate: Abacavir, Adenosine, Adenosine triphosphate, Ribavirin | 15.11 | ||
| dpcADRB2 | Beta-2 adrenergic receptor | 0 | 1866 | 84.77 | ND | 92.98 | 0.60 | ND | 0.9 | Nature11159 | Mammalian | Angina pectoris Anxiety Arrhythmia Atrioventricular block Bradycardia Bronchospasm Cardiac arrest Cardiac failure Cardiac failure congestive Dry eye Fear Myocardial infarction Neurotoxicity Palpitations Peripheral coldness Raynaud's phenomenon Sleep disorder Tachycardia Tension Tremor Vasodilatation Ventricular arrhythmia | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Asthma Cardiac arrhythmias Chronic obstructive pulmonary disease, unspecified Depression Glaucoma Hypertension Inflammation Multiple sclerosis Obstructive airway disease Respiratory distress syndrome Skeletal muscle wasting Skeletal muscle weakness | Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine. | Beta-2 adrenergic receptor agonist: Amphetamine, Arbutamine, Arformoterol, Bambuterol, Clenbuterol, Dipivefrin, Dobutamine, Droxidopa, Epinephrine, Fenoterol, Formoterol, Indacaterol, Isoetarine, Isoprenaline, Mephentermine, Norepinephrine, Olodaterol, Orciprenaline, Phenylpropanolamine, Pirbuterol, Procaterol, Ritodrine, Salbutamol, Salmeterol, Terbutaline Beta-2 adrenergic receptor antagonist: Alprenolol, Asenapine, Betaxolol, Bethanidine, Bevantolol, Bisoprolol, Bupranolol, Carteolol, Carvedilol, Desipramine, Labetalol, Levobunolol, Metipranolol, Metoprolol, Nadolol, Nebivolol, Nortriptyline, Oxprenolol, Propranolol, Sotalol, Timolol Beta-2 adrenergic receptor antagonist;partial agonist: Penbutolol Beta-2 adrenergic receptor binder: Amitriptyline, Cabergoline, Mirtazapine, Trimipramine Beta-2 adrenergic receptor partial agonist: Acebutolol, Bopindolol, Pindolol, Pseudoephedrine Beta-2 adrenergic receptor unknown: Atenolol, Olanzapine, Phenoxybenzamine | 15.11 | |
| dpcAK1C1 | Aldo-keto reductase family 1 member C1 | 0 | 162 | 86.09 | ND | 96.51 | 0.74 | ND | 0.6 | Mammalian | Expressed in all tissues tested including liver, prostate, testis, adrenal gland, brain, uterus, mammary gland and keratinocytes. Highest levels found in liver, mammary gland and brain. {ECO:0000269|PubMed:11013348}. | Enzyme | Converts progesterone to its inactive form, 20-alpha- dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine, may have a role in the transport of bile. May have a role in monitoring the intrahepatic bile acid concentration. Has a low bile-binding ability. May play a role in myelin formation. {ECO:0000269|PubMed:11013348, ECO:0000269|PubMed:8573067}. | Aldo-keto reductase family 1 member C1 inhibitor: Acetylsalicylic acid, Salicylic acid | 15.11 | |||
| dpcAK1C2 | Aldo-keto reductase family 1 member C2 | 0 | 270 | 70.37 | ND | 92.81 | 0.70 | ND | 0.4 | Mammalian | Expressed in fetal testes. Expressed in fetal and adult adrenal glands. {ECO:0000269|PubMed:21802064}. | Enzyme | 46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. {ECO:0000269|PubMed:21802064}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha- DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability. {ECO:0000269|PubMed:15929998, ECO:0000269|PubMed:17034817, ECO:0000269|PubMed:17442338, ECO:0000269|PubMed:8573067}. | Aldo-keto reductase family 1 member C2 inducer: Ursodeoxycholic acid | 15.11 | ||
| dpcALDH2 | Aldehyde dehydrogenase, mitochondrial | 0 | 60 | 86.37 | ND | 96.71 | 0.00 | ND | 0.7 | Mammalian | Oxidoreductase | Alcoholism | Aldehyde dehydrogenase, mitochondrial inhibitor: Disulfiram, Nitric Oxide Aldehyde dehydrogenase, mitochondrial substrate: Amyl Nitrite, Benzyl alcohol, Nitroglycerin Aldehyde dehydrogenase, mitochondrial unknown: Guanidine | 15.11 | ||||
| dpcALDR | Aldose reductase | 0 | 1393 | 78.66 | ND | 92.51 | 0.52 | ND | 0.8 | Mammalian | Highly expressed in embryonic epithelial cells (EUE) in response to osmotic stress. {ECO:0000269|PubMed:8435445}. | Gastrointestinal disorder | Enzyme | Analgesics
Diabetic complications Diabetic neuropathy Diabetic retinopathy Neuropathic pain Noninsulin-dependent diabetes mellitus | Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies. | Aldose reductase inhibitor: Sulindac | 15.11 | |
| dpcALK | ALK tyrosine kinase receptor | 0 | 751 | 89.11 | ND | 93.77 | 0.63 | ND | 0.8 | Mammalian | Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells. {ECO:0000269|PubMed:9174053}. | Kinase | Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. {ECO:0000269|PubMed:18724359, ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth. | Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK. {ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:11387242, ECO:0000269|PubMed:11809760, ECO:0000269|PubMed:12107166, ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:15908427, ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988}. | ALK tyrosine kinase receptor antagonist: Ceritinib ALK tyrosine kinase receptor inhibitor: Crizotinib ALK tyrosine kinase receptor unknown: Adenosine triphosphate | 15.11 | ||
| dpcAMPE | Glutamyl aminopeptidase | 0 | 48 | 78.98 | ND | 98.87 | 0.34 | ND | 1.0 | Mammalian | Expressed by epithelial cells of the proximal tubule cells and the glomerulus of the nephron. Also found in a variety of other tissues. | Protease | Hypertension | Appears to have a role in the catabolic pathway of the renin-angiotensin system. Probably plays a role in regulating growth and differentiation of early B-lineage cells. | 15.11 | |||
| dpcANDR | Androgen receptor | 0 | 1802 | 76.02 | ND | 91.51 | 0.62 | ND | 0.7 | Nature11159 VirtualToxLab | Mammalian | Isoform 2 is mainly expressed in heart and skeletal muscle. {ECO:0000269|PubMed:15634333}. | Acne Amenorrhoea Azoospermia Bone disorder Breast pain Cushingoid Depression Electrolyte imbalance Endocrine disorder Epiphyses premature fusion Gynaecomastia Hepatic function abnormal Hirsutism Hypercalcaemia Infertility Jaundice cholestatic Libido decreased Menstrual disorder Metrorrhagia Oedema Osteoporosis Priapism Virilism Weight increased | Nuclear receptor | Androgen insensitivity syndrome (AIS) [MIM:300068]: An X- linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10221770, ECO:0000269|PubMed:10404311, ECO:0000269|PubMed:10458483, ECO:0000269|PubMed:10571951, ECO:0000269|PubMed:10590024, ECO:0000269|PubMed:10690872, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:11744994, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1426313, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:1464650, ECO:0000269|PubMed:1480178, ECO:0000269|PubMed:1487249, ECO:0000269|PubMed:1569163, ECO:0000269|PubMed:1609793, ECO:0000269|PubMed:1775137, ECO:0000269|PubMed:1999491, ECO:0000269|PubMed:2082179, ECO:0000269|PubMed:2594783, ECO:0000269|PubMed:7537149, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7633398, ECO:0000269|PubMed:7641413, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7962294, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:7981689, ECO:0000269|PubMed:7993455, ECO:0000269|PubMed:8040309, ECO:0000269|PubMed:8096390, ECO:0000269|PubMed:8103398, ECO:0000269|PubMed:8162033, ECO:0000269|PubMed:8224266, ECO:0000269|PubMed:8281140, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8413310, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8626869, ECO:0000269|PubMed:8647313, ECO:0000269|PubMed:8683794, ECO:0000269|PubMed:8723113, ECO:0000269|PubMed:8768864, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8830623, ECO:0000269|PubMed:8918984, ECO:0000269|PubMed:8990010, ECO:0000269|PubMed:9001799, ECO:0000269|PubMed:9007482, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9106550, ECO:0000269|PubMed:9160185, ECO:0000269|PubMed:9252933, ECO:0000269|PubMed:9255042, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9328206, ECO:0000269|PubMed:9544375, ECO:0000269|PubMed:9554754, ECO:0000269|PubMed:9610419, ECO:0000269|PubMed:9627582, ECO:0000269|PubMed:9698822, ECO:0000269|PubMed:9788719, ECO:0000269|PubMed:9851768, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.109, ECO:0000269|Ref.175}. Note=The disease is caused by mutations affecting the gene represented in this entry. Spinal and bulbar muscular atrophy X-linked 1 (SMAX1) [MIM:313200]: An X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. {ECO:0000269|PubMed:15851746}. Note=The disease is caused by mutations affecting the gene represented in this entry. Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. Note=Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. Androgen insensitivity, partial (PAIS) [MIM:312300]: A disorder that is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10470409, ECO:0000269|PubMed:10502786, ECO:0000269|PubMed:10543676, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:1303262, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1424203, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:2010552, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7649358, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7909256, ECO:0000269|PubMed:7910529, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:8033918, ECO:0000269|PubMed:8097257, ECO:0000269|PubMed:8126121, ECO:0000269|PubMed:8205256, ECO:0000269|PubMed:8281139, ECO:0000269|PubMed:8325932, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8550758, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8823308, ECO:0000269|PubMed:8824883, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9196614, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9329414, ECO:0000269|PubMed:9543136, ECO:0000269|PubMed:9607727, ECO:0000269|PubMed:9768671, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.117}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. {ECO:0000269|PubMed:14664718, ECO:0000269|PubMed:15563469, ECO:0000269|PubMed:17591767, ECO:0000269|PubMed:17911242, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:19345326, ECO:0000269|PubMed:20980437}. | Androgen receptor agonist: Danazol, Drostanolone, Fludrocortisone, Fluoxymesterone, Levonorgestrel, Methyltestosterone, Nandrolone decanoate, Nandrolone phenpropionate, Oxandrolone, Testosterone, Testosterone Propionate Androgen receptor antagonist: Bicalutamide, Cyproterone acetate, Drospirenone, Flutamide, Nilutamide, Spironolactone Androgen receptor binder: Ketoconazole Androgen receptor inhibitor: Enzalutamide | 15.11 |
| dpcANM3 | Protein arginine N-methyltransferase 3 | 0 | 48 | 97.39 | ND | 99.82 | 0.64 | ND | 0.5 | Mammalian | Writer | Methylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in some proteins. | 15.11 | |||||
| dpcAOC1 | Amiloride-sensitive amine oxidase [copper-containing] | 0 | 40 | 75.97 | ND | 99.06 | 0.37 | ND | 0.6 | Mammalian | Placenta and kidney. | Enzyme | Catalyzes the degradation of compounds such as putrescine, histamine, spermine, and spermidine, substances involved in allergic and immune responses, cell proliferation, tissue differentiation, tumor formation, and possibly apoptosis. Placental DAO is thought to play a role in the regulation of the female reproductive function. | Amiloride-sensitive amine oxidase [copper-containing] inhibitor: Amiloride | 15.11 | |||
| dpcAT1A1 | Sodium/potassium-transporting ATPase subunit alpha-1 | 0 | 44 | 71.15 | ND | 87.14 | 0.21 | ND | 0.7 | Mammalian | This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients. | 15.11 | ||||||
| dpcBACE2 | Beta-secretase 2 | 0 | 417 | 80.74 | ND | 98.36 | 0.48 | ND | 0.5 | Mammalian | Brain. Present in neurons within the hippocampus, frontal cortex and temporal cortex (at protein level). Expressed at low levels in most peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at low levels in the brain. Found in spinal cord, medulla oblongata, substantia nigra and locus coruleus. Expressed in the ductal epithelium of both normal and malignant prostate. {ECO:0000269|PubMed:10591213, ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:10683441, ECO:0000269|PubMed:10749877, ECO:0000269|PubMed:10838186, ECO:0000269|PubMed:10965118, ECO:0000269|PubMed:11083922}. | Protease | Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C- terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672. {ECO:0000269|PubMed:10591213, ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:11423558, ECO:0000269|PubMed:15857888, ECO:0000269|PubMed:16816112}. | 15.11 | ||||
| dpcBCL2 | Apoptosis regulator Bcl-2 | 0 | 251 | 79.08 | ND | 94.62 | 0.65 | ND | 0.7 | Mammalian | Expressed in a variety of tissues. | Other ion channel | Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. | Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785). {ECO:0000269|PubMed:17418785, ECO:0000269|PubMed:18570871}. | Apoptosis regulator Bcl-2 modulator: Ibuprofen | 15.11 | ||
| dpcBGAL | Beta-galactosidase | 0 | 65 | 91.14 | ND | 90.15 | 0.43 | ND | 0.6 | Mammalian | Enzyme | GM1-gangliosidosis 1 (GM1G1) [MIM:230500]: An autosomal recessive lysosomal storage disease marked by the accumulation of GM1 gangliosides, glycoproteins and keratan sulfate primarily in neurons of the central nervous system. GM1-gangliosidosis type 1 is characterized by onset within the first three months of life, central nervous system degeneration, coarse facial features, hepatosplenomegaly, skeletal dysmorphology reminiscent of Hurler syndrome, and rapidly progressive psychomotor deterioration. Urinary oligosaccharide levels are high. It leads to death usually between the first and second year of life. {ECO:0000269|PubMed:10338095, ECO:0000269|PubMed:10737981, ECO:0000269|PubMed:10839995, ECO:0000269|PubMed:1487238, ECO:0000269|PubMed:15365997, ECO:0000269|PubMed:15714521, ECO:0000269|PubMed:15791924, ECO:0000269|PubMed:16538002, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:1928092, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:25936995, ECO:0000269|PubMed:8213816, ECO:0000269|Ref.24, ECO:0000269|Ref.27}. Note=The disease is caused by mutations affecting the gene represented in this entry. GM1-gangliosidosis 2 (GM1G2) [MIM:230600]: A gangliosidosis characterized by onset between ages 1 and 5. The main symptom is locomotor ataxia, ultimately leading to a state of decerebration with epileptic seizures. Patients do not display the skeletal changes associated with the infantile form, but they nonetheless excrete elevated amounts of beta-linked galactose- terminal oligosaccharides. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10737981, ECO:0000269|PubMed:12644936, ECO:0000269|PubMed:15714521, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:25936995, ECO:0000269|PubMed:8213816}. Note=The disease is caused by mutations affecting the gene represented in this entry. GM1-gangliosidosis 3 (GM1G3) [MIM:230650]: A gangliosidosis with a variable phenotype. Patients show mild skeletal abnormalities, dysarthria, gait disturbance, dystonia and visual impairment. Visceromegaly is absent. Intellectual deficit can initially be mild or absent but progresses over time. Inheritance is autosomal recessive. {ECO:0000269|PubMed:11511921, ECO:0000269|PubMed:15986423, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:25936995, ECO:0000269|PubMed:8198123, ECO:0000269|Ref.24, ECO:0000269|Ref.26}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mucopolysaccharidosis 4B (MPS4B) [MIM:253010]: A form of mucopolysaccharidosis type 4, an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate. Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal and there is no direct central nervous system involvement, although the skeletal changes may result in neurologic complications. There is variable severity, but patients with the severe phenotype usually do not survive past the second or third decade of life. {ECO:0000269|PubMed:11511921, ECO:0000269|PubMed:12393180, ECO:0000269|PubMed:16538002, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:1928092, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:7586649}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans. Isoform 2 has no beta-galactosidase catalytic activity, but plays functional roles in the formation of extracellular elastic fibers (elastogenesis) and in the development of connective tissue. Seems to be identical to the elastin-binding protein (EBP), a major component of the non-integrin cell surface receptor expressed on fibroblasts, smooth muscle cells, chondroblasts, leukocytes, and certain cancer cell types. In elastin producing cells, associates with tropoelastin intracellularly and functions as a recycling molecular chaperone which facilitates the secretions of tropoelastin and its assembly into elastic fibers. | 15.11 | ||||
| dpcBIRC2 | Baculoviral IAP repeat-containing protein 2 | 0 | 123 | 94.67 | ND | 98.74 | 0.49 | ND | 0.8 | Mammalian | Present in many fetal and adult tissues. Mainly expressed in adult skeletal muscle, thymus, testis, ovary, and pancreas, low or absent in brain and peripheral blood leukocytes. | Enzyme | Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin- protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin- protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO, IKBKE and MXD1/MAD1. Can also function as an E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase- dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle. {ECO:0000269|PubMed:15665297, ECO:0000269|PubMed:18082613, ECO:0000269|PubMed:21145488, ECO:0000269|PubMed:21653699, ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:23453969}. | 15.11 | ||||
| dpcBMP2K | BMP-2-inducible protein kinase | 0 | 65 | 88.22 | ND | 88.89 | 0.55 | ND | 0.8 | Mammalian | Kinase | May be involved in osteoblast differentiation. | 15.11 | |||||
| dpcBMR1B | Bone morphogenetic protein receptor type-1B | 0 | 70 | 92.92 | ND | 88.66 | 0.36 | ND | 0.8 | Mammalian | Kinase | Acromesomelic chondrodysplasia, with genital anomalies (AMDGA) [MIM:609441]: A form of chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). {ECO:0000269|PubMed:15805157}. Note=The disease is caused by mutations affecting the gene represented in this entry. Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. {ECO:0000269|PubMed:14523231, ECO:0000269|PubMed:16957682}. Note=The disease is caused by mutations affecting the gene represented in this entry. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP7/OP-1 and GDF5. Positively regulates chondrocyte differentiation through GDF5 interaction (By similarity). {ECO:0000250|UniProtKB:P36898}. | 15.11 | ||||
| dpcBMX | Cytoplasmic tyrosine-protein kinase BMX | 0 | 84 | 78.19 | ND | 83.41 | 0.37 | ND | 0.6 | Mammalian | Highly expressed in cells with great migratory potential, including endothelial cells and metastatic carcinoma cell lines. | Kinase | Non-receptor tyrosine kinase that plays central but diverse modulatory roles in various signaling processes involved in the regulation of actin reorganization, cell migration, cell proliferation and survival, cell adhesion, and apoptosis. Participates in signal transduction stimulated by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen receptors and integrins. Induces tyrosine phosphorylation of BCAR1 in response to integrin regulation. Activation of BMX by integrins is mediated by PTK2/FAK1, a key mediator of integrin signaling events leading to the regulation of actin cytoskeleton and cell motility. Plays a critical role in TNF-induced angiogenesis, and implicated in the signaling of TEK and FLT1 receptors, 2 important receptor families essential for angiogenesis. Required for the phosphorylation and activation of STAT3, a transcription factor involved in cell differentiation. Also involved in interleukin-6 (IL6) induced differentiation. Plays also a role in programming adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts. May be involved in regulation of endocytosis through its interaction with an endosomal protein RUFY1. May also play a role in the growth and differentiation of hematopoietic cells; as well as in signal transduction in endocardial and arterial endothelial cells. {ECO:0000269|PubMed:10688651, ECO:0000269|PubMed:11331870, ECO:0000269|PubMed:12370298, ECO:0000269|PubMed:12832404, ECO:0000269|PubMed:15788485, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:9520419}. | 15.11 | ||||
| dpcBRD2 | Bromodomain-containing protein 2 | 0 | 75 | 97.69 | ND | 99.75 | 0.14 | ND | 0.3 | Mammalian | Reader | May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly. {ECO:0000250, ECO:0000269|PubMed:18406326}. | 15.11 | |||||
| dpcBRD4 | Bromodomain-containing protein 4 | 0 | 212 | 92.40 | ND | 95.38 | 0.46 | ND | 0.5 | Mammalian | Ubiquitously expressed. {ECO:0000269|PubMed:12543779}. | Reader | Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. {ECO:0000269|PubMed:11733348, ECO:0000269|PubMed:12543779}. | Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P- TEFb complex and recruiting it to promoters: BRD4 is required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P- TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo (PubMed:22509028). In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters. {ECO:0000269|PubMed:22509028}. Isoform B: Acts as a chromatin insulator in the DNA damage response pathway. Inhibits DNA damage response signaling by recruiting the condensin-2 complex to acetylated histones, leading to chromatin structure remodeling, insulating the region from DNA damage response by limiting spreading of histone H2AFX/H2A.x phosphorylation. | 15.11 | |||
| dpcBTK | Tyrosine-protein kinase BTK | 0 | 341 | 84.95 | ND | 86.96 | 0.58 | ND | 0.8 | Mammalian | Predominantly expressed in B-lymphocytes. | Kinase | X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin. {ECO:0000269|PubMed:10220140, ECO:0000269|PubMed:10612838, ECO:0000269|PubMed:10678660, ECO:0000269|PubMed:7627183, ECO:0000269|PubMed:7633420, ECO:0000269|PubMed:7633429, ECO:0000269|PubMed:7711734, ECO:0000269|PubMed:7809124, ECO:0000269|PubMed:7849006, ECO:0000269|PubMed:7849697, ECO:0000269|PubMed:7849721, ECO:0000269|PubMed:7880320, ECO:0000269|PubMed:7897635, ECO:0000269|PubMed:8013627, ECO:0000269|PubMed:8162018, ECO:0000269|PubMed:8162056, ECO:0000269|PubMed:8634718, ECO:0000269|PubMed:8695804, ECO:0000269|PubMed:8723128, ECO:0000269|PubMed:8834236, ECO:0000269|PubMed:9260159, ECO:0000269|PubMed:9280283, ECO:0000269|PubMed:9445504, ECO:0000269|PubMed:9545398}. Note=The disease is caused by mutations affecting the gene represented in this entry. X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). Note=The disease may be caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. {ECO:0000269|PubMed:11606584, ECO:0000269|PubMed:16415872, ECO:0000269|PubMed:16517732, ECO:0000269|PubMed:16738337, ECO:0000269|PubMed:17932028, ECO:0000269|PubMed:9012831}. | Tyrosine-protein kinase BTK inhibitor: Ibrutinib | 15.11 | ||
| dpcCAH1 | Carbonic anhydrase 1 | 0 | 2851 | 80.72 | ND | 93.55 | 0.56 | ND | 0.7 | Mammalian | Aplastic anaemia Decreased appetite Electrolyte imbalance Glycosuria Gout Haemolysis Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Hyponatraemia Pancreatic disorder Pancreatitis Purine metabolism disorder Thrombocytopenia Xanthopsia | Lyase | Glaucoma
Hypertension Pancreatic cancer | Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea. {ECO:0000269|PubMed:10550681}. | Carbonic anhydrase 1 inhibitor: Methyclothiazide | 15.11 | ||
| dpcCAH12 | Carbonic anhydrase 12 | 0 | 1156 | 80.50 | ND | 90.60 | 0.60 | ND | 0.7 | Mammalian | Highly expressed in colon, kidney, prostate, intestine and activated lymphocytes. Expressed at much higher levels in the renal cell cancers than in surrounding normal kidney tissue. Moderately expressed in pancreas, ovary and testis. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Photosensitivity reaction Purine metabolism disorder Thrombocytopenia | Lyase | Hyperchlorhidrosis, isolated (HCHLH) [MIM:143860]: A disorder characterized by excessive sweating and increased sweat chloride levels. Affected individuals suffer from episodes of hyponatremic dehydration and report increased amounts of visible salt precipitates in sweat. {ECO:0000269|PubMed:21035102}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Reversible hydration of carbon dioxide. | Carbonic anhydrase 12 inhibitor: Benzthiazide | 15.11 | |
| dpcCAH13 | Carbonic anhydrase 13 | 0 | 222 | 84.29 | ND | 88.09 | 0.70 | ND | 0.8 | Mammalian | Expressed in thymus, small intestine, spleen, prostate, ovary, colon and testis. {ECO:0000269|PubMed:14600151}. | Electrolyte imbalance Haemorrhagic diathesis Hypokalaemia Paraesthesia | Lyase | Reversible hydration of carbon dioxide. | Carbonic anhydrase 13 inhibitor: Zonisamide | 15.11 | ||
| dpcCAH14 | Carbonic anhydrase 14 | 0 | 384 | 75.68 | ND | 88.42 | 0.55 | ND | 0.7 | Mammalian | High expression in all parts of the central nervous system and lower expression in adult liver, heart, small intestine, colon, kidney, urinary bladder and skeletal muscle. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Photosensitivity reaction Purine metabolism disorder | Lyase | Renal failure | Reversible hydration of carbon dioxide. | Carbonic anhydrase 14 inhibitor: Acetazolamide | 15.11 | |
| dpcCAH4 | Carbonic anhydrase 4 | 0 | 1187 | 80.42 | ND | 93.21 | 0.68 | ND | 0.5 | Mammalian | Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels. {ECO:0000269|PubMed:15563508}. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatic disorder Pancreatitis Photosensitivity reaction Purine metabolism disorder Thirst Thrombocytopenia Xanthopsia | Lyase | Retinitis pigmentosa 17 (RP17) [MIM:600852]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:15563508, ECO:0000269|PubMed:17652713, ECO:0000269|PubMed:20450258}. Note=The disease is caused by mutations affecting the gene represented in this entry. Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype. | Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid. {ECO:0000269|PubMed:15563508}. | Carbonic anhydrase 4 inhibitor: Methyclothiazide | 15.11 | |
| dpcCAH7 | Carbonic anhydrase 7 | 0 | 364 | 72.40 | ND | 89.00 | 0.70 | ND | 0.7 | Mammalian | Lyase | Reversible hydration of carbon dioxide. | Carbonic anhydrase 7 inhibitor: Methazolamide | 15.11 | ||||
| dpcCALRL | Calcitonin gene-related peptide type 1 receptor | 0 | 379 | 94.49 | ND | 99.08 | 0.63 | ND | 0.9 | Mammalian | Predominantly expressed in the lung and heart. | Family B G protein-coupled receptor | Cluster Headaches
Diabetes mellitus Migraine Opioid dependence | Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. {ECO:0000250, ECO:0000269|PubMed:22102369}. | 15.11 | |||
| dpcCAN1 | Calpain-1 catalytic subunit | 0 | 538 | 82.07 | ND | 98.11 | 0.63 | ND | 0.8 | Mammalian | Ubiquitous. | Protease | Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. | 15.11 | ||||
| dpcCASP1 | Caspase-1 | 0 | 649 | 89.80 | ND | 96.10 | 0.69 | ND | 0.8 | Mammalian | Expressed in larger amounts in spleen and lung. Detected in liver, heart, small intestine, colon, thymus, prostate, skeletal muscle, peripheral blood leukocytes, kidney and testis. No expression in the brain. {ECO:0000269|PubMed:15498465}. | Protease | Brain inflammation
Cerebral ischemia Diabetic retinopathy Inflammation | Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis. {ECO:0000269|PubMed:15498465, ECO:0000269|PubMed:7876192}. | Caspase-1 negative modulator: Minocycline | 15.11 | ||
| dpcCASP7 | Caspase-7 | 0 | 348 | 72.94 | ND | 93.68 | 0.70 | ND | 0.7 | Mammalian | Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain. | Protease | Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly- 217' bond. Overexpression promotes programmed cell death. | 15.11 | ||||
| dpcCASP8 | Caspase-8 | 0 | 328 | 83.70 | ND | 93.47 | 0.69 | ND | 0.7 | Mammalian | Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle. | Protease | Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. {ECO:0000269|PubMed:12353035}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:9006941}. | 15.11 | |||
| dpcCATB | Cathepsin B | 0 | 1262 | 74.53 | ND | 89.89 | 0.55 | ND | 0.8 | Mammalian | Protease | Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis. | 15.11 | |||||
| dpcCATC | Dipeptidyl peptidase 1 | 0 | 85 | 77.63 | ND | 89.58 | 0.45 | ND | 0.9 | Mammalian | Ubiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas. {ECO:0000269|PubMed:9092576}. | Protease | Papillon-Lefevre syndrome (PLS) [MIM:245000]: An autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees. {ECO:0000269|PubMed:10581027, ECO:0000269|PubMed:10662808, ECO:0000269|PubMed:11106356, ECO:0000269|PubMed:11158173, ECO:0000269|PubMed:11180012, ECO:0000269|PubMed:11180601, ECO:0000269|PubMed:11886537, ECO:0000269|PubMed:12112662, ECO:0000269|PubMed:12809647, ECO:0000269|PubMed:14974080, ECO:0000269|PubMed:15108292, ECO:0000269|PubMed:15991336, ECO:0000269|PubMed:25799584}. Note=The disease is caused by mutations affecting the gene represented in this entry. Haim-Munk syndrome (HMS) [MIM:245010]: An autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis. {ECO:0000269|PubMed:10662807}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodontititis, aggressive, 1 (AP1) [MIM:170650]: A disease characterized by severe and protracted gingival infections, generalized or localized, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting. {ECO:0000269|PubMed:10662808, ECO:0000269|PubMed:14974080}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B. Can also activate neuraminidase and factor XIII. {ECO:0000269|PubMed:1586157}. | 15.11 | |||
| dpcCBP | CREB-binding protein | 0 | 141 | 80.00 | ND | 83.84 | 0.13 | ND | 0.5 | Mammalian | Writer | Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Rubinstein-Taybi syndrome 1 (RSTS1) [MIM:180849]: A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. {ECO:0000269|PubMed:11331617, ECO:0000269|PubMed:12114483, ECO:0000269|PubMed:12566391, ECO:0000269|PubMed:15706485, ECO:0000269|PubMed:20684013, ECO:0000269|PubMed:25388907}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK- ARNTL/BMAL1 heterodimers. Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). {ECO:0000269|PubMed:11154691, ECO:0000269|PubMed:12738767, ECO:0000269|PubMed:12929931, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:24939902, ECO:0000269|PubMed:9707565}. | 15.11 | ||||
| dpcCBPA1 | Carboxypeptidase A1 | 0 | 136 | 72.63 | ND | 96.31 | 0.61 | ND | 0.7 | Mammalian | Pancreas. {ECO:0000269|PubMed:7556081}. | Protease | Carboxypeptidase that catalyzes the release of a C- terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro. {ECO:0000250}. | 15.11 | ||||
| dpcCBPB1 | Carboxypeptidase B | 0 | 77 | 76.72 | ND | 94.17 | 0.78 | ND | 0.7 | Mammalian | Protease | 15.11 | ||||||
| dpcCBPB2 | Carboxypeptidase B2 | 0 | 87 | 71.94 | ND | 92.13 | 0.77 | ND | 0.5 | Mammalian | Plasma; synthesized in the liver. | Protease | Thrombosis | Cleaves C-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities. Down- regulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin. {ECO:0000269|PubMed:10574983}. | 15.11 | |||
| dpcCDC7 | Cell division cycle 7-related protein kinase | 0 | 458 | 91.07 | ND | 94.39 | 0.54 | ND | 0.7 | Mammalian | Kinase | Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3. {ECO:0000269|PubMed:12065429}. | 15.11 | |||||
| dpcCDK5 | Cyclin-dependent-like kinase 5 | 0 | 625 | 78.31 | ND | 87.54 | 0.49 | ND | 0.7 | Mammalian | Isoform 1 is ubiquitously expressed. Accumulates in cortical neurons (at protein level). Isoform 2 has only been detected in testis, skeletal muscle, colon, bone marrow and ovary. {ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:19693690}. | Kinase | Lissencephaly 7, with cerebellar hypoplasia (LIS7) [MIM:616342]: A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six- layered cortex. LIS7 patients manifest lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy. {ECO:0000269|PubMed:25560765}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3- type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma- dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin- dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1- EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution. {ECO:0000269|PubMed:12393264, ECO:0000269|PubMed:12691662, ECO:0000269|PubMed:15992363, ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:17121855, ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17611284, ECO:0000269|PubMed:17671990, ECO:0000269|PubMed:18042622, ECO:0000269|PubMed:19081376, ECO:0000269|PubMed:19693690, ECO:0000269|PubMed:20061803, ECO:0000269|PubMed:20213743, ECO:0000269|PubMed:20826806, ECO:0000269|PubMed:21209322, ECO:0000269|PubMed:21220307, ECO:0000269|PubMed:21442427, ECO:0000269|PubMed:21465480, ECO:0000269|PubMed:21499257, ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:9822744}. | 15.11 | |||
| dpcCDK8 | Cyclin-dependent kinase 8 | 0 | 264 | 82.04 | ND | 87.42 | 0.38 | ND | 1.0 | Mammalian | Kinase | Cancer, unspecific | Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. {ECO:0000269|PubMed:10993082, ECO:0000269|PubMed:15546612}. | 15.11 | ||||
| dpcCDK9 | Cyclin-dependent kinase 9 | 0 | 264 | 83.75 | ND | 89.57 | 0.39 | ND | 0.8 | Mammalian | Ubiquitous. | Kinase | Note=Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy, and confers predisposition to heart failure. | Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single- stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation. {ECO:0000269|PubMed:10393184, ECO:0000269|PubMed:10574912, ECO:0000269|PubMed:10757782, ECO:0000269|PubMed:10912001, ECO:0000269|PubMed:11112772, ECO:0000269|PubMed:11145967, ECO:0000269|PubMed:11575923, ECO:0000269|PubMed:11809800, ECO:0000269|PubMed:11884399, ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:14701750, ECO:0000269|PubMed:15564463, ECO:0000269|PubMed:16109376, ECO:0000269|PubMed:16109377, ECO:0000269|PubMed:17956865, ECO:0000269|PubMed:18362169, ECO:0000269|PubMed:19575011, ECO:0000269|PubMed:19844166, ECO:0000269|PubMed:20081228, ECO:0000269|PubMed:20493174, ECO:0000269|PubMed:20930849, ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:21127351, ECO:0000269|PubMed:9857195}. | 15.11 | |||
| dpcCDKL5 | Cyclin-dependent kinase-like 5 | 0 | 60 | 99.54 | ND | 98.75 | 0.46 | ND | 0.7 | Mammalian | Expressed in brain, lung, kidney, prostate, ovary, placenta, pancreas and testis. | Kinase | Note=Chromosomal aberrations involving CDKL5 are found in patients manifesting early-onset seizures and spams and psychomotor impairment. Translocation t(X;6)(p22.3;q14); translocation t(X;7)(p22.3;p15). Epileptic encephalopathy, early infantile, 2 (EIEE2) [MIM:300672]: A severe form of epilepsy characterized by seizures or spasms beginning in infancy. Patients with epileptic encephalopathy early infantile type 2 manifest features resembling Rett syndrome such as microcephaly, lack of speech development, stereotypic hand movements. However, EIEE2 and Rett syndrome are considered two distinct entities. {ECO:0000269|PubMed:12736870, ECO:0000269|PubMed:15492925, ECO:0000269|PubMed:15499549, ECO:0000269|PubMed:15689447, ECO:0000269|PubMed:15917271, ECO:0000269|PubMed:16015284, ECO:0000269|PubMed:16611748, ECO:0000269|PubMed:17993579, ECO:0000269|PubMed:18790821, ECO:0000269|PubMed:18809835, ECO:0000269|PubMed:19241098, ECO:0000269|PubMed:19253388, ECO:0000269|PubMed:24564546}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates phosphorylation of MECP2. {ECO:0000269|PubMed:15917271, ECO:0000269|PubMed:16935860}. | 15.11 | |||
| dpcCETP | Cholesteryl ester transfer protein {ECO:0000303|PubMed:3600759} | 0 | 676 | 85.96 | ND | 96.55 | 0.51 | ND | 0.7 | Mammalian | Expressed by the liver and secreted in plasma. | Other ion channel | Hyperalphalipoproteinemia 1 (HALP1) [MIM:143470]: A condition characterized by high levels of high density lipoprotein (HDL) and increased HDL cholesterol levels. {ECO:0000269|PubMed:12091484, ECO:0000269|PubMed:2215607, ECO:0000269|PubMed:8408659}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles. Allows the net movement of cholesteryl ester from high density lipoproteins/HDL to triglyceride-rich very low density lipoproteins/VLDL, and the equimolar transport of triglyceride from VLDL to HDL (PubMed:3600759, PubMed:24293641). Regulates the reverse cholesterol transport, by which excess cholesterol is removed from peripheral tissues and returned to the liver for elimination (PubMed:17237796). {ECO:0000269|PubMed:24293641, ECO:0000303|PubMed:17237796, ECO:0000305|PubMed:3600759}. | 15.11 | |||
| dpcCHK1 | Serine/threonine-protein kinase Chk1 | 0 | 1722 | 90.24 | ND | 96.63 | 0.59 | ND | 0.8 | Mammalian | Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon. {ECO:0000269|PubMed:9278511, ECO:0000269|PubMed:9382850}. | Kinase | Solid tumors | Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser- 124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell- cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest. Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition. | 15.11 | |||
| dpcCHK2 | Serine/threonine-protein kinase Chk2 | 0 | 528 | 85.83 | ND | 92.08 | 0.61 | ND | 0.7 | Mammalian | High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues. | Kinase | Li-Fraumeni syndrome 2 (LFS2) [MIM:609265]: A highly penetrant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers. {ECO:0000269|PubMed:11719428}. Note=The disease is caused by mutations affecting the gene represented in this entry. Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:12533788}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Osteogenic sarcoma (OSRC) [MIM:259500]: A sarcoma originating in bone-forming cells, affecting the ends of long bones. Note=The gene represented in this entry may be involved in disease pathogenesis. Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:12094328, ECO:0000269|PubMed:21618645, ECO:0000269|PubMed:25619829}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. {ECO:0000269|PubMed:12094328}. | Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X- R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition (PubMed:25361978). {ECO:0000250|UniProtKB:Q9Z265, ECO:0000269|PubMed:10097108, ECO:0000269|PubMed:10724175, ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:12402044, ECO:0000269|PubMed:12607004, ECO:0000269|PubMed:12717439, ECO:0000269|PubMed:12810724, ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:17101782, ECO:0000269|PubMed:17380128, ECO:0000269|PubMed:17715138, ECO:0000269|PubMed:18317453, ECO:0000269|PubMed:18644861, ECO:0000269|PubMed:18728393, ECO:0000269|PubMed:20364141, ECO:0000269|PubMed:25361978, ECO:0000269|PubMed:25619829, ECO:0000269|PubMed:9836640, ECO:0000269|PubMed:9889122}. | 15.11 | |||
| dpcCLK1 | Dual specificity protein kinase CLK1 | 0 | 402 | 85.86 | ND | 92.22 | 0.40 | ND | 0.7 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA. {ECO:0000269|PubMed:10480872, ECO:0000269|PubMed:19168442}. | 15.11 | ||||
| dpcCLK2 | Dual specificity protein kinase CLK2 | 0 | 483 | 82.29 | ND | 90.03 | 0.26 | ND | 0.7 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. {ECO:0000269|PubMed:10480872, ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:8910305, ECO:0000269|PubMed:9637771}. | 15.11 | ||||
| dpcCLK3 | Dual specificity protein kinase CLK3 | 0 | 138 | 77.89 | ND | 83.70 | 0.09 | ND | 0.4 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Phosphorylates SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. {ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:9637771}. | 15.11 | ||||
| dpcCOMT | Catechol O-methyltransferase | 0 | 82 | 71.36 | ND | 91.96 | 0.68 | ND | 0.8 | Mammalian | Brain, liver, placenta, lymphocytes and erythrocytes. | Transferase | Parkinson's disease | Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol. | Catechol O-methyltransferase cofactor: S-Adenosylmethionine | 15.11 | ||
| dpcCP1A1 | Cytochrome P450 1A1 | 0 | 202 | 82.09 | ND | 88.66 | 0.73 | ND | 0.5 | Mammalian | Lung, lymphocytes and placenta. | Cytochrome P450 | Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. | Cytochrome P450 1A1 inducer: Cytochrome P450 1A1 inhibitor: Vitamin A | 15.11 | |||
| dpcCP2C8 | Cytochrome P450 2C8 | 0 | 328 | 81.86 | ND | 90.47 | 0.33 | ND | 0.8 | Mammalian | Cytochrome P450 | Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol). {ECO:0000269|PubMed:7574697}. | Cytochrome P450 2C8 inhibitor: Cyclosporine | 15.11 | ||||
| dpcCRFR1 | Corticotropin-releasing factor receptor 1 | 0 | 1224 | 91.07 | ND | 97.85 | 0.52 | ND | 0.6 | Nature11159 | Mammalian | Predominantly expressed in the cerebellum, pituitary, cerebral cortex and olfactory lobe. {ECO:0000269|PubMed:8243652}. | Family B G protein-coupled receptor | Anxiety Disorders
Depression Innate anxiety Irritable Bowel Syndrome (IBS) Obesity Stress-related disorders | G-protein coupled receptor for CRH (corticotropin- releasing factor) and UCN (urocortin). Has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. Inhibits the activity of the calcium channel CACNA1H. Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli. {ECO:0000269|PubMed:18292205, ECO:0000269|PubMed:18801728, ECO:0000269|PubMed:23576434, ECO:0000269|PubMed:23863939}. | 15.11 | ||
| dpcCSF1R | Macrophage colony-stimulating factor 1 receptor | 0 | 875 | 87.24 | ND | 95.34 | 0.60 | ND | 0.7 | Mammalian | Expressed in bone marrow and in differentiated blood mononuclear cells. | Kinase | Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers. Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection. Leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:221820]: An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes. {ECO:0000269|PubMed:22197934, ECO:0000269|PubMed:24532199}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5- trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP- 1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:12882960, ECO:0000269|PubMed:15117969, ECO:0000269|PubMed:16170366, ECO:0000269|PubMed:16337366, ECO:0000269|PubMed:16648572, ECO:0000269|PubMed:17121910, ECO:0000269|PubMed:18467591, ECO:0000269|PubMed:18814279, ECO:0000269|PubMed:19193011, ECO:0000269|PubMed:19934330, ECO:0000269|PubMed:20489731, ECO:0000269|PubMed:20504948, ECO:0000269|PubMed:20829061, ECO:0000269|PubMed:7683918}. | Macrophage colony-stimulating factor 1 receptor antagonist: Imatinib | 15.11 | ||
| dpcCSK | Tyrosine-protein kinase CSK | 0 | 160 | 77.62 | ND | 88.90 | 0.13 | ND | 0.6 | Mammalian | Expressed in lung and macrophages. {ECO:0000269|PubMed:1371489}. | Kinase | Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T- cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK. {ECO:0000269|PubMed:1639064, ECO:0000269|PubMed:9281320}. | 15.11 | ||||
| dpcCSK21 | Casein kinase II subunit alpha | 0 | 400 | 78.93 | ND | 90.40 | 0.67 | ND | 0.7 | Mammalian | Expressed in gastric carcinoma tissue and the expression gradually increases with the progression of the carcinoma (at protein level). {ECO:0000269|PubMed:24962073}. | Kinase | Breast cancer
Cancer, unspecific | Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV. Phosphorylates PML at 'Ser-565' and primes it for ubiquitin- mediated degradation. Plays an important role in the circadian clock function by phosphorylating ARNTL/BMAL1 at 'Ser-90' which is pivotal for its interaction with CLOCK and which controls CLOCK nuclear entry (PubMed:11239457, PubMed:11704824, PubMed:16193064, PubMed:19188443, PubMed:20625391, PubMed:22406621). Phosphorylates CCAR2 at 'Thr-454' in gastric carcinoma tissue (PubMed:24962073). {ECO:0000269|PubMed:11239457, ECO:0000269|PubMed:11704824, ECO:0000269|PubMed:16193064, ECO:0000269|PubMed:19188443, ECO:0000269|PubMed:20625391, ECO:0000269|PubMed:22406621, ECO:0000269|PubMed:24962073}. | 15.11 | |||
| dpcCSK22 | Casein kinase II subunit alpha' | 0 | 101 | 92.72 | ND | 88.76 | 0.52 | ND | 0.6 | Mammalian | Kinase | Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV. {ECO:0000269|PubMed:11239457, ECO:0000269|PubMed:11704824, ECO:0000269|PubMed:16193064}. | 15.11 | |||||
| dpcCSKP | Peripheral plasma membrane protein CASK | 0 | 59 | 97.19 | ND | 99.34 | 0.73 | ND | 0.4 | Mammalian | Ubiquitous. Expression is significantly greater in brain relative to kidney, lung, and liver and in fetal brain and kidney relative to lung and liver. {ECO:0000269|PubMed:11003712}. | Enzyme | Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:300749]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Affected individuals can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus. {ECO:0000269|PubMed:19165920, ECO:0000269|PubMed:19377476}. Note=The disease is caused by mutations affecting the gene represented in this entry. FG syndrome 4 (FGS4) [MIM:300422]: FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. {ECO:0000269|PubMed:19200522}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TBR1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. | 15.11 | |||
| dpcCTRA | Chymotrypsinogen A | 0 | 206 | 88.20 | ND | 95.27 | 0.45 | ND | 1.0 | Mammalian | Protease | 15.11 | ||||||
| dpcDAPK1 | Death-associated protein kinase 1 | 0 | 72 | 74.45 | ND | 84.43 | 0.73 | ND | 0.7 | Mammalian | Isoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas. {ECO:0000269|PubMed:18422656}. | Kinase | Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript- selective translation inhibition. Isoform 2 cannot induce apoptosis but can induce membrane blebbing. | 15.11 | ||||
| dpcDAPK2 | Death-associated protein kinase 2 | 0 | 67 | 75.99 | ND | 83.04 | 0.00 | ND | 0.4 | Mammalian | Expressed in neutrophils and eosinophils (PubMed:24163421). Isoform 2 is expressed in embryonic stem cells (at protein level). Isoform 1 is ubiquitously expressed in all tissue types examined with high levels in heart, lung and skeletal muscle. {ECO:0000269|PubMed:10376525, ECO:0000269|PubMed:17347302, ECO:0000269|PubMed:21408167, ECO:0000269|PubMed:24163421}. | Kinase | Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell death signals, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Acts as a mediator of anoikis and a suppressor of beta-catenin-dependent anchorage-independent growth of malignant epithelial cells. May play a role in granulocytic maturation (PubMed:17347302). Regulates granulocytic motility by controlling cell spreading and polarization (PubMed:24163421). {ECO:0000269|PubMed:17347302, ECO:0000269|PubMed:24163421, ECO:0000269|PubMed:26047703}. Isoform 2 is not regulated by calmodulin. It can phosphorylate MYL9. It can induce membrane blebbing and autophagic cell death. | 15.11 | ||||
| dpcDAPK3 | Death-associated protein kinase 3 | 0 | 364 | 84.12 | ND | 89.75 | 0.43 | ND | 0.7 | Mammalian | Widely expressed. Isoform 1 and isoform 2 are expressed in the bladder smooth muscle. {ECO:0000269|PubMed:15292222, ECO:0000269|PubMed:17126281}. | Kinase | Serine/threonine kinase which is involved in the regulation of apoptosis, autophagy, transcription, translation and actin cytoskeleton reorganization. Involved in the regulation of smooth muscle contraction. Regulates both type I (caspase- dependent) apoptotic and type II (caspase-independent) autophagic cell deaths signal, depending on the cellular setting. Involved in regulation of starvation-induced autophagy. Regulates myosin phosphorylation in both smooth muscle and non-muscle cells. In smooth muscle, regulates myosin either directly by phosphorylating MYL12B and MYL9 or through inhibition of smooth muscle myosin phosphatase (SMPP1M) via phosphorylation of PPP1R12A; the inhibition of SMPP1M functions to enhance muscle responsiveness to Ca(2+) and promote a contractile state. Phosphorylates MYL12B in non-muscle cells leading to reorganization of actin cytoskeleton. Isoform 2 can phosphorylate myosin, PPP1R12A and MYL12B. Overexpression leads to condensation of actin stress fibers into thick bundles. Involved in actin filament focal adhesion dynamics. The function in both reorganization of actin cytoskeleton and focal adhesion dissolution is modulated by RhoD. Positively regulates canonical Wnt/beta-catenin signaling through interaction with NLK and TCF7L2. Phosphorylates RPL13A on 'Ser-77' upon interferon-gamma activation which is causing RPL13A release from the ribosome, RPL13A association with the GAIT complex and its subsequent involvement in transcript-selective translation inhibition. Enhances transcription from AR-responsive promoters in a hormone- and kinase-dependent manner. Involved in regulation of cell cycle progression and cell proliferation. May be a tumor suppressor. {ECO:0000269|PubMed:10356987, ECO:0000269|PubMed:11384979, ECO:0000269|PubMed:11781833, ECO:0000269|PubMed:12917339, ECO:0000269|PubMed:15096528, ECO:0000269|PubMed:15367680, ECO:0000269|PubMed:16219639, ECO:0000269|PubMed:17126281, ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:18995835, ECO:0000269|PubMed:21169990, ECO:0000269|PubMed:21408167, ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:21487036, ECO:0000269|PubMed:23454120}. | 15.11 | ||||
| dpcDCAM | S-adenosylmethionine decarboxylase proenzyme | 0 | 53 | 81.39 | ND | 88.71 | 0.13 | ND | 1.7 | Mammalian | Enzyme | Cancer, unspecific
Parasitic diseases Proliferative diseases | Essential for biosynthesis of the polyamines spermidine and spermine. Promotes maintenance and self-renewal of embryonic stem cells, by maintaining spermine levels (By similarity). {ECO:0000250}. | S-adenosylmethionine decarboxylase proenzyme cofactor: S-Adenosylmethionine | 15.11 | |||
| dpcDCK | Deoxycytidine kinase | 0 | 94 | 96.41 | ND | 100.00 | 0.72 | ND | 0.6 | Mammalian | Enzyme | Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents. {ECO:0000269|PubMed:18377927, ECO:0000269|PubMed:20614893}. | Deoxycytidine kinase substrate: Cladribine | 15.11 | ||||
| dpcDDR1 | Epithelial discoidin domain-containing receptor 1 | 0 | 101 | 91.07 | ND | 85.53 | 0.62 | ND | 0.8 | Mammalian | Detected in T-47D, MDA-MB-175 and HBL-100 breast carcinoma cells, A-431 epidermoid carcinoma cells, SW48 and SNU-C2B colon carcinoma cells and Hs 294T melanoma cells (at protein level). Expressed at low levels in most adult tissues and is highest in the brain, lung, placenta and kidney. Lower levels of expression are detected in melanocytes, heart, liver, skeletal muscle and pancreas. Abundant in breast carcinoma cell lines. In the colonic mucosa, expressed in epithelia but not in the connective tissue of the lamina propria. In the thyroid gland, expressed in the epithelium of the thyroid follicles. In pancreas, expressed in the islets of Langerhans cells, but not in the surrounding epithelial cells of the exocrine pancreas. In kidney, expressed in the epithelia of the distal tubules. Not expressed in connective tissue, endothelial cells, adipose tissue, muscle cells or cells of hematopoietic origin. {ECO:0000269|PubMed:7845687, ECO:0000269|PubMed:7848919, ECO:0000269|PubMed:8247543}. | Kinase | Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11. {ECO:0000250, ECO:0000269|PubMed:12065315, ECO:0000269|PubMed:16234985, ECO:0000269|PubMed:16337946, ECO:0000269|PubMed:19401332, ECO:0000269|PubMed:20093046, ECO:0000269|PubMed:20432435, ECO:0000269|PubMed:20884741, ECO:0000269|PubMed:21044884, ECO:0000269|PubMed:9659899}. | Epithelial discoidin domain-containing receptor 1 antagonist: Imatinib | 15.11 | |||
| dpcDEFM | Peptide deformylase, mitochondrial | 0 | 45 | 73.91 | ND | 99.51 | 0.69 | ND | 0.7 | Mammalian | Ubiquitous. | Enzyme | Removes the formyl group from the N-terminal Met of newly synthesized proteins. {ECO:0000250}. | 15.11 | ||||
| dpcDHB1 | Estradiol 17-beta-dehydrogenase 1 | 0 | 298 | 88.42 | ND | 98.31 | 0.63 | ND | 0.6 | Mammalian | Enzyme | Breast cancer (hormone-sensitive) | Favors the reduction of estrogens and androgens. Also has 20-alpha-HSD activity. Uses preferentially NADH. | 15.11 | ||||
| dpcDOT1L | Histone-lysine N-methyltransferase, H3 lysine-79 specific | 0 | 61 | 99.66 | ND | 99.95 | 0.83 | ND | 0.5 | Mammalian | Writer | Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA. | 15.11 | |||||
| dpcDPEP1 | Dipeptidase 1 | 0 | 132 | 71.28 | ND | 99.55 | 0.73 | ND | 0.4 | Mammalian | Protease | Bacterial infections | Hydrolyzes a wide range of dipeptides. Implicated in the renal metabolism of glutathione and its conjugates. Converts leukotriene D4 to leukotriene E4; it may play an important role in the regulation of leukotriene activity. | Dipeptidase 1 inhibitor: Cilastatin | 15.11 | |||
| dpcDPP2 | Dipeptidyl peptidase 2 | 0 | 1200 | 77.62 | ND | 96.77 | 0.70 | ND | 0.6 | Mammalian | Detected in seminal plasma (at protein level). {ECO:0000269|PubMed:15487984}. | Protease | Plays an important role in the degradation of some oligopeptides. {ECO:0000269|PubMed:15487984}. | 15.11 | ||||
| dpcDPP4 | Dipeptidyl peptidase 4 | 0 | 2990 | 82.78 | ND | 96.66 | 0.58 | ND | 0.7 | Mammalian | Expressed specifically in lymphatic vessels but not in blood vessels in the skin, small intestine, esophagus, ovary, breast and prostate glands. Not detected in lymphatic vessels in the lung, kidney, uterus, liver and stomach (at protein level). Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon. {ECO:0000269|PubMed:1677636, ECO:0000269|PubMed:18708048}. | Protease | Autoimmune diseases
Diabetes mellitus Malignancies Noninsulin-dependent diabetes mellitus Obesity | Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF- kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones (By similarity). Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N- termini provided that the penultimate residue is proline. {ECO:0000250|UniProtKB:P27487, ECO:0000269|PubMed:14719797}. | Dipeptidyl peptidase 4 inhibitor: Atorvastatin | 15.11 | ||
| dpcDUT | Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial | 0 | 117 | 95.77 | ND | 99.90 | 0.78 | ND | 0.5 | Mammalian | Found in a variety of tissues. Isoform 3 expression is constitutive, while isoform 2 expression correlates with the onset of DNA replication (at protein level). Isoform 2 degradation coincides with the cessation of nuclear DNA replication (at protein level). {ECO:0000269|PubMed:9228092}. | Enzyme | This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA. {ECO:0000269|PubMed:8805593}. | 15.11 | ||||
| dpcDYR | Dihydrofolate reductase | 0 | 1500 | 89.50 | ND | 98.62 | 0.56 | ND | 0.8 | Mammalian | Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain. {ECO:0000269|PubMed:21310276}. | Oxidoreductase | Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]: An inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms. {ECO:0000269|PubMed:21310276, ECO:0000269|PubMed:21310277}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1. {ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:21876188}. | Dihydrofolate reductase inhibitor: Pyrimethamine | 15.11 | ||
| dpcDYR1A | Dual specificity tyrosine-phosphorylation-regulated kinase 1A | 0 | 1928 | 80.49 | ND | 88.75 | 0.43 | ND | 0.6 | Mammalian | Ubiquitous. Highest levels in skeletal muscle, testis, fetal lung and fetal kidney. {ECO:0000269|PubMed:10329007, ECO:0000269|PubMed:8769099, ECO:0000269|PubMed:8872470, ECO:0000269|PubMed:8975710}. | Kinase | Mental retardation, autosomal dominant 7 (MRD7) [MIM:614104]: A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21294719}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Modulates alternative splicing by phosphorylating the splice factor SRSF6 (By similarity). Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates such as CRY2, FOXO1, SRSF6 and SIRT1. Exhibits a sugstrate preference for proline at position P+1 and arginine at position P-3. {ECO:0000250, ECO:0000269|PubMed:20981014, ECO:0000269|PubMed:21127067, ECO:0000269|PubMed:23665168, ECO:0000269|PubMed:8769099}. | 15.11 | |||
| dpcDYRK2 | Dual specificity tyrosine-phosphorylation-regulated kinase 2 | 0 | 141 | 89.37 | ND | 98.16 | 0.07 | ND | 0.7 | Mammalian | Testis, after the onset of spermatogenesis. {ECO:0000269|PubMed:9748265}. | Kinase | Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser- 641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457', promoting TERT ubiquitination by the EDVP complex. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro). {ECO:0000269|PubMed:11311121, ECO:0000269|PubMed:12588975, ECO:0000269|PubMed:14593110, ECO:0000269|PubMed:15910284, ECO:0000269|PubMed:16511445, ECO:0000269|PubMed:16611631, ECO:0000269|PubMed:17349958, ECO:0000269|PubMed:18455992, ECO:0000269|PubMed:18599021, ECO:0000269|PubMed:19287380, ECO:0000269|PubMed:22307329, ECO:0000269|PubMed:22878263, ECO:0000269|PubMed:23362280, ECO:0000269|PubMed:9748265}. | 15.11 | ||||
| dpcE2AK2 | Interferon-induced, double-stranded RNA-activated protein kinase | 0 | 136 | 83.26 | ND | 86.24 | 0.21 | ND | 0.7 | Mammalian | Highly expressed in thymus, spleen and bone marrow compared to non-hematopoietic tissues such as small intestine, liver, or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer disease (AD) brain. Elevated levels seen in breast and colon carcinomas,and which correlates with tumor progression and invasiveness or risk of progression. {ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:23403623}. | Kinase | IFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation. Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1). Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (EIF2S1), this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser- 312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin. {ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380, ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853, ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191, ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114, ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651, ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662, ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035}. | 15.11 | ||||
| dpcE2AK3 | Eukaryotic translation initiation factor 2-alpha kinase 3 | 0 | 64 | 83.22 | ND | 98.69 | 0.78 | ND | 0.7 | Mammalian | Ubiquitous. A high level expression is seen in secretory tissues. | Kinase | Wolcott-Rallison syndrome (WRS) [MIM:226980]: A rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, mental retardation and cardiovascular abnormalities. {ECO:0000269|PubMed:10932183}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function (By similarity). {ECO:0000250}. | 15.11 | |||
| dpcEGLN1 | Egl nine homolog 1 | 0 | 245 | 78.84 | ND | 95.62 | 0.74 | ND | 0.9 | Mammalian | According to PubMed:11056053, widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to PubMed:12351678 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. According to PubMed:12788921; expressed in adult and fetal heart, brain, liver, lung, skeletal muscle and kidney. Also expressed in placenta. Highest levels in adult heart, brain, lung and liver and fetal brain, heart spleen and skeletal muscle. {ECO:0000269|PubMed:11056053, ECO:0000269|PubMed:12163023, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:12788921}. | Enzyme | Erythrocytosis, familial, 3 (ECYT3) [MIM:609820]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels. {ECO:0000269|PubMed:16407130, ECO:0000269|PubMed:17579185}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:15897452, ECO:0000269|PubMed:19339211, ECO:0000269|PubMed:21792862, ECO:0000269|PubMed:25129147}. | 15.11 | |||
| dpcELNE | Neutrophil elastase | 0 | 1163 | 73.29 | ND | 94.01 | 0.67 | ND | 0.8 | Mammalian | Bone marrow cells. | Protease | Cyclic haematopoiesis (CH) [MIM:162800]: Autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency. {ECO:0000269|PubMed:10581030, ECO:0000269|PubMed:11001877, ECO:0000269|PubMed:14962902, ECO:0000269|PubMed:23463630}. Note=The disease is caused by mutations affecting the gene represented in this entry. Neutropenia, severe congenital 1, autosomal dominant (SCN1) [MIM:202700]: A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. {ECO:0000269|PubMed:11001877, ECO:0000269|PubMed:11675333, ECO:0000269|PubMed:12091371, ECO:0000269|PubMed:14962902, ECO:0000269|PubMed:17436313, ECO:0000269|PubMed:18946670, ECO:0000269|PubMed:19036076, ECO:0000269|PubMed:19415009, ECO:0000269|PubMed:19927291, ECO:0000269|PubMed:20220065, ECO:0000269|PubMed:20803142, ECO:0000269|PubMed:21425445, ECO:0000269|PubMed:23463630}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis. {ECO:0000269|PubMed:15140022}. | 15.11 | |||
| dpcENPL | Endoplasmin | 0 | 55 | 73.74 | ND | 99.32 | 0.42 | ND | 0.6 | Mammalian | Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors (By similarity). Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity. {ECO:0000250, ECO:0000269|PubMed:18264092}. | Endoplasmin other/unknown: Rifabutin | 15.11 | |||||
| dpcEPHA2 | Ephrin type-A receptor 2 | 0 | 729 | 75.40 | ND | 88.30 | 0.30 | ND | ND | Mammalian | Expressed in brain and glioma tissue and glioma cell lines (at protein level). Expressed most highly in tissues that contain a high proportion of epithelial cells, e.g. skin, intestine, lung, and ovary. Ref.10 | Kinase | Breast cancer
Cancer, unspecific Pancreatic cancer HCV infection | Receptor for members of the ephrin-a family. Binds to Ephrin-A1, -A3, -A4 and -A5. | Ephrin type-A receptor 2 inhibitor: Dasatinib | ND | ||
| dpcEPHA7 | Ephrin type-A receptor 7 | 0 | 69 | 95.17 | ND | 80.53 | 0.32 | ND | 0.4 | Mammalian | Widely expressed. | Kinase | Receptor tyrosine kinase which binds promiscuously GPI- anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Among GPI-anchored ephrin-A ligands, EFNA5 is a cognate/functional ligand for EPHA7 and their interaction regulates brain development modulating cell-cell adhesion and repulsion. Has a repellent activity on axons and is for instance involved in the guidance of corticothalamic axons and in the proper topographic mapping of retinal axons to the colliculus. May also regulate brain development through a caspase(CASP3)-dependent proapoptotic activity. Forward signaling may result in activation of components of the ERK signaling pathway including MAP2K1, MAP2K2, MAPK1 AND MAPK3 which are phosphorylated upon activation of EPHA7. {ECO:0000269|PubMed:17726105}. | 15.11 | ||||
| dpcEPHB2 | Ephrin type-B receptor 2 | 0 | 96 | 80.23 | ND | 88.07 | 0.05 | ND | 0.4 | Mammalian | Brain, heart, lung, kidney, placenta, pancreas, liver and skeletal muscle. Preferentially expressed in fetal brain. | Kinase | Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:15300251, ECO:0000269|PubMed:16155194}. Note=The gene represented in this entry may be involved in disease pathogenesis. EPHB2 mutations have been found in a prostate cancer cell line derived from a brain metastasis. | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. In addition to axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor. {ECO:0000269|PubMed:15300251}. | 15.11 | |||
| dpcEPHB4 | Ephrin type-B receptor 4 | 0 | 421 | 94.71 | ND | 96.49 | 0.54 | ND | 0.7 | Mammalian | Abundantly expressed in placenta but also detected in kidney, liver, lung, pancreas, skeletal muscle and heart. Expressed in primitive and myeloid, but not lymphoid, hematopoietic cells. Also observed in cell lines derived from liver, breast, colon, lung, melanocyte and cervix. {ECO:0000269|PubMed:8188704}. | Kinase | Lung Cancer
Solid tumors | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4- mediated forward signaling controls cellular repulsion and segregation form EFNB2-expressing cells. Plays also a role in postnatal blood vessel remodeling, morphogenesis and permeability and is thus important in the context of tumor angiogenesis. {ECO:0000269|PubMed:12734395, ECO:0000269|PubMed:16424904}. | 15.11 | |||
| dpcERBB4 | Receptor tyrosine-protein kinase erbB-4 | 0 | 186 | 83.33 | ND | 91.24 | 0.54 | ND | 0.8 | Mammalian | Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart. {ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:9334263}. | Kinase | Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:24119685}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis. {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:10358079, ECO:0000269|PubMed:10722704, ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:11390655, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:8617750, ECO:0000269|PubMed:9135143, ECO:0000269|PubMed:9168115, ECO:0000269|PubMed:9334263}. | Receptor tyrosine-protein kinase erbB-4 inhibitor: Afatinib | 15.11 | ||
| dpcERG7 | Lanosterol synthase | 0 | 144 | 73.64 | ND | 93.19 | 0.40 | ND | 0.8 | Mammalian | Enzyme | Hypercholesterolemia | Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus. {ECO:0000269|PubMed:7639730}. | 15.11 | ||||
| dpcERR1 | Steroid hormone receptor ERR1 | 0 | 98 | 77.93 | ND | 93.61 | 0.68 | ND | 0.3 | Mammalian | Nuclear receptor | Breast cancer
Diabetes mellitus Metabolic disorder, unspecified Obesity | Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle. {ECO:0000269|PubMed:12522104, ECO:0000269|PubMed:16150865, ECO:0000269|PubMed:17676930, ECO:0000269|PubMed:18063693, ECO:0000269|PubMed:23836911, ECO:0000269|PubMed:9271417}. | 15.11 | ||||
| dpcESR1 | Estrogen receptor | 0 | 1820 | 88.68 | ND | 94.11 | 0.63 | ND | 0.8 | Nature11159 VirtualToxLab | Mammalian | Widely expressed. Isoform 3 is not expressed in the pituitary gland. {ECO:0000269|PubMed:10970861}. | Acne Blood urea increased Bone disorder Breast pain Chloasma Depression Electrolyte imbalance Embolism arterial Endometrial cancer Endometrial hyperplasia Epiphyses premature fusion Erythema multiforme Fibrocystic breast disease Gynaecomastia Hepatic function abnormal Hypercalcaemia Jaundice Menstrual disorder Metrorrhagia Neoplasm Oedema Porphyria non-acute Sodium retention Urticaria Uterine inflammation Weight increased | Nuclear receptor | Estrogen resistance (ESTRR) [MIM:615363]: A disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present. {ECO:0000269|PubMed:23841731, ECO:0000269|PubMed:8961262}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA- binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF- kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA- binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1. {ECO:0000269|PubMed:10681512, ECO:0000269|PubMed:10816575, ECO:0000269|PubMed:11477071, ECO:0000269|PubMed:11682626, ECO:0000269|PubMed:14764652, ECO:0000269|PubMed:15078875, ECO:0000269|PubMed:15891768, ECO:0000269|PubMed:16043358, ECO:0000269|PubMed:16617102, ECO:0000269|PubMed:16684779, ECO:0000269|PubMed:17922032, ECO:0000269|PubMed:17932106, ECO:0000269|PubMed:18247370, ECO:0000269|PubMed:19350539, ECO:0000269|PubMed:20074560, ECO:0000269|PubMed:20705611, ECO:0000269|PubMed:21330404, ECO:0000269|PubMed:22083956, ECO:0000269|PubMed:7651415, ECO:0000269|PubMed:9328340}. | Estrogen receptor agonist: Diethylstilbestrol | 15.11 |
| dpcESR2 | Estrogen receptor beta | 0 | 1459 | 88.96 | ND | 95.68 | 0.49 | ND | 0.7 | Nature11159 VirtualToxLab | Mammalian | Isoform beta-1 is expressed in testis and ovary, and at a lower level in heart, brain, placenta, liver, skeletal muscle, spleen, thymus, prostate, colon, bone marrow, mammary gland and uterus. Also found in uterine bone, breast, and ovarian tumor cell lines, but not in colon and liver tumors. Isoform beta-2 is expressed in spleen, thymus, testis and ovary and at a lower level in skeletal muscle, prostate, colon, small intestine, leukocytes, bone marrow, mammary gland and uterus. Isoform beta-3 is found in testis. Isoform beta-4 is expressed in testis, and at a lower level in spleen, thymus, ovary, mammary gland and uterus. Isoform beta-5 is expressed in testis, placenta, skeletal muscle, spleen and leukocytes, and at a lower level in heart, lung, liver, kidney, pancreas, thymus, prostate, colon, small intestine, bone marrow, mammary gland and uterus. Not expressed in brain. | Acne Blood urea increased Bone disorder Breast pain Chloasma Depression Electrolyte imbalance Endometrial cancer Endometrial hyperplasia Epiphyses premature fusion Erythema multiforme Fibrocystic breast disease Gynaecomastia Hepatic function abnormal Hypercalcaemia Jaundice Menstrual disorder Metrorrhagia Neoplasm Oedema Porphyria non-acute Sodium retention Urticaria Uterine inflammation Weight increased | Nuclear receptor | Breast cancer
Cardiovascular disease, unspecified ER beta-positive prostate tumors Neurodegenerative diseases Vascular injury response | Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual. {ECO:0000269|PubMed:20074560}. | Estrogen receptor beta agonist: Diethylstilbestrol | 15.11 |
| dpcEST1 | Liver carboxylesterase 1 | 0 | 373 | 70.32 | ND | 83.41 | 0.54 | ND | 1.0 | Mammalian | Expressed predominantly in liver with lower levels in heart and lung. {ECO:0000269|PubMed:10562416}. | Enzyme | Alzheimer's disease
Atherosclerosis Cardiovascular disease, unspecified Cocaine overdose Hypercholesterolaemia Protection against chemical weapons like Sarin, Soman and VX gas | Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester. Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine. Catalyzes the transesterification of cocaine to form cocaethylene. Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate. {ECO:0000269|PubMed:7980644, ECO:0000269|PubMed:9169443}. | Liver carboxylesterase 1 other: Oseltamivir | 15.11 | ||
| dpcF16P1 | Fructose-1,6-bisphosphatase 1 | 0 | 395 | 89.26 | ND | 98.23 | 0.83 | ND | 0.5 | Mammalian | Expressed in pancreatic islets. {ECO:0000269|PubMed:18375435}. | Enzyme | Fructose-1,6-bisphosphatase deficiency (FBP1D) [MIM:229700]: An autosomal recessive metabolic disorder characterized by impaired gluconeogenesis, and episodes of hypoglycemia and metabolic acidosis that can be lethal in newborn infants or young children. {ECO:0000269|PubMed:12126934, ECO:0000269|PubMed:9382095}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations, acting as a rate-limiting enzyme in gluconeogenesis. Plays a role in regulating glucose sensing and insulin secretion of pancreatic beta-cells. Appears to modulate glycerol gluconeogenesis in liver. Important regulator of appetite and adiposity; increased expression of the protein in liver after nutrient excess increases circulating satiety hormones and reduces appetite-stimulating neuropeptides and thus seems to provide a feedback mechanism to limit weight gain. {ECO:0000269|PubMed:16497803, ECO:0000269|PubMed:18375435, ECO:0000269|PubMed:22517657}. | Fructose-1,6-bisphosphatase 1 antagonist: Adenosine monophosphate Fructose-1,6-bisphosphatase 1 inhibitory allosteric modulator: | 15.11 | ||
| dpcFA10 | Coagulation factor X | 0 | 4297 | 93.35 | ND | 97.68 | 0.65 | ND | 0.8 | Mammalian | Plasma; synthesized in the liver. {ECO:0000269|PubMed:6587384}. | Protease | Factor X deficiency (FA10D) [MIM:227600]: A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis. {ECO:0000269|PubMed:10468877, ECO:0000269|PubMed:10746568, ECO:0000269|PubMed:11248282, ECO:0000269|PubMed:11728527, ECO:0000269|PubMed:12574802, ECO:0000269|PubMed:12945883, ECO:0000269|PubMed:15075089, ECO:0000269|PubMed:15650540, ECO:0000269|PubMed:17393015, ECO:0000269|PubMed:19135706, ECO:0000269|PubMed:1973167, ECO:0000269|PubMed:1985698, ECO:0000269|PubMed:25313940, ECO:0000269|PubMed:2790181, ECO:0000269|PubMed:7669671, ECO:0000269|PubMed:7860069, ECO:0000269|PubMed:8529633, ECO:0000269|PubMed:8845463, ECO:0000269|PubMed:8910490}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting. | Coagulation factor X activator: Antihemophilic Factor | 15.11 | ||
| dpcFA11 | Coagulation factor XI | 0 | 153 | 94.24 | ND | 99.76 | 0.63 | ND | 0.9 | Mammalian | Isoform 2 is produced by platelets and megakaryocytes but absent from other blood cells. | Protease | Factor XI deficiency (FA11D) [MIM:612416]: A hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. {ECO:0000269|PubMed:10027710, ECO:0000269|PubMed:10606881, ECO:0000269|PubMed:11895778, ECO:0000269|PubMed:15026311, ECO:0000269|PubMed:15180874, ECO:0000269|PubMed:1547342, ECO:0000269|PubMed:15953011, ECO:0000269|PubMed:16607084, ECO:0000269|PubMed:18005151, ECO:0000269|PubMed:21457405, ECO:0000269|PubMed:21668437, ECO:0000269|PubMed:21999818, ECO:0000269|PubMed:22016685, ECO:0000269|PubMed:22159456, ECO:0000269|PubMed:22322133, ECO:0000269|PubMed:2813350, ECO:0000269|PubMed:7669672, ECO:0000269|PubMed:7888672, ECO:0000269|PubMed:9401068, ECO:0000269|PubMed:9787168}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. | Coagulation factor XI ligand: Coagulation Factor IX | 15.11 | ||
| dpcFA7 | Coagulation factor VII | 0 | 342 | 89.60 | ND | 98.10 | 0.54 | ND | 0.7 | Mammalian | Plasma. | Protease | Factor VII deficiency (FA7D) [MIM:227500]: A hemorrhagic disease with variable presentation. The clinical picture can be very severe, with the early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, moderate with cutaneous-mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by a surgical intervention. Finally, numerous subjects are completely asymptomatic despite very low factor VII levels. {ECO:0000269|PubMed:10862079, ECO:0000269|PubMed:11091194, ECO:0000269|PubMed:11129332, ECO:0000269|PubMed:12472587, ECO:0000269|PubMed:14717781, ECO:0000269|PubMed:1634227, ECO:0000269|PubMed:18976247, ECO:0000269|PubMed:19432927, ECO:0000269|PubMed:19751712, ECO:0000269|PubMed:2070047, ECO:0000269|PubMed:21206266, ECO:0000269|PubMed:21372693, ECO:0000269|PubMed:7974346, ECO:0000269|PubMed:7981691, ECO:0000269|PubMed:8043443, ECO:0000269|PubMed:8204879, ECO:0000269|PubMed:8364544, ECO:0000269|PubMed:8652821, ECO:0000269|PubMed:8844208, ECO:0000269|PubMed:8883260, ECO:0000269|PubMed:8940045, ECO:0000269|PubMed:9414278, ECO:0000269|PubMed:9452082, ECO:0000269|PubMed:9576180}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium. | 15.11 | |||
| dpcFA9 | Coagulation factor IX {ECO:0000303|PubMed:3857619} | 0 | 168 | 97.43 | ND | 99.91 | 0.65 | ND | 0.6 | Mammalian | Detected in blood plasma (at protein level) (PubMed:3857619, PubMed:8295821, PubMed:2592373, PubMed:9169594, PubMed:19846852). Synthesized primarily in the liver and secreted in plasma. {ECO:0000269|PubMed:19846852, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:3857619}. | Protease | Hemophilia B (HEMB) [MIM:306900]: An X-linked blood coagulation disorder characterized by a permanent tendency to hemorrhage, due to factor IX deficiency. It is phenotypically similar to hemophilia A, but patients present with fewer symptoms. Many patients are asymptomatic until the hemostatic system is stressed by surgery or trauma. {ECO:0000269|PubMed:10094553, ECO:0000269|PubMed:10698280, ECO:0000269|PubMed:11122099, ECO:0000269|PubMed:12588353, ECO:0000269|PubMed:12604421, ECO:0000269|PubMed:1346975, ECO:0000269|PubMed:1615485, ECO:0000269|PubMed:1902289, ECO:0000269|PubMed:1958666, ECO:0000269|PubMed:2162822, ECO:0000269|PubMed:2339358, ECO:0000269|PubMed:2372509, ECO:0000269|PubMed:2472424, ECO:0000269|PubMed:25251685, ECO:0000269|PubMed:25470321, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:2713493, ECO:0000269|PubMed:2714791, ECO:0000269|PubMed:2738071, ECO:0000269|PubMed:2753873, ECO:0000269|PubMed:2773937, ECO:0000269|PubMed:2775660, ECO:0000269|PubMed:3009023, ECO:0000269|PubMed:3243764, ECO:0000269|PubMed:3401602, ECO:0000269|PubMed:3790720, ECO:0000269|PubMed:6603618, ECO:0000269|PubMed:7981722, ECO:0000269|PubMed:8076946, ECO:0000269|PubMed:8199596, ECO:0000269|PubMed:8257988, ECO:0000269|PubMed:8295821, ECO:0000269|PubMed:8680410, ECO:0000269|PubMed:9222764, ECO:0000269|PubMed:9452115, ECO:0000269|PubMed:9590153, ECO:0000269|PubMed:9600455}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide (PubMed:12588353, PubMed:2738071, PubMed:3009023, PubMed:8295821, PubMed:9169594, PubMed:9600455, PubMed:25251685). Mutation in position 93 (Alabama) probably fails to bind to cell membranes (PubMed:3790720). Mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya or Hilo) prevent cleavage of the activation peptide (PubMed:6603618, PubMed:8076946, PubMed:12588353, PubMed:2162822, PubMed:25251685, PubMed:2713493). {ECO:0000269|PubMed:12588353, ECO:0000269|PubMed:2162822, ECO:0000269|PubMed:25251685, ECO:0000269|PubMed:2713493, ECO:0000269|PubMed:2738071, ECO:0000269|PubMed:3009023, ECO:0000269|PubMed:3790720, ECO:0000269|PubMed:6603618, ECO:0000269|PubMed:8076946, ECO:0000269|PubMed:8295821, ECO:0000269|PubMed:9169594, ECO:0000269|PubMed:9600455}. Thrombophilia, X-linked, due to factor IX defect (THPH8) [MIM:300807]: A hemostatic disorder characterized by a tendency to thrombosis. {ECO:0000269|PubMed:19846852}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa. {ECO:0000269|PubMed:1730085, ECO:0000269|PubMed:19846852, ECO:0000269|PubMed:20121197, ECO:0000269|PubMed:20121198, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:8295821}. | Coagulation factor IX {ECO:0000303|PubMed:3857619} cofactor: Antihemophilic Factor | 15.11 | ||
| dpcFABP4 | Fatty acid-binding protein, adipocyte | 0 | 122 | 93.96 | ND | 97.44 | 0.79 | ND | 0.6 | Mammalian | Fatty acid binding protein family | Atherosclerosis | Lipid transport protein in adipocytes. Binds both long chain fatty acids and retinoic acid. Delivers long-chain fatty acids and retinoic acid to their cognate receptors in the nucleus (By similarity). {ECO:0000250}. | 15.11 | ||||
| dpcFABPH | Fatty acid-binding protein, heart | 0 | 56 | 90.35 | ND | 98.34 | 0.69 | ND | 0.3 | Mammalian | Fatty acid binding protein family | FABP are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters. | 15.11 | |||||
| dpcFAK1 | Focal adhesion kinase 1 | 0 | 579 | 84.59 | ND | 94.70 | 0.38 | ND | 0.8 | Mammalian | Detected in B and T-lymphocytes. Isoform 1 and isoform 6 are detected in lung fibroblasts (at protein level). Ubiquitous. {ECO:0000269|PubMed:20109444, ECO:0000269|PubMed:7692878, ECO:0000269|PubMed:8247543, ECO:0000269|PubMed:8422239}. | Kinase | Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer. | Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:11331870, ECO:0000269|PubMed:11980671, ECO:0000269|PubMed:15166238, ECO:0000269|PubMed:15561106, ECO:0000269|PubMed:15895076, ECO:0000269|PubMed:16919435, ECO:0000269|PubMed:16927379, ECO:0000269|PubMed:17395594, ECO:0000269|PubMed:17431114, ECO:0000269|PubMed:17968709, ECO:0000269|PubMed:18006843, ECO:0000269|PubMed:18206965, ECO:0000269|PubMed:18256281, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:18497331, ECO:0000269|PubMed:18677107, ECO:0000269|PubMed:19138410, ECO:0000269|PubMed:19147981, ECO:0000269|PubMed:19224453, ECO:0000269|PubMed:20332118, ECO:0000269|PubMed:20495381, ECO:0000269|PubMed:21454698}. | 15.11 | |||
| dpcFAK2 | Protein-tyrosine kinase 2-beta | 0 | 257 | 82.16 | ND | 88.02 | 0.29 | ND | 1.0 | Mammalian | Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes. {ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:9545257}. | Kinase | Note=Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer. | Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T- cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2. {ECO:0000269|PubMed:10022920, ECO:0000269|PubMed:12771146, ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:15050747, ECO:0000269|PubMed:15166227, ECO:0000269|PubMed:17634955, ECO:0000269|PubMed:18086875, ECO:0000269|PubMed:18339875, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18765415, ECO:0000269|PubMed:19086031, ECO:0000269|PubMed:19207108, ECO:0000269|PubMed:19244237, ECO:0000269|PubMed:19428251, ECO:0000269|PubMed:19648005, ECO:0000269|PubMed:19880522, ECO:0000269|PubMed:20001213, ECO:0000269|PubMed:20381867, ECO:0000269|PubMed:20521079, ECO:0000269|PubMed:21357692, ECO:0000269|PubMed:21533080, ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:8670418, ECO:0000269|PubMed:8849729}. | Protein-tyrosine kinase 2-beta antagonist: Leflunomide | 15.11 | ||
| dpcFAS | Fatty acid synthase | 0 | 933 | 77.95 | ND | 87.88 | 0.31 | ND | 0.5 | Mammalian | Ubiquitous. Prominent expression in brain, lung, and liver. {ECO:0000269|PubMed:7567999, ECO:0000269|PubMed:7595075}. | Transferase | Endometrial carcinoma
Leukemia, unspecified Malaria Mesothelioma Metastatic osteosarcoma in the lung Obesity Prostate cancer Tumors | Fatty acid synthetase catalyzes the formation of long- chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein. | Fatty acid synthase inhibitor: Cerulenin | 15.11 | ||
| dpcFES | Tyrosine-protein kinase Fes/Fps | 0 | 126 | 92.91 | ND | 86.05 | 0.38 | ND | 0.6 | Mammalian | Widely expressed. Detected in adult colon epithelium. {ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:19051325}. | Kinase | Note=Has been shown to act as proto-oncogene in some types of cancer, possibly due to abnormal activation of the kinase. Has been shown to act as tumor suppressor in other types of cancer. Expressed and present as activated kinase in a subset of acute myeloid leukemia patients; promotes survival of leukemia cells (PubMed:20111072). Expression is absent in K562 leukemia cells; ectopic expression of FSP/FES restores myeloid differentiation (PubMed:2656706). May function as tumor suppressor in colorectal cancer; expression is reduced or absent in samples from some colon cancer patients (PubMed:16455651). Ectopic expression of FSP/FES suppresses anchorage-independent growth in colon cancer cell lines (PubMed:16455651). Up-regulated in prostate cancer, and might be a predictor of recurrence after radical surgery (PubMed:21563194). May promote growth of renal carcinoma cells (PubMed:19082481). {ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:19082481, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21563194, ECO:0000269|PubMed:2656706}. | Tyrosine-protein kinase that acts downstream of cell surface receptors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, cell attachment and cell spreading. Plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Acts down- stream of the activated FCER1 receptor and the mast/stem cell growth factor receptor KIT. Plays a role in the regulation of mast cell degranulation. Plays a role in the regulation of cell differentiation and promotes neurite outgrowth in response to NGF signaling. Plays a role in cell scattering and cell migration in response to HGF-induced activation of EZR. Phosphorylates BCR and down-regulates BCR kinase activity. Phosphorylates HCLS1/HS1, PECAM1, STAT3 and TRIM28. {ECO:0000269|PubMed:11509660, ECO:0000269|PubMed:15302586, ECO:0000269|PubMed:15485904, ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:17595334, ECO:0000269|PubMed:18046454, ECO:0000269|PubMed:19001085, ECO:0000269|PubMed:19051325, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:2656706, ECO:0000269|PubMed:8955135}. | 15.11 | |||
| dpcFFAR1 | Free fatty acid receptor 1 | 0 | 429 | 97.28 | ND | 99.87 | 0.55 | ND | 0.4 | Mammalian | Detected in brain and pancreas. Detected in pancreatic beta cells. {ECO:0000269|PubMed:12496284, ECO:0000269|PubMed:16289108}. | Family A G protein-coupled receptor | G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis. Fatty acid binding increases glucose- stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (By similarity). Ligand binding leads to a conformation change that triggers signaling via G-proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration. Seems to act through a G(q) and G(i)-mediated pathway. {ECO:0000250|UniProtKB:Q76JU9, ECO:0000269|PubMed:12496284, ECO:0000269|PubMed:17699519, ECO:0000269|PubMed:24130766}. | Free fatty acid receptor 1 agonist: Icosapent | 15.11 | |||
| dpcFGFR1 | Fibroblast growth factor receptor 1 | 0 | 1091 | 84.59 | ND | 92.96 | 0.55 | ND | 0.6 | Mammalian | Detected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform 17, isoform 18 and isoform 19 are not detected in these cells. {ECO:0000269|PubMed:1652059}. | Kinase | Pfeiffer syndrome (PS) [MIM:101600]: A syndrome characterized by the association of craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly of the fingers and toes. Three subtypes are known: mild autosomal dominant form (type 1); cloverleaf skull, elbow ankylosis, early death, sporadic (type 2); craniosynostosis, early demise, sporadic (type 3). {ECO:0000269|PubMed:7874169}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:147950]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:12627230, ECO:0000269|PubMed:15001591, ECO:0000269|PubMed:15605412, ECO:0000269|PubMed:15845591, ECO:0000269|PubMed:16606836, ECO:0000269|PubMed:16757108, ECO:0000269|PubMed:16764984, ECO:0000269|PubMed:16882753, ECO:0000269|PubMed:17154279, ECO:0000269|PubMed:19820032, ECO:0000269|PubMed:21700882, ECO:0000269|PubMed:22927827, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900, ECO:0000269|PubMed:26277103}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FGFR1 also have a mutation other HH-associated genes including DUSP6, FGF8, FGF17, FLRT3, GNRH1, GNRHR, HS6ST1, IL17RD, ANOS1, KISS1R, NSMF, PROKR2, SPRY4 and TACR3 (PubMed:23643382). {ECO:0000269|PubMed:23643382}. Osteoglophonic dysplasia (OGD) [MIM:166250]: Characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant. {ECO:0000269|PubMed:15625620, ECO:0000269|PubMed:16470795}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hartsfield syndrome (HRTFDS) [MIM:615465]: A syndrome characterized by the triad of holoprosencephaly, ectrodactyly, and cleft/lip palate. Profound mental retardation is also present. Multiple other congenital anomalies usually occur. {ECO:0000269|PubMed:23812909, ECO:0000269|PubMed:24888332}. Note=The disease is caused by mutations affecting the gene represented in this entry. Trigonocephaly 1 (TRIGNO1) [MIM:190440]: A keel-shaped deformation of the forehead, caused by premature fusion of the metopic sutures. It results in a triangular shape of the head. {ECO:0000269|PubMed:11173846}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with ZMYM2. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow. {ECO:0000269|PubMed:9716603}. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1OP. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity and be responsible for the transforming activity. {ECO:0000269|PubMed:10688839, ECO:0000269|PubMed:15034873, ECO:0000269|PubMed:16946300, ECO:0000269|PubMed:17389761, ECO:0000269|PubMed:9949182}. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(8;9)(p12;q33) with CNTRL. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein CNTRL-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation. {ECO:0000250|UniProtKB:P16092, ECO:0000269|PubMed:10830168, ECO:0000269|PubMed:11353842, ECO:0000269|PubMed:12181353, ECO:0000269|PubMed:1379697, ECO:0000269|PubMed:1379698, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19261810, ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:20133753, ECO:0000269|PubMed:20139426, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:8622701, ECO:0000269|PubMed:8663044}. | 15.11 | |||
| dpcFGFR2 | Fibroblast growth factor receptor 2 | 0 | 125 | 74.49 | ND | 90.22 | 0.20 | ND | 0.8 | Mammalian | Kinase | Crouzon syndrome (CS) [MIM:123500]: An autosomal dominant syndrome characterized by craniosynostosis, hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism. {ECO:0000269|PubMed:10574673, ECO:0000269|PubMed:11173845, ECO:0000269|PubMed:11380921, ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7581378, ECO:0000269|PubMed:7655462, ECO:0000269|PubMed:7874170, ECO:0000269|PubMed:7987400, ECO:0000269|PubMed:8528214, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:8946174, ECO:0000269|PubMed:8956050, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9152842, ECO:0000269|PubMed:9521581, ECO:0000269|PubMed:9677057, ECO:0000269|Ref.10}. Note=The disease is caused by mutations affecting the gene represented in this entry. Jackson-Weiss syndrome (JWS) [MIM:123150]: An autosomal dominant craniosynostosis syndrome characterized by craniofacial abnormalities and abnormality of the feet: broad great toes with medial deviation and tarsal-metatarsal coalescence. {ECO:0000269|PubMed:7874170, ECO:0000269|PubMed:8528214, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:9385368, ECO:0000269|PubMed:9677057}. Note=The disease is caused by mutations affecting the gene represented in this entry. Apert syndrome (APRS) [MIM:101200]: A syndrome characterized by facio-cranio-synostosis, osseous and membranous syndactyly of the four extremities, and midface hypoplasia. The craniosynostosis is bicoronal and results in acrocephaly of brachysphenocephalic type. Syndactyly of the fingers and toes may be total (mitten hands and sock feet) or partial affecting the second, third, and fourth digits. Intellectual deficit is frequent and often severe, usually being associated with cerebral malformations. {ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7668257, ECO:0000269|PubMed:7719344, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9452027, ECO:0000269|PubMed:9677057}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pfeiffer syndrome (PS) [MIM:101600]: A syndrome characterized by the association of craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly of the fingers and toes. Three subtypes are known: mild autosomal dominant form (type 1); cloverleaf skull, elbow ankylosis, early death, sporadic (type 2); craniosynostosis, early demise, sporadic (type 3). {ECO:0000269|PubMed:10394936, ECO:0000269|PubMed:10945669, ECO:0000269|PubMed:11173845, ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7719333, ECO:0000269|PubMed:7719345, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9150725, ECO:0000269|PubMed:9693549, ECO:0000269|PubMed:9719378}. Note=The disease is caused by mutations affecting the gene represented in this entry. Beare-Stevenson cutis gyrata syndrome (BSTVS) [MIM:123790]: An autosomal dominant disease characterized by craniofacial anomalies, particularly craniosynostosis, and ear defects, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, and prominent umbilical stump. The skin furrows have a corrugated appearance and are widespread. Cutis gyrata variably affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet. {ECO:0000269|PubMed:12000365, ECO:0000269|PubMed:8696350}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial scaphocephaly syndrome (FSPC) [MIM:609579]: An autosomal dominant craniosynostosis syndrome characterized by scaphocephaly, macrocephaly, hypertelorism, maxillary retrusion, and mild intellectual disability. Scaphocephaly is the most common of the craniosynostosis conditions and is characterized by a long, narrow head. It is due to premature fusion of the sagittal suture or from external deformation. {ECO:0000269|PubMed:16061565}. Note=The disease is caused by mutations affecting the gene represented in this entry. Lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]: An autosomal dominant ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Lacrimo-auriculo-dento-digital syndrome is characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. {ECO:0000269|PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry. Antley-Bixler syndrome, without genital anomalies or disordered steroidogenesis (ABS2) [MIM:207410]: A rare syndrome characterized by craniosynostosis, radiohumeral synostosis present from the perinatal period, midface hypoplasia, choanal stenosis or atresia, femoral bowing and multiple joint contractures. Arachnodactyly and/or camptodactyly have also been reported. {ECO:0000269|PubMed:10633130}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bent bone dysplasia syndrome (BBDS) [MIM:614592]: A perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Dysmorphic facial features included low-set ears, hypertelorism, midface hypoplasia, prematurely erupted fetal teeth, and micrognathia. {ECO:0000269|PubMed:22387015}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1. {ECO:0000269|PubMed:12529371, ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:15629145, ECO:0000269|PubMed:16384934, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19103595, ECO:0000269|PubMed:19387476, ECO:0000269|PubMed:19410646, ECO:0000269|PubMed:21596750, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor receptor 2 binder: Palifermin | 15.11 | |||
| dpcFGFR3 | Fibroblast growth factor receptor 3 | 0 | 208 | 85.42 | ND | 91.23 | 0.09 | ND | 0.9 | Mammalian | Expressed in brain, kidney and testis. Very low or no expression in spleen, heart, and muscle. In 20- to 22- week old fetuses it is expressed at high level in kidney, lung, small intestine and brain, and to a lower degree in spleen, liver, and muscle. Isoform 2 is detected in epithelial cells. Isoform 1 is not detected in epithelial cells. Isoform 1 and isoform 2 are detected in fibroblastic cells. {ECO:0000269|PubMed:1664411}. | Kinase | Achondroplasia (ACH) [MIM:100800]: A frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. {ECO:0000269|PubMed:7758520, ECO:0000269|PubMed:7847369, ECO:0000269|PubMed:8078586}. Note=The disease is caused by mutations affecting the gene represented in this entry. Crouzon syndrome with acanthosis nigricans (CAN) [MIM:612247]: Classic Crouzon disease which is caused by mutations in the FGFR2 gene is characterized by craniosynostosis (premature fusion of the skull sutures), and facial hypoplasia. Crouzon syndrome with acanthosis nigricans (a skin disorder characterized by pigmentation anomalies), CAN, is considered to be an independent disorder from classic Crouzon syndrome. CAN is characterized by additional more severe physical manifestation, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, and is caused by a specific mutation (Ala-391 to Glu) in the transmembrane domain of FGFR3. It is proposed to have an autosomal dominant mode of inheritance. {ECO:0000269|PubMed:17935505, ECO:0000269|PubMed:7493034}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thanatophoric dysplasia 1 (TD1) [MIM:187600]: A neonatal lethal skeletal dysplasia. Affected individuals manifest severe shortening of the limbs with macrocephaly, narrow thorax, short ribs, and curved femurs. {ECO:0000269|PubMed:10360402, ECO:0000269|PubMed:10671061, ECO:0000269|PubMed:7773297, ECO:0000269|PubMed:8589699, ECO:0000269|PubMed:8845844, ECO:0000269|PubMed:9790257}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thanatophoric dysplasia 2 (TD2) [MIM:187601]: A neonatal lethal skeletal dysplasia causing severe shortening of the limbs, narrow thorax and short ribs. Patients with thanatophoric dysplasia type 2 have straight femurs and cloverleaf skull. {ECO:0000269|PubMed:7773297}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypochondroplasia (HCH) [MIM:146000]: Autosomal dominant disease and is characterized by disproportionate short stature. It resembles achondroplasia, but with a less severe phenotype. {ECO:0000269|PubMed:10215410, ECO:0000269|PubMed:10777366, ECO:0000269|PubMed:11055896, ECO:0000269|PubMed:12707965, ECO:0000269|PubMed:7670477, ECO:0000269|PubMed:9452043}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. {ECO:0000269|PubMed:10471491, ECO:0000269|PubMed:11314002}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Somatic mutations can constitutively activate FGFR3. Cervical cancer (CERCA) [MIM:603956]: A malignant neoplasm of the cervix, typically originating from a dysplastic or premalignant lesion previously present at the active squamocolumnar junction. The transformation from mild dysplastic to invasive carcinoma generally occurs slowly within several years, although the rate of this process varies widely. Carcinoma in situ is particularly known to precede invasive cervical cancer in most cases. Cervical cancer is strongly associated with infection by oncogenic types of human papillomavirus. {ECO:0000269|PubMed:10471491}. Note=The gene represented in this entry is involved in disease pathogenesis. Camptodactyly tall stature and hearing loss syndrome (CATSHL syndrome) [MIM:610474]: Autosomal dominant syndrome characterized by permanent and irreducible flexion of one or more fingers of the hand and/or feet, tall stature, scoliosis and/or a pectus excavatum, and hearing loss. Affected individuals have developmental delay and/or mental retardation, and several of these have microcephaly. Radiographic findings included tall vertebral bodies with irregular borders and broad femoral metaphyses with long tubular shafts. On audiological exam, each tested member have bilateral sensorineural hearing loss and absent otoacoustic emissions. The hearing loss was congenital or developed in early infancy, progressed variably in early childhood, and range from mild to severe. Computed tomography and magnetic resonance imaging reveal that the brain, middle ear, and inner ear are structurally normal. {ECO:0000269|PubMed:17033969}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple myeloma (MM) [MIM:254500]: A malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. {ECO:0000269|PubMed:11529856, ECO:0000269|PubMed:9207791}. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving FGFR3 is found in multiple myeloma. Translocation t(4;14)(p16.3;q32.3) with the IgH locus. Lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]: An autosomal dominant ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Lacrimo-auriculo-dento-digital syndrome is characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. {ECO:0000269|PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry. Keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900]: Epidermal nevi of the common, non-organoid and non- epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. {ECO:0000269|PubMed:16841094}. Note=The disease is caused by mutations affecting the gene represented in this entry. Muenke syndrome (MNKS) [MIM:602849]: A condition characterized by premature closure of coronal suture of skull during development (coronal craniosynostosis), which affects the shape of the head and face. It may be uni- or bilateral. When bilateral, it is characterized by a skull with a small antero- posterior diameter (brachycephaly), often with a decrease in the depth of the orbits and hypoplasia of the maxillae. Unilateral closure of the coronal sutures leads to flattening of the orbit on the involved side (plagiocephaly). The intellect is normal. In addition to coronal craniosynostosis some affected individuals show skeletal abnormalities of hands and feet, sensorineural hearing loss, mental retardation and respiratory insufficiency. {ECO:0000269|PubMed:11746040, ECO:0000269|PubMed:9042914, ECO:0000269|PubMed:9950359}. Note=The disease is caused by mutations affecting the gene represented in this entry. Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:15772091}. Note=The disease is caused by mutations affecting the gene represented in this entry. Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:19855393}. Note=The gene represented in this entry may be involved in disease pathogenesis. Achondroplasia, severe, with developmental delay and acanthosis nigricans (SADDAN) [MIM:616482]: A severe form of achondroplasia associated with developmental delay and acanthosis nigricans. Patients manifest short-limb dwarfism, with a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. Acanthosis nigricans is a skin condition characterized by brown-pigmented, velvety verrucosities in body folds and creases. {ECO:0000269|PubMed:10053006}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:14534538, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17145761, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:19286672, ECO:0000269|PubMed:8663044}. | 15.11 | |||
| dpcFGFR4 | Fibroblast growth factor receptor 4 | 0 | 82 | 77.80 | ND | 81.42 | 0.12 | ND | 0.3 | Mammalian | Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. {ECO:0000269|PubMed:10631118}. | Kinase | Obesity | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645, ECO:0000269|PubMed:8663044}. | 15.11 | |||
| dpcFKB1A | Peptidyl-prolyl cis-trans isomerase FKBP1A | 0 | 452 | 79.24 | ND | 97.51 | 0.70 | ND | 0.7 | Mammalian | Isomerase | Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. {ECO:0000269|PubMed:16720724, ECO:0000269|PubMed:9233797}. | Peptidyl-prolyl cis-trans isomerase FKBP1A potentiator: Pimecrolimus | 15.11 | ||||
| dpcFKBP4 | Peptidyl-prolyl cis-trans isomerase FKBP4 | 0 | 60 | 99.31 | ND | 99.97 | 0.30 | ND | 0.6 | Mammalian | Widely expressed. {ECO:0000269|PubMed:1279700}. | Enzyme | Neurological diseases | Immunophilin protein with PPIase and co-chaperone activities. Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria. {ECO:0000269|PubMed:1279700, ECO:0000269|PubMed:1376003, ECO:0000269|PubMed:19945390, ECO:0000269|PubMed:21730050, ECO:0000269|PubMed:2378870}. | 15.11 | |||
| dpcFKBP5 | Peptidyl-prolyl cis-trans isomerase FKBP5 | 0 | 76 | 98.46 | ND | 99.82 | 0.06 | ND | 0.6 | Mammalian | Widely expressed, enriched in testis compared to other tissues. | Enzyme | Immunophilin protein with PPIase and co-chaperone activities. Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). Plays a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors maintaining the complex into the cytoplasm when unliganded. | 15.11 | ||||
| dpcFLT3 | Receptor-type tyrosine-protein kinase FLT3 | 0 | 1224 | 75.04 | ND | 91.38 | 0.44 | ND | 0.9 | Mammalian | Detected in bone marrow, in hematopoietic stem cells, in myeloid progenitor cells and in granulocyte/macrophage progenitor cells (at protein level). Detected in bone marrow, liver, thymus, spleen and lymph node, and at low levels in kidney and pancreas. Highly expressed in T-cell leukemia. {ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:7507245, ECO:0000269|PubMed:8394751, ECO:0000269|PubMed:8637232}. | Kinase | Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:11290608, ECO:0000269|PubMed:11442493, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:18305215, ECO:0000269|PubMed:8946930, ECO:0000269|PubMed:9737679}. Note=The gene represented in this entry may be involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase. | Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways. {ECO:0000269|PubMed:10080542, ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:16627759, ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21067588, ECO:0000269|PubMed:21262971, ECO:0000269|PubMed:21516120, ECO:0000269|PubMed:7507245}. | Receptor-type tyrosine-protein kinase FLT3 antagonist: Sorafenib | 15.11 | ||
| dpcFYN | Tyrosine-protein kinase Fyn | 0 | 440 | 84.05 | ND | 91.42 | 0.29 | ND | 0.7 | Mammalian | Isoform 1 is highly expressed in the brain. Isoform 2 is expressed in cells of hemopoietic lineages, especially T-lymphocytes. {ECO:0000269|PubMed:10196263}. | Kinase | Philadelphia-positive leukemia | Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta- catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1. {ECO:0000269|PubMed:11005864, ECO:0000269|PubMed:11162638, ECO:0000269|PubMed:11536198, ECO:0000269|PubMed:12788081, ECO:0000269|PubMed:14707117, ECO:0000269|PubMed:14761972, ECO:0000269|PubMed:15536091, ECO:0000269|PubMed:15557120, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:16841086, ECO:0000269|PubMed:17194753, ECO:0000269|PubMed:18056706, ECO:0000269|PubMed:18258597, ECO:0000269|PubMed:19179337, ECO:0000269|PubMed:19652227, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:22080863, ECO:0000269|PubMed:7568038, ECO:0000269|PubMed:7822789}. | Tyrosine-protein kinase Fyn multitarget: Dasatinib | 15.11 | ||
| dpcGABR1 | Gamma-aminobutyric acid type B receptor subunit 1 | 0 | 69 | 99.18 | ND | 91.06 | 0.52 | ND | 0.4 | Mammalian | Highly expressed in brain and weakly in heart, small intestine and uterus. Isoform 1A is mostly expressed in granular cell and molecular layer. Isoform 1B is mostly expressed in Purkinje cells. Isoform 1E is predominantly expressed in peripheral tissues as kidney, lung, trachea, colon, small intestine, stomach, bone marrow, thymus and mammary gland. {ECO:0000269|PubMed:9844003}. | Family C G protein-coupled receptor | Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Calcium is required for high affinity binding to GABA. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception. Activated by (-)-baclofen, cgp27492 and blocked by phaclofen. Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites. | Gamma-aminobutyric acid type B receptor subunit 1 agonist: Baclofen | 15.11 | |||
| dpcGCKR | Glucokinase regulatory protein | 0 | 50 | 96.71 | ND | 99.99 | 0.64 | ND | 0.5 | Mammalian | Found in liver and pancreas. Not detected in muscle, brain, heart, thymus, intestine, uterus, adipose tissue, kidney, adrenal, lung or spleen. {ECO:0000269|PubMed:19643913, ECO:0000269|PubMed:9570959}. | Inhibits glucokinase (GCK) by forming an inactive complex with this enzyme. The affinity of GCKR for GCK is modulated by fructose metabolites: GCKR with bound fructose 6- phosphate has increased affinity for GCK, while GCKR with bound fructose 1-phosphate has strongly decreased affinity for GCK and does not inhibit GCK activity. {ECO:0000269|PubMed:23621087, ECO:0000269|PubMed:23733961}. | 15.11 | |||||
| dpcGCR | Glucocorticoid receptor | 0 | 1819 | 72.82 | ND | 95.43 | 0.63 | ND | 0.6 | Nature11159 VirtualToxLab | Mammalian | Widely expressed. In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart. {ECO:0000269|PubMed:10902803}. | Acne Adrenal disorder Adrenal insufficiency Adrenal suppression Amenorrhoea Bone disorder Calcium metabolism disorder Cataract Cushingoid Depression Dysphonia Embolism arterial Endocrine disorder Epidural lipomatosis Epistaxis Euphoric mood Fluid retention Foot and mouth disease Fracture Fungal infection Glaucoma Growth retardation Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Impaired healing Increased appetite Intracranial pressure increased Menstrual disorder Muscular weakness Nitrogen balance negative Oedema Oral candidiasis Osteonecrosis Osteoporosis Pancreatic disorder Pancreatitis acute Peptic ulcer Phosphorus metabolism disorder Sepsis Skin atrophy Skin striae Superinfection Telangiectasia | Nuclear receptor | Glucocorticoid resistance, generalized (GCCR) [MIM:615962]: An autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of Cushing syndrome typical signs. Clinical features include hypoglycemia, hypertension, metabolic alkalosis, chronic fatigue and profound anxiety. {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946}. Note=The disease is caused by mutations affecting the gene represented in this entry. Glucocorticoid resistance (GCRES) [MIM:138040]: Hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant. {ECO:0000269|PubMed:11589680, ECO:0000269|PubMed:12050230, ECO:0000269|PubMed:7683692}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic genes expression. {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946, ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:21664385}. | Glucocorticoid receptor agonist: Flunisolide | 15.11 |
| dpcGRIK1 | Glutamate receptor ionotropic, kainate 1 | 0 | 257 | 89.43 | ND | 96.34 | 0.30 | ND | 0.8 | Mammalian | Most abundant in the cerebellum and the suprachiasmatic nuclei (SCN) of the hypothalamus. | Ligand-gated ion channel | Analgesics
Epilepsy Pain | Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus. | Glutamate receptor ionotropic, kainate 1 antagonist: Topiramate | 15.11 | ||
| dpcGRIK3 | Glutamate receptor ionotropic, kainate 3 | 0 | 66 | 98.33 | ND | 99.62 | 0.43 | ND | 0.7 | Mammalian | Expressed in the deep cortical layers, dentate gyrus, reticular thalamic nucleus, mammillary bodies, pons, and cerebellum of the adult. | Ligand-gated ion channel | Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA. {ECO:0000269|PubMed:21907808}. | 15.11 | ||||
| dpcGRM1 | Metabotropic glutamate receptor 1 | 0 | 701 | 78.29 | ND | 96.08 | 0.59 | ND | 0.8 | Mammalian | Detected in brain. | Family C G protein-coupled receptor | Spinocerebellar ataxia, autosomal recessive, 13 (SCAR13) [MIM:614831]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR13 is characterized by delayed psychomotor development beginning in infancy. Affected individuals show mild to profound mental retardation with poor or absent speech as well as gait and stance ataxia and hyperreflexia. {ECO:0000269|PubMed:22901947}. Note=The disease is caused by mutations affecting the gene represented in this entry. | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum. {ECO:0000269|PubMed:24603153, ECO:0000269|PubMed:7476890}. | 15.11 | |||
| dpcGRM3 | Metabotropic glutamate receptor 3 | 0 | 192 | 77.19 | ND | 97.83 | 0.63 | ND | 0.6 | Mammalian | Detected in brain cortex, thalamus, subthalamic nucleus, substantia nigra, hypothalamus, hippocampus, corpus callosum, caudate nucleus and amygdala. {ECO:0000269|PubMed:8840013}. | Family C G protein-coupled receptor | Alzheimer's disease
Analgesics Epilepsy Pain Psychosis Schizophrenia and Schizoaffective Disorders Traumatic brain injury | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:8840013}. | 15.11 | |||
| dpcGRM5 | Metabotropic glutamate receptor 5 | 0 | 2236 | 83.71 | ND | 96.72 | 0.34 | ND | 0.8 | Mammalian | Family C G protein-coupled receptor | Analgesics
Anxiety Disorders Convulsions Depression Drug dependence Gastroesophageal Reflux Disease (GERD) Inflammatory pain Migraine and Cluster Headaches Neuronal injury Parkinson's disease | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. Plays an important role in the regulation of synaptic plasticity and the modulation of the neural network activity. {ECO:0000269|PubMed:7908515, ECO:0000269|Ref.7}. | Metabotropic glutamate receptor 5 antagonist: Acamprosate Metabotropic glutamate receptor 5 inhibitor: Rufinamide | 15.11 | |||
| dpcGSHR | Glutathione reductase, mitochondrial | 0 | 118 | 71.75 | ND | 89.37 | 0.94 | ND | 0.2 | Mammalian | Oxidoreductase | Maintains high levels of reduced glutathione in the cytosol. | Glutathione reductase, mitochondrial : Flavin adenine dinucleotide, Glutathione Glutathione reductase, mitochondrial inhibitor: Carmustine | 15.11 | ||||
| dpcGSK3B | Glycogen synthase kinase-3 beta | 0 | 2337 | 83.76 | ND | 91.99 | 0.45 | ND | 0.8 | Mammalian | Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Colocalizes with EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain. {ECO:0000269|PubMed:21029237}. | Kinase | Alzheimer's disease
Bipolar affective disorder Brain injury Immunodeficiency Ischemia Noninsulin-dependent diabetes mellitus | Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation. Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). {ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20932480, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:8397507, ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}. | Glycogen synthase kinase-3 beta inhibitor: Lithium | 15.11 | ||
| dpcHCK | Tyrosine-protein kinase HCK | 0 | 326 | 94.46 | ND | 94.78 | 0.44 | ND | 0.8 | Mammalian | Detected in monocytes and neutrophils (at protein level). Expressed predominantly in cells of the myeloid and B-lymphoid lineages. Highly expressed in granulocytes. Detected in tonsil. {ECO:0000269|PubMed:3453117, ECO:0000269|PubMed:8064233, ECO:0000269|PubMed:8995234}. | Kinase | Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity. Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation. | Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS. {ECO:0000269|PubMed:10092522, ECO:0000269|PubMed:10779760, ECO:0000269|PubMed:10973280, ECO:0000269|PubMed:11741929, ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:12411494, ECO:0000269|PubMed:15010462, ECO:0000269|PubMed:15952790, ECO:0000269|PubMed:15998323, ECO:0000269|PubMed:17310994, ECO:0000269|PubMed:17535448, ECO:0000269|PubMed:19114024, ECO:0000269|PubMed:19903482, ECO:0000269|PubMed:20452982, ECO:0000269|PubMed:21338576, ECO:0000269|PubMed:7535819, ECO:0000269|PubMed:8132624, ECO:0000269|PubMed:9406996, ECO:0000269|PubMed:9407116}. | Tyrosine-protein kinase HCK inhibitor: Bosutinib | 15.11 | ||
| dpcHDAC2 | Histone deacetylase 2 | 0 | 461 | 78.20 | ND | 95.36 | 0.50 | ND | 0.8 | Mammalian | Widely expressed; lower levels in brain and lung. | Eraser | Colon cancer | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation. Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A. {ECO:0000269|PubMed:19343227, ECO:0000269|PubMed:21965678}. | Histone deacetylase 2 : Valproic Acid Histone deacetylase 2 activator: Aminophylline, Oxtriphylline, Theophylline Histone deacetylase 2 inhibitor: Panobinostat, Vorinostat Histone deacetylase 2 other: Lovastatin | 15.11 | ||
| dpcHDAC8 | Histone deacetylase 8 | 0 | 669 | 74.38 | ND | 91.50 | 0.72 | ND | 0.5 | Mammalian | Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney. {ECO:0000269|PubMed:10926844, ECO:0000269|PubMed:14701748, ECO:0000269|PubMed:15772115, ECO:0000269|PubMed:16538051}. | Eraser | Cornelia de Lange syndrome 5 (CDLS5) [MIM:300882]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:22885700}. Note=The disease is caused by mutations affecting the gene represented in this entry. Wilson-Turner X-linked mental retardation syndrome (WTS) [MIM:309585]: A neurologic disorder characterized by severe intellectual disability, dysmorphic facial features, hypogonadism, short stature, and truncal obesity. Affected females have a milder phenotype than affected males. {ECO:0000269|PubMed:22889856}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. {ECO:0000269|PubMed:10748112, ECO:0000269|PubMed:10922473, ECO:0000269|PubMed:10926844, ECO:0000269|PubMed:14701748, ECO:0000269|PubMed:22885700}. | Histone deacetylase 8 : Vorinostat Histone deacetylase 8 inhibitor: Panobinostat | 15.11 | ||
| dpcHMDH | 3-hydroxy-3-methylglutaryl-coenzyme A reductase | 0 | 738 | 90.55 | ND | 99.11 | 0.51 | ND | 0.8 | Mammalian | Myalgia | Oxidoreductase | Atherosclerosis
Cardiovascular disease, unspecified Cervical cancer Coronary heart disease Dyslipidemia Head and neck squamous cell carcinomas Hypercholesterolemia Hypertriglyceridemia Myocardial infarction | Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins. | 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor: Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin | 15.11 | ||
| dpcHPRT | Hypoxanthine-guanine phosphoribosyltransferase | 0 | 87 | 94.11 | ND | 94.75 | 0.33 | ND | 0.4 | Mammalian | Enzyme | Lesch-Nyhan syndrome (LNS) [MIM:300322]: Characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self- mutilation. {ECO:0000269|PubMed:15571223, ECO:0000269|PubMed:17027311, ECO:0000269|PubMed:2071157, ECO:0000269|PubMed:2246854, ECO:0000269|PubMed:2347587, ECO:0000269|PubMed:2358296, ECO:0000269|PubMed:24940672, ECO:0000269|PubMed:2910902, ECO:0000269|PubMed:3265398, ECO:0000269|PubMed:3384338, ECO:0000269|PubMed:6853716, ECO:0000269|PubMed:7627191, ECO:0000269|PubMed:9452051}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gout HPRT-related (GOUT-HPRT) [MIM:300323]: Characterized by partial enzyme activity and hyperuricemia. {ECO:0000269|PubMed:15571223, ECO:0000269|PubMed:17027311, ECO:0000269|PubMed:20544509, ECO:0000269|PubMed:24940672, ECO:0000269|PubMed:2909537, ECO:0000269|PubMed:3198771, ECO:0000269|PubMed:3358423, ECO:0000269|PubMed:6572373, ECO:0000269|PubMed:6706936, ECO:0000269|PubMed:6853490, ECO:0000269|PubMed:7987318}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5- phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway. | Hypoxanthine-guanine phosphoribosyltransferase inhibitor: Azathioprine, Mercaptopurine Hypoxanthine-guanine phosphoribosyltransferase substrate: Tioguanine | 15.11 | |||
| dpcHS90B | Heat shock protein HSP 90-beta | 0 | 379 | 83.31 | ND | 94.84 | 0.78 | ND | 0.6 | Mammalian | Other cytosolic protein | Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. {ECO:0000269|PubMed:16478993, ECO:0000269|PubMed:19696785}. | 15.11 | |||||
| dpcHXK4 | Glucokinase | 0 | 564 | 88.93 | ND | 98.74 | 0.30 | ND | 0.6 | Mammalian | Isoform 1 is expressed in pancreas. Isoform 2 and isoform 3 is expressed in liver. | Enzyme | Maturity-onset diabetes of the young 2 (MODY2) [MIM:125851]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:10588527, ECO:0000269|PubMed:10694920, ECO:0000269|PubMed:11106831, ECO:0000269|PubMed:11372010, ECO:0000269|PubMed:1303265, ECO:0000269|PubMed:1464666, ECO:0000269|PubMed:1502186, ECO:0000269|PubMed:8168652, ECO:0000269|PubMed:8325892, ECO:0000269|PubMed:8495817, ECO:0000269|PubMed:9049484, ECO:0000269|PubMed:9662401}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperinsulinemic hypoglycemia 3 (HHF3) [MIM:602485]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269|PubMed:9435328}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage. | 15.11 | |||
| dpcHYES | Bifunctional epoxide hydrolase 2 | 0 | 1186 | 87.03 | ND | 98.12 | 0.50 | ND | 0.8 | Mammalian | Detected in liver, intestine, ovary and kidney. Detected at low levels in heart and muscle. {ECO:0000269|PubMed:15601917, ECO:0000269|PubMed:8750907}. | Protease | Cardiovascular disease, unspecified
Hypertension Renal diseases | Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo- 9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro- 9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy- octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate (By similarity). {ECO:0000250}. | 15.11 | |||
| dpcIGF1R | Insulin-like growth factor 1 receptor | 0 | 1176 | 79.85 | ND | 96.48 | 0.73 | ND | 0.7 | Mammalian | Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney. {ECO:0000269|PubMed:12019176, ECO:0000269|PubMed:8247543, ECO:0000269|PubMed:9202395, ECO:0000269|PubMed:9355755}. | Kinase | Insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]: A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels. {ECO:0000269|PubMed:14657428, ECO:0000269|PubMed:15928254}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K- driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R. When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. | Insulin-like growth factor 1 receptor : Insulin Lispro, Insulin Regular, Insulin, porcine Insulin-like growth factor 1 receptor agonist: Insulin Glargine, Mecasermin | 15.11 | ||
| dpcIKKB | Inhibitor of nuclear factor kappa-B kinase subunit beta | 0 | 897 | 85.19 | ND | 95.47 | 0.60 | ND | 0.7 | Mammalian | Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood. | Kinase | Immunodeficiency 15 (IMD15) [MIM:615592]: An autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T- cells, and impaired differentiation and activation of immune cells. {ECO:0000269|PubMed:24369075}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine kinase that plays an essential role in the NF- kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF- dependent inactivation of this pro-apoptotic transcription factor. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation. {ECO:0000269|PubMed:11297557, ECO:0000269|PubMed:15084260, ECO:0000269|PubMed:17213322, ECO:0000269|PubMed:19716809, ECO:0000269|PubMed:20410276, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20797629, ECO:0000269|PubMed:21138416}. | Inhibitor of nuclear factor kappa-B kinase subunit beta : Acetylsalicylic acid Inhibitor of nuclear factor kappa-B kinase subunit beta inducer: Arsenic trioxide Inhibitor of nuclear factor kappa-B kinase subunit beta inhibitor: Acetylcysteine, Auranofin, Mesalazine, Sulfasalazine | 15.11 | ||
| dpcINSR | Insulin receptor | 0 | 884 | 84.80 | ND | 94.84 | 0.58 | ND | 0.6 | Mammalian | Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas. {ECO:0000269|PubMed:10207053, ECO:0000269|PubMed:2369896, ECO:0000269|PubMed:9202395, ECO:0000269|PubMed:9355755}. | Kinase | Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10443650, ECO:0000269|PubMed:12023989, ECO:0000269|PubMed:17201797, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:8314008}. Note=The disease is caused by mutations affecting the gene represented in this entry. Leprechaunism (LEPRCH) [MIM:246200]: Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive. {ECO:0000269|PubMed:12538626, ECO:0000269|PubMed:12970295, ECO:0000269|PubMed:1607067, ECO:0000269|PubMed:1730625, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2479553, ECO:0000269|PubMed:2834824, ECO:0000269|PubMed:7538143, ECO:0000269|PubMed:7815442, ECO:0000269|PubMed:8188715, ECO:0000269|PubMed:8326490, ECO:0000269|PubMed:8419945, ECO:0000269|PubMed:8636294, ECO:0000269|PubMed:9249867, ECO:0000269|PubMed:9703342}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:1470163, ECO:0000269|PubMed:1607076, ECO:0000269|PubMed:7657032}. Note=The gene represented in this entry may be involved in disease pathogenesis. Familial hyperinsulinemic hypoglycemia 5 (HHF5) [MIM:609968]: Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. {ECO:0000269|PubMed:15161766}. Note=The disease is caused by mutations affecting the gene represented in this entry. Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]: Characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. {ECO:0000269|PubMed:10733238, ECO:0000269|PubMed:11260230, ECO:0000269|PubMed:12107746, ECO:0000269|PubMed:12970295, ECO:0000269|PubMed:1563582, ECO:0000269|PubMed:1963473, ECO:0000269|PubMed:2002058, ECO:0000269|PubMed:2168397, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2544998, ECO:0000269|PubMed:3283938, ECO:0000269|PubMed:8243830, ECO:0000269|PubMed:8288049, ECO:0000269|PubMed:8314008, ECO:0000269|PubMed:8388389, ECO:0000269|PubMed:9175790}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src- homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti- apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K- AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. {ECO:0000269|PubMed:12138094, ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16831875, ECO:0000269|PubMed:8257688, ECO:0000269|PubMed:8276809, ECO:0000269|PubMed:8452530, ECO:0000269|PubMed:9428692}. | Insulin receptor : Mecasermin Insulin receptor agonist: Insulin Aspart, Insulin Detemir, Insulin Glargine, Insulin Glulisine, Insulin Lispro, Insulin Regular, Insulin, isophane Insulin receptor binder: Insulin, porcine | 15.11 | ||
| dpcIRAK4 | Interleukin-1 receptor-associated kinase 4 | 0 | 375 | 85.21 | ND | 88.84 | 0.24 | ND | 0.7 | Mammalian | Kinase | Recurrent isolated invasive pneumococcal disease 1 (IPD1) [MIM:610799]: Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. {ECO:0000269|PubMed:16950813}. Note=The disease is caused by mutations affecting the gene represented in this entry. IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. {ECO:0000269|PubMed:12637671, ECO:0000269|PubMed:12925671, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:19663824, ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino- mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA- IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. {ECO:0000269|PubMed:11960013, ECO:0000269|PubMed:12538665, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:17217339, ECO:0000269|PubMed:17337443, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509, ECO:0000269|PubMed:24316379}. | 15.11 | ||||
| dpcITA2B | Integrin alpha-IIb | 0 | 41 | 92.36 | ND | 99.96 | 0.47 | ND | 0.5 | Mammalian | Isoform 1 and isoform 2 were identified in platelets and megakaryocytes, but not in reticulocytes or in Jurkat and U-937 white blood cell line. Isoform 3 is expressed by leukemia, prostate adenocarcinoma and melanoma cells but not by platelets or normal prostate or breast epithelial cells. | Membrane receptor | Glanzmann thrombasthenia (GT) [MIM:273800]: A common inherited disease of platelet aggregation. It is characterized by mucocutaneous bleeding of mild-to-moderate severity. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb-IIIa complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the GPIIb-IIIa complex at reduced levels, have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. {ECO:0000269|PubMed:10607701, ECO:0000269|PubMed:11798398, ECO:0000269|PubMed:12083483, ECO:0000269|PubMed:12181054, ECO:0000269|PubMed:12424194, ECO:0000269|PubMed:12506038, ECO:0000269|PubMed:15099289, ECO:0000269|PubMed:15219201, ECO:0000269|PubMed:17018384, ECO:0000269|PubMed:20020534, ECO:0000269|PubMed:7508443, ECO:0000269|PubMed:7706461, ECO:0000269|PubMed:8282784, ECO:0000269|PubMed:8704171, ECO:0000269|PubMed:9215749, ECO:0000269|PubMed:9473221, ECO:0000269|PubMed:9722314, ECO:0000269|PubMed:9734640, ECO:0000269|PubMed:9763559, ECO:0000269|PubMed:9920835}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bleeding disorder, platelet-type 16 (BDPLT16) [MIM:187800]: An autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities. {ECO:0000269|PubMed:21454453, ECO:0000269|PubMed:9834222}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha- IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface. | Integrin alpha-IIb antagonist: Abciximab, Tirofiban | 15.11 | ||
| dpcITAL | Integrin alpha-L | 0 | 139 | 87.15 | ND | 98.71 | 0.56 | ND | 0.9 | Mammalian | Leukocytes. | Adhesion | Integrin alpha-L/beta-2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. It is involved in a variety of immune phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell mediated killing, and antibody dependent killing by granulocytes and monocytes. | Integrin alpha-L : Anti-thymocyte Globulin (Rabbit) Integrin alpha-L antibody: Efalizumab Integrin alpha-L other/unknown: Lovastatin | 15.11 | |||
| dpcITK | Tyrosine-protein kinase ITK/TSK | 0 | 683 | 91.78 | ND | 97.00 | 0.56 | ND | 0.7 | Mammalian | T-cell lines and natural killer cell lines. | Kinase | Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011]: A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma. {ECO:0000269|PubMed:19425169}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. {ECO:0000269|PubMed:12186560, ECO:0000269|PubMed:12682224, ECO:0000269|PubMed:21725281}. | Tyrosine-protein kinase ITK/TSK inhibitor: Pazopanib | 15.11 | ||
| dpcJAK1 | Tyrosine-protein kinase JAK1 | 0 | 482 | 89.85 | ND | 96.09 | 0.70 | ND | 0.6 | Mammalian | Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue. {ECO:0000269|PubMed:7896447}. | Kinase | Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. {ECO:0000269|PubMed:11909529}. | Tyrosine-protein kinase JAK1 inhibitor: Ruxolitinib, Tofacitinib | 15.11 | |||
| dpcJAK2 | Tyrosine-protein kinase JAK2 | 0 | 1284 | 91.82 | ND | 94.34 | 0.58 | ND | 0.8 | Mammalian | Ubiquitously expressed throughout most tissues. {ECO:0000269|PubMed:16424865}. | Kinase | Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Budd-Chiari syndrome (BDCHS) [MIM:600880]: A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. {ECO:0000269|PubMed:16707754}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Polycythemia vera (PV) [MIM:263300]: A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly. {ECO:0000269|PubMed:15781101, ECO:0000269|PubMed:15793561, ECO:0000269|PubMed:15858187, ECO:0000269|PubMed:16603627}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thrombocythemia 3 (THCYT3) [MIM:614521]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. {ECO:0000269|PubMed:16325696, ECO:0000269|PubMed:22397670}. Note=The disease may be caused by mutations affecting the gene represented in this entry. Myelofibrosis (MYELOF) [MIM:254450]: A disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry. Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:16247455}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin. {ECO:0000269|PubMed:12023369, ECO:0000269|PubMed:19783980, ECO:0000269|PubMed:20098430, ECO:0000269|PubMed:21423214}. | Tyrosine-protein kinase JAK2 inhibitor: Ruxolitinib, Tofacitinib | 15.11 | ||
| dpcJAK3 | Tyrosine-protein kinase JAK3 | 0 | 877 | 87.98 | ND | 96.03 | 0.53 | ND | 0.6 | Mammalian | In NK cells and an NK-like cell line but not in resting T-cells or in other tissues. The S-form is more commonly seen in hematopoietic lines, whereas the B-form is detected in cells both of hematopoietic and epithelial origins. {ECO:0000269|PubMed:7535338}. | Kinase | Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:600802]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:10982185, ECO:0000269|PubMed:14615376, ECO:0000269|PubMed:7659163, ECO:0000269|PubMed:9354668, ECO:0000269|PubMed:9753072}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion. {ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:20440074, ECO:0000269|PubMed:7662955, ECO:0000269|PubMed:8022485}. | Tyrosine-protein kinase JAK3 inhibitor: Tofacitinib | 15.11 | ||
| dpcKAPCA | cAMP-dependent protein kinase catalytic subunit alpha | 0 | 509 | 79.77 | ND | 90.03 | 0.43 | ND | 0.7 | Mammalian | Isoform 1 is ubiquitous. Isoform 2 is sperm- specific and is enriched in pachytene spermatocytes but is not detected in round spermatids. {ECO:0000269|PubMed:10906071, ECO:0000269|PubMed:21812984}. | Kinase | Primary pigmented nodular adrenocortical disease 4 (PPNAD4) [MIM:615830]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:24571724, ECO:0000269|PubMed:24700472, ECO:0000269|PubMed:24747643, ECO:0000269|PubMed:24855271}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose- mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B- alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha- difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. {ECO:0000269|PubMed:15642694, ECO:0000269|PubMed:15905176, ECO:0000269|PubMed:16387847, ECO:0000269|PubMed:17333334, ECO:0000269|PubMed:17565987, ECO:0000269|PubMed:17693412, ECO:0000269|PubMed:18836454, ECO:0000269|PubMed:19949837, ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:21423175, ECO:0000269|PubMed:21514275, ECO:0000269|PubMed:21812984}. | 15.11 | |||
| dpcKC1D | Casein kinase I isoform delta | 0 | 463 | 79.72 | ND | 89.55 | 0.50 | ND | 0.7 | Mammalian | Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. However, kinase activity is not uniform, with highest kinase activity in splenocytes. In blood, highly expressed in hemopoietic cells and mature granulocytes. Also found in monocytes and lymphocytes. {ECO:0000269|PubMed:15070676, ECO:0000269|PubMed:16027726}. | Kinase | Advanced sleep phase syndrome, familial, 2 (FASPS2) [MIM:615224]: A disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. {ECO:0000269|PubMed:15800623, ECO:0000269|PubMed:23636092}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In balance with PP1, determines the circadian period length through the regulation of the speed and rhythmicity of PER1 and PER2 phospohorylation. Controls PER1 and PER2 nuclear transport and degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate. {ECO:0000269|PubMed:10606744, ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16027726, ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:19043076, ECO:0000269|PubMed:19339517, ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20637175, ECO:0000269|PubMed:20696890, ECO:0000269|PubMed:20699359, ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092}. | 15.11 | |||
| dpcKC1G1 | Casein kinase I isoform gamma-1 | 0 | 231 | 78.76 | ND | 87.78 | 0.35 | ND | 0.8 | Mammalian | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Regulates fast synaptic transmission mediated by glutamate (By similarity). Phosphorylates CLSPN. {ECO:0000250, ECO:0000269|PubMed:21680713}. | 15.11 | |||||
| dpcKC1G2 | Casein kinase I isoform gamma-2 | 0 | 270 | 86.33 | ND | 87.63 | 0.36 | ND | 0.5 | Mammalian | Testis. | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates COL4A3BP/CERT, MTA1 and SMAD3. Involved in brain development and vesicular trafficking and neurotransmitter releasing from small synaptic vesicles. Regulates fast synaptic transmission mediated by glutamate. SMAD3 phosphorylation promotes its ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Hyperphosphorylation of the serine-repeat motif of COL4A3BP/CERT leads to its inactivation by dissociation from the Golgi complex, thus down-regulating ER-to-Golgi transport of ceramide and sphingomyelin synthesis. Triggers PER1 proteasomal degradation probably through phosphorylation. {ECO:0000269|PubMed:15077195, ECO:0000269|PubMed:15342122, ECO:0000269|PubMed:15917222, ECO:0000269|PubMed:18794808, ECO:0000269|PubMed:19005213}. | 15.11 | ||||
| dpcKC1G3 | Casein kinase I isoform gamma-3 | 0 | 193 | 79.80 | ND | 87.79 | 0.34 | ND | 0.6 | Mammalian | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Regulates fast synaptic transmission mediated by glutamate (By similarity). {ECO:0000250}. | 15.11 | |||||
| dpcKCC2A | Calcium/calmodulin-dependent protein kinase type II subunit alpha | 0 | 113 | 83.09 | ND | 80.73 | 0.00 | ND | 0.8 | Mammalian | Kinase | CaM-kinase II (CAMK2) is a prominent kinase in the central nervous system that may function in long-term potentiation and neurotransmitter release. Member of the NMDAR signaling complex in excitatory synapses it may regulate NMDAR-dependent potentiation of the AMPAR and synaptic plasticity (By similarity). {ECO:0000250}. | 15.11 | |||||
| dpcKCC2B | Calcium/calmodulin-dependent protein kinase type II subunit beta | 0 | 224 | 81.47 | ND | 83.11 | 0.31 | ND | 0.5 | Mammalian | Widely expressed. Expressed in adult and fetal brain. Expression is slightly lower in fetal brain. Expressed in skeletal muscle. {ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic reticulum Ca(2+) transport in skeletal muscle. In neurons, plays an essential structural role in the reorganization of the actin cytoskeleton during plasticity by binding and bundling actin filaments in a kinase-independent manner. This structural function is required for correct targeting of CaMK2A, which acts downstream of NMDAR to promote dendritic spine and synapse formation and maintain synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. In developing hippocampal neurons, promotes arborization of the dendritic tree and in mature neurons, promotes dendritic remodeling. Participates in the modulation of skeletal muscle function in response to exercise. In slow-twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of triadin, a ryanodine receptor-coupling factor, and phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2. {ECO:0000269|PubMed:16690701}. | 15.11 | ||||
| dpcKCC2D | Calcium/calmodulin-dependent protein kinase type II subunit delta | 0 | 338 | 77.34 | ND | 87.39 | 0.39 | ND | 0.7 | Mammalian | Expressed in cardiac muscle and skeletal muscle. Isoform Delta 3, isoform Delta 2, isoform Delta 8 and isoform Delta 9 are expressed in cardiac muscle. Isoform Delta 11 is expressed in skeletal muscle. {ECO:0000269|PubMed:10189359, ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser- 2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program. Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis. May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor- coupling factor. {ECO:0000269|PubMed:16690701, ECO:0000269|PubMed:17179159}. | 15.11 | ||||
| dpcKCC2G | Calcium/calmodulin-dependent protein kinase type II subunit gamma | 0 | 233 | 87.51 | ND | 92.80 | 0.36 | ND | 0.8 | Mammalian | Expressed in skeletal muscle. {ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in sarcoplsamic reticulum Ca(2+) transport in skeletal muscle and may function in dendritic spine and synapse formation and neuronal plasticity. In slow- twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of the ryanodine receptor-coupling factor triadin. In neurons, may participate in the promotion of dendritic spine and synapse formation and maintenance of synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. {ECO:0000269|PubMed:16690701}. | Calcium/calmodulin-dependent protein kinase type II subunit gamma inhibitor: Bosutinib | 15.11 | |||
| dpcKIF11 | Kinesin-like protein KIF11 | 0 | 758 | 89.60 | ND | 96.16 | 0.52 | ND | 0.7 | Mammalian | Other cytosolic protein | Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:152950]: An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes. {ECO:0000269|PubMed:22284827}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays. {ECO:0000269|PubMed:19001501}. | 15.11 | ||||
| dpcKIT | Mast/stem cell growth factor receptor Kit | 0 | 807 | 88.13 | ND | 95.18 | 0.44 | ND | 0.8 | Mammalian | Isoform 1 and isoform 2 are detected in spermatogonia and Leydig cells. Isoform 3 is detected in round spermatids, elongating spermatids and spermatozoa (at protein level). Widely expressed. Detected in the hematopoietic system, the gastrointestinal system, in melanocytes and in germ cells. {ECO:0000269|PubMed:20601678, ECO:0000269|PubMed:2448137}. | Kinase | Piebald trait (PBT) [MIM:172800]: Autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. {ECO:0000269|PubMed:11074500, ECO:0000269|PubMed:1370874, ECO:0000269|PubMed:1376329, ECO:0000269|PubMed:1717985, ECO:0000269|PubMed:7687267, ECO:0000269|PubMed:8680409, ECO:0000269|PubMed:9450866, ECO:0000269|PubMed:9699740}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gastrointestinal stromal tumor (GIST) [MIM:606764]: Common mesenchymal neoplasms arising in the gastrointestinal tract, most often in the stomach. They are histologically, immunohistochemically, and genetically different from typical leiomyomas, leiomyosarcomas, and schwannomas. Most GISTs are composed of a fairly uniform population of spindle-shaped cells. Some tumors are dominated by epithelioid cells or contain a mixture of spindle and epithelioid morphologies. Primary GISTs in the gastrointestinal tract commonly metastasize in the omentum and mesenteries, often as multiple nodules. However, primary tumors may also occur outside of the gastrointestinal tract, in other intra-abdominal locations, especially in the omentum and mesentery. {ECO:0000269|PubMed:11505412, ECO:0000269|PubMed:15824741, ECO:0000269|PubMed:9438854, ECO:0000269|PubMed:9697690}. Note=The gene represented in this entry is involved in disease pathogenesis. Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. Note=The gene represented in this entry may be involved in disease pathogenesis. Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. Note=The gene represented in this entry is involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase. | Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1. {ECO:0000269|PubMed:10397721, ECO:0000269|PubMed:12444928, ECO:0000269|PubMed:12511554, ECO:0000269|PubMed:12878163, ECO:0000269|PubMed:17904548, ECO:0000269|PubMed:19265199, ECO:0000269|PubMed:21135090, ECO:0000269|PubMed:21640708, ECO:0000269|PubMed:7520444, ECO:0000269|PubMed:9528781}. | Mast/stem cell growth factor receptor Kit Inhibitor: Lenvatinib Mast/stem cell growth factor receptor Kit antagonist: Dasatinib, Imatinib, Nilotinib, Sorafenib, Sunitinib Mast/stem cell growth factor receptor Kit inhibitor: Pazopanib, Ponatinib, Regorafenib Mast/stem cell growth factor receptor Kit multitarget: | 15.11 | ||
| dpcKKCC2 | Calcium/calmodulin-dependent protein kinase kinase 2 | 0 | 77 | 89.95 | ND | 83.44 | 0.53 | ND | 0.7 | Mammalian | Ubiquitously expressed with higher levels in the brain. Intermediate levels are detected in spleen, prostate, thyroid and leukocytes. The lowest level is in lung. {ECO:0000269|PubMed:9662074}. | Kinase | Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Isoform 1, isoform 2 and isoform 3 phosphorylate CAMK1 and CAMK4. Isoform 3 phosphorylates CAMK1D. Isoform 4, isoform 5 and isoform 6 lacking part of the calmodulin- binding domain are inactive. Efficiently phosphorylates 5'-AMP- activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals (By similarity). Seems to be involved in hippocampal activation of CREB1 (By similarity). May play a role in neurite growth. Isoform 3 may promote neurite elongation, while isoform 1 may promoter neurite branching. {ECO:0000250, ECO:0000269|PubMed:11395482, ECO:0000269|PubMed:12935886, ECO:0000269|PubMed:21957496, ECO:0000269|PubMed:9662074}. | 15.11 | ||||
| dpcKPCB | Protein kinase C beta type | 0 | 351 | 73.50 | ND | 97.21 | 0.55 | ND | 0.8 | Mammalian | Kinase | B-lineage malignancies
Diabetes mellitus Diabetic retinopathy Macular edema | Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosome, oxidative stress-induced apoptosis, androgen receptor-dependent transcription regulation, insulin signaling and endothelial cells proliferation. Plays a key role in B-cell activation by regulating BCR-induced NF-kappa-B activation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11/CARMA1 at 'Ser-559', 'Ser-644' and 'Ser-652'. Phosphorylation induces CARD11/CARMA1 association with lipid rafts and recruitment of the BCL10-MALT1 complex as well as MAP3K7/TAK1, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. Plays a direct role in the negative feedback regulation of the BCR signaling, by down-modulating BTK function via direct phosphorylation of BTK at 'Ser-180', which results in the alteration of BTK plasma membrane localization and in turn inhibition of BTK activity. Involved in apoptosis following oxidative damage: in case of oxidative conditions, specifically phosphorylates 'Ser-36' of isoform p66Shc of SHC1, leading to mitochondrial accumulation of p66Shc, where p66Shc acts as a reactive oxygen species producer. Acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag for epigenetic transcriptional activation that prevents demethylation of histone H3 'Lys-4' (H3K4me) by LSD1/KDM1A. In insulin signaling, may function downstream of IRS1 in muscle cells and mediate insulin-dependent DNA synthesis through the RAF1- MAPK/ERK signaling cascade. May participate in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. Under high glucose in pancreatic beta-cells, is probably involved in the inhibition of the insulin gene transcription, via regulation of MYC expression. In endothelial cells, activation of PRKCB induces increased phosphorylation of RB1, increased VEGFA-induced cell proliferation, and inhibits PI3K/AKT-dependent nitric oxide synthase (NOS3/eNOS) regulation by insulin, which causes endothelial dysfunction. Also involved in triglyceride homeostasis (By similarity). Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. {ECO:0000250, ECO:0000269|PubMed:11598012, ECO:0000269|PubMed:19176525, ECO:0000269|PubMed:20228790}. | 15.11 | ||||
| dpcKPCD | Protein kinase C delta type | 0 | 785 | 73.58 | ND | 93.00 | 0.53 | ND | 0.8 | Mammalian | Kinase | Autoimmune lymphoproliferative syndrome 3 (ALPS3) [MIM:615559]: A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. CVID9 patients have B-cell deficiency and severe autoimmunity. {ECO:0000269|PubMed:23319571}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor- initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Negatively regulates B cell proliferation and also has an important function in self- antigen induced B cell tolerance induction. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53. In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)- induced inhibition of cell cycle progression at G1/S phase by up- regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1. Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro- survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl- phenylalanine (fMLP)-treated cells, is required for NCF1 (p47- phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways. May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation. Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release. Phosphorylates MUC1 in the C- terminal and regulates the interaction between MUC1 and beta- catenin. The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (By similarity). {ECO:0000250, ECO:0000269|PubMed:11748588, ECO:0000269|PubMed:11877440, ECO:0000269|PubMed:15774464, ECO:0000269|PubMed:16940418, ECO:0000269|PubMed:19587372, ECO:0000269|PubMed:19801500}. | Protein kinase C delta type ligand: Ingenol Mebutate | 15.11 | |||
| dpcKPCI | Protein kinase C iota type | 0 | 107 | 74.32 | ND | 84.73 | 0.50 | ND | 0.6 | Mammalian | Predominantly expressed in lung and brain, but also expressed at lower levels in many tissues including pancreatic islets. Highly expressed in non-small cell lung cancers. {ECO:0000269|PubMed:15994303, ECO:0000269|PubMed:7607695, ECO:0000269|PubMed:8226978}. | Kinase | Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non- small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis. {ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10467349, ECO:0000269|PubMed:10906326, ECO:0000269|PubMed:11042363, ECO:0000269|PubMed:11724794, ECO:0000269|PubMed:12871960, ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15994303, ECO:0000269|PubMed:18270268, ECO:0000269|PubMed:19327373, ECO:0000269|PubMed:21189248, ECO:0000269|PubMed:21419810, ECO:0000269|PubMed:8226978, ECO:0000269|PubMed:9346882}. | 15.11 | ||||
| dpcKPCT | Protein kinase C theta type | 0 | 576 | 78.01 | ND | 92.28 | 0.59 | ND | 0.8 | Mammalian | Expressed in skeletal muscle, T-cells, megakaryoblastic cells and platelets. {ECO:0000269|PubMed:7686153}. | Kinase | Not Available | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non- redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non- canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. {ECO:0000269|PubMed:11342610, ECO:0000269|PubMed:14988727, ECO:0000269|PubMed:15364919, ECO:0000269|PubMed:16252004, ECO:0000269|PubMed:16356855, ECO:0000269|PubMed:16709830, ECO:0000269|PubMed:19549985, ECO:0000269|PubMed:8657160}. | 15.11 | |||
| dpcKPYM | Pyruvate kinase PKM | 0 | 1131 | 80.91 | ND | 90.18 | 0.39 | ND | 0.6 | Mammalian | Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. {ECO:0000269|PubMed:18191611}. | Enzyme | Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival. {ECO:0000269|PubMed:17308100, ECO:0000269|PubMed:18191611, ECO:0000269|PubMed:21620138}. | 15.11 | ||||
| dpcKS6A3 | Ribosomal protein S6 kinase alpha-3 | 0 | 594 | 80.99 | ND | 88.71 | 0.42 | ND | 0.7 | Mammalian | Expressed in many tissues, highest levels in skeletal muscle. | Kinase | Coffin-Lowry syndrome (CLS) [MIM:303600]: A X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders. {ECO:0000269|PubMed:10094187, ECO:0000269|PubMed:10528858, ECO:0000269|PubMed:14986828, ECO:0000269|PubMed:15214012, ECO:0000269|PubMed:8955270, ECO:0000269|PubMed:9837815}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mental retardation, X-linked 19 (MRX19) [MIM:300844]: A non-syndromic form of mild to moderate mental retardation. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation. {ECO:0000269|PubMed:10319851, ECO:0000269|PubMed:17100996}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR- independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro- apoptotic proteins BAD and DAPK1 and suppressing their pro- apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Phosphorylates DAPK1. {ECO:0000269|PubMed:10436156, ECO:0000269|PubMed:16213824, ECO:0000269|PubMed:16223362, ECO:0000269|PubMed:17360704, ECO:0000269|PubMed:18722121, ECO:0000269|PubMed:8250835, ECO:0000269|PubMed:9770464}. | 15.11 | |||
| dpcKS6A5 | Ribosomal protein S6 kinase alpha-5 | 0 | 248 | 87.54 | ND | 95.38 | 0.33 | ND | 1.0 | Mammalian | Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver. {ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9873047}. | Kinase | Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression. In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress. In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential. Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation. Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto- oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro- inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti- inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors. Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury. {ECO:0000269|PubMed:11909979, ECO:0000269|PubMed:12569367, ECO:0000269|PubMed:12628924, ECO:0000269|PubMed:12763138, ECO:0000269|PubMed:12773393, ECO:0000269|PubMed:15010469, ECO:0000269|PubMed:18511904, ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9873047}. | 15.11 | ||||
| dpcKS6B1 | Ribosomal protein S6 kinase beta-1 | 0 | 442 | 82.98 | ND | 90.50 | 0.35 | ND | 0.8 | Mammalian | Widely expressed. {ECO:0000269|PubMed:9804755}. | Kinase | Cancer, unspecific
Solid tumors | Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the pre-initiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative feedback mechanism for the RPS6KB1 anti- apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1- 2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin. Phosphorylates and activates the pyrimidine biosynthesis enzyme CAD, downstream of MTOR. {ECO:0000269|PubMed:11500364, ECO:0000269|PubMed:12801526, ECO:0000269|PubMed:14673156, ECO:0000269|PubMed:15071500, ECO:0000269|PubMed:15341740, ECO:0000269|PubMed:16286006, ECO:0000269|PubMed:17052453, ECO:0000269|PubMed:17053147, ECO:0000269|PubMed:17936702, ECO:0000269|PubMed:18952604, ECO:0000269|PubMed:19085255, ECO:0000269|PubMed:19720745, ECO:0000269|PubMed:19935711, ECO:0000269|PubMed:19995915, ECO:0000269|PubMed:23429703}. | 15.11 | |||
| dpcKSYK | Tyrosine-protein kinase SYK | 0 | 582 | 90.93 | ND | 95.87 | 0.59 | ND | 0.7 | Mammalian | Widely expressed in hematopoietic cells (at protein level). Within the B-cells compartment it is for instance expressed for pro-B-cells to plasma cells. {ECO:0000269|PubMed:8163536}. | Kinase | Allergic Reaction
Asthma Inflammatory diseases Lymphoma, Non-Hodgkin's Obstructive airway disease Rheumatoid arthritis Thrombocytopenia | Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine- phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T- cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. {ECO:0000269|PubMed:12387735, ECO:0000269|PubMed:12456653, ECO:0000269|PubMed:15388330, ECO:0000269|PubMed:19909739, ECO:0000269|PubMed:8657103, ECO:0000269|PubMed:9535867}. | 15.11 | |||
| dpcLCK | Tyrosine-protein kinase Lck | 0 | 1767 | 87.34 | ND | 95.11 | 0.54 | ND | 0.8 | Mammalian | Expressed specifically in lymphoid cells. | Kinase | Note=A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB. Immunodeficiency 22 (IMD22) [MIM:615758]: A primary immunodeficiency characterized by T-cell dysfunction. Affected individuals present with lymphopenia, recurrent infections, severe diarrhea, and failure to thrive. {ECO:0000269|PubMed:22985903}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T- cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. {ECO:0000269|PubMed:16339550, ECO:0000269|PubMed:16709819, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20851766, ECO:0000269|PubMed:21269457, ECO:0000269|PubMed:22080863}. | Tyrosine-protein kinase Lck Inhibitor: Nintedanib Tyrosine-protein kinase Lck inhibitor: Ponatinib Tyrosine-protein kinase Lck multitarget: Dasatinib | 15.11 | ||
| dpcLDHA | L-lactate dehydrogenase A chain | 0 | 97 | 80.12 | ND | 99.10 | 0.44 | ND | 0.9 | Mammalian | Enzyme | Glycogen storage disease 11 (GSD11) [MIM:612933]: A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue. {ECO:0000269|PubMed:2334430}. Note=The disease is caused by mutations affecting the gene represented in this entry. | 15.11 | |||||
| dpcLGUL | Lactoylglutathione lyase | 0 | 63 | 71.14 | ND | 96.26 | 0.41 | ND | 0.9 | Mammalian | Enzyme | Tumors | Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione. Involved in the regulation of TNF-induced transcriptional activity of NF- kappa-B. Required for normal osteoclastogenesis. {ECO:0000269|PubMed:19199007, ECO:0000269|PubMed:23122816, ECO:0000269|PubMed:9705294}. | Lactoylglutathione lyase : Glutathione Lactoylglutathione lyase inhibitor: Indomethacin | 15.11 | |||
| dpcLIMK1 | LIM domain kinase 1 | 0 | 437 | 85.14 | ND | 87.02 | 0.18 | ND | 0.8 | Mammalian | Highest expression in both adult and fetal nervous system. Detected ubiquitously throughout the different regions of adult brain, with highest levels in the cerebral cortex. Expressed to a lesser extent in heart and skeletal muscle. | Kinase | Note=LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. | Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin- 2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes. Required for atypical chemokine receptor ACKR2-induced phosphorylation of cofilin (CFL1). {ECO:0000269|PubMed:10196227, ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:11832213, ECO:0000269|PubMed:12807904, ECO:0000269|PubMed:15660133, ECO:0000269|PubMed:16230460, ECO:0000269|PubMed:18028908, ECO:0000269|PubMed:23633677}. | LIM domain kinase 1 inhibitor: Dabrafenib | 15.11 | ||
| dpcLIMK2 | LIM domain kinase 2 | 0 | 120 | 75.84 | ND | 85.50 | 0.76 | ND | 0.7 | Mammalian | Highest expression in the placenta; moderate level in liver, lung, kidney, and pancreas. LIMK2a is found to be more abundant then LIMK2b in liver, colon, stomach, and spleen, while in brain, kidney, and placenta LIMK2b is the dominant form. In adult lung, both LIMK2a and LIMK2b is nearly equally observed. {ECO:0000269|PubMed:8954941}. | Kinase | Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro. {ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:11018042}. | 15.11 | ||||
| dpcLKHA4 | Leukotriene A-4 hydrolase | 0 | 480 | 76.68 | ND | 97.67 | 0.63 | ND | 0.6 | Mammalian | Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts. | Protease | Inflammation
Leukemia, Myeloid Myocardial infarction Oesophageal cancer Solid tumors | Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity. {ECO:0000269|PubMed:11917124, ECO:0000269|PubMed:12207002, ECO:0000269|PubMed:15078870, ECO:0000269|PubMed:18804029, ECO:0000269|PubMed:1897988, ECO:0000269|PubMed:1975494, ECO:0000269|PubMed:2244921}. | 15.11 | |||
| dpcLMBL3 | Lethal(3)malignant brain tumor-like protein 3 | 0 | 93 | 94.83 | ND | 99.61 | 0.73 | ND | 0.6 | Mammalian | Reader | Putative Polycomb group (PcG) protein. PcG proteins maintain the transcriptionally repressive state of genes, probably via a modification of chromatin, rendering it heritably changed in its expressibility. Required for normal maturation of myeloid progenitor cells (By similarity). {ECO:0000250}. | 15.11 | |||||
| dpcLPAR1 | Lysophosphatidic acid receptor 1 | 0 | 132 | 73.30 | ND | 98.84 | 0.41 | ND | 0.5 | Mammalian | Expressed in many adult organs, including brain, heart, colon, small intestine, placenta, prostate, ovary, pancreas, testes, spleen, skeletal muscle, and kidney. Little or no expression in liver, lung, thymus, or peripheral blood leukocytes (PubMed:9070858). Detected in lung fibroblasts from bronchoalveolar fluid from patients with idiopathic pulmonary fibrosis (PubMed:18066075). Detected in bone marrow-derived mesenchymal stem cells (PubMed:19733258). {ECO:0000269|PubMed:18066075, ECO:0000269|PubMed:19733258, ECO:0000269|PubMed:9070858}. | Family A G protein-coupled receptor | Multiple sclerosis | Receptor for lysophosphatidic acid (LPA) (PubMed:9070858, PubMed:19306925, PubMed:25025571, PubMed:26091040). Plays a role in the reorganization of the actin cytoskeleton, cell migration, differentiation and proliferation, and thereby contributes to the responses to tissue damage and infectious agents. Activates downstream signaling cascades via the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. Signaling inhibits adenylyl cyclase activity and decreases cellular cAMP levels (PubMed:26091040). Signaling triggers an increase of cytoplasmic Ca(2+) levels (PubMed:19656035, PubMed:19733258, PubMed:26091040). Activates RALA; this leads to the activation of phospholipase C (PLC) and the formation of inositol 1,4,5-trisphosphate (PubMed:19306925). Signaling mediates activation of down-stream MAP kinases (By similarity). Contributes to the regulation of cell shape. Promotes Rho-dependent reorganization of the actin cytoskeleton in neuronal cells and neurite retraction (PubMed:26091040). Promotes the activation of Rho and the formation of actin stress fibers (PubMed:26091040). Promotes formation of lamellipodia at the leading edge of migrating cells via activation of RAC1 (By similarity). Through its function as lysophosphatidic acid receptor, plays a role in chemotaxis and cell migration, including responses to injury and wounding (PubMed:18066075, PubMed:19656035, PubMed:19733258). Plays a role in triggering inflammation in response to bacterial lipopolysaccharide (LPS) via its interaction with CD14. Promotes cell proliferation in response to lysophosphatidic acid. Required for normal skeleton development. May play a role in osteoblast differentiation. Required for normal brain development. Required for normal proliferation, survival and maturation of newly formed neurons in the adult dentate gyrus. Plays a role in pain perception and in the initiation of neuropathic pain (By similarity). {ECO:0000250|UniProtKB:P61793, ECO:0000269|PubMed:18066075, ECO:0000269|PubMed:19306925, ECO:0000269|PubMed:19656035, ECO:0000269|PubMed:19733258, ECO:0000269|PubMed:25025571, ECO:0000269|PubMed:26091040, ECO:0000269|PubMed:9070858, ECO:0000305|PubMed:11093753, ECO:0000305|PubMed:9069262}. | 15.11 | |||
| dpcLYN | Tyrosine-protein kinase Lyn | 0 | 458 | 87.89 | ND | 92.50 | 0.36 | ND | 0.8 | Mammalian | Detected in monocytes (at protein level). Detected in placenta, and in fetal brain, lung, liver and kidney. Widely expressed in a variety of organs, tissues, and cell types such as epidermoid, hematopoietic, and neuronal cells. Expressed in primary neuroblastoma tumors. {ECO:0000269|PubMed:3561390, ECO:0000269|PubMed:8064233}. | Kinase | Note=Constitutively phosphorylated and activated in cells from a number of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) patients. Mediates phosphorylation of the BCR-ABL fusion protein. Abnormally elevated expression levels or activation of LYN signaling may play a role in survival and proliferation of some types of cancer cells. | Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down- regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down- regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, PTK2B/PYK2, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3- kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr- 72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. {ECO:0000269|PubMed:10574931, ECO:0000269|PubMed:10748115, ECO:0000269|PubMed:10891478, ECO:0000269|PubMed:11435302, ECO:0000269|PubMed:11517336, ECO:0000269|PubMed:11825908, ECO:0000269|PubMed:14726379, ECO:0000269|PubMed:15795233, ECO:0000269|PubMed:16467205, ECO:0000269|PubMed:17640867, ECO:0000269|PubMed:17977829, ECO:0000269|PubMed:18056483, ECO:0000269|PubMed:18070987, ECO:0000269|PubMed:18235045, ECO:0000269|PubMed:18577747, ECO:0000269|PubMed:18802065, ECO:0000269|PubMed:19290919, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:7687428}. | Tyrosine-protein kinase Lyn : Bosutinib Tyrosine-protein kinase Lyn Inhibitor: Nintedanib Tyrosine-protein kinase Lyn inhibitor: Ponatinib | 15.11 | ||
| dpcM3K5 | Mitogen-activated protein kinase kinase kinase 5 | 0 | 130 | 85.20 | ND | 99.10 | 0.67 | ND | 0.5 | Mammalian | Abundantly expressed in heart and pancreas. | Kinase | Cardiac diseases
Malignant fibrous histiocytomas | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). {ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666, ECO:0000269|PubMed:10849426, ECO:0000269|PubMed:11029458, ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11689443, ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12697749, ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544, ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:17220297, ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:8940179, ECO:0000269|PubMed:8974401, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}. | 15.11 | |||
| dpcM3K7 | Mitogen-activated protein kinase kinase kinase 7 | 0 | 107 | 98.72 | ND | 98.48 | 0.29 | ND | 1.1 | Mammalian | Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form. {ECO:0000269|PubMed:11118615}. | Kinase | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2- induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. {ECO:0000269|PubMed:10094049, ECO:0000269|PubMed:11460167, ECO:0000269|PubMed:12589052, ECO:0000269|PubMed:16845370, ECO:0000269|PubMed:16893890, ECO:0000269|PubMed:21512573, ECO:0000269|PubMed:8663074, ECO:0000269|PubMed:9079627}. | 15.11 | ||||
| dpcM3K9 | Mitogen-activated protein kinase kinase kinase 9 | 0 | 117 | 81.74 | ND | 84.80 | 0.63 | ND | 0.6 | Mammalian | Expressed in epithelial tumor cell lines of colonic, breast and esophageal origin. {ECO:0000269|PubMed:8477742}. | Kinase | Note=May play a role in esophageal cancer susceptibility and/or development. | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Plays also a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. {ECO:0000269|PubMed:11416147, ECO:0000269|PubMed:15610029}. | 15.11 | |||
| dpcM4K4 | Mitogen-activated protein kinase kinase kinase kinase 4 | 0 | 596 | 78.72 | ND | 87.79 | 0.48 | ND | 0.5 | Mammalian | Appears to be ubiquitous. Expressed in all tissue types examined. Isoform 5 appears to be more abundant in the brain. Isoform 4 is predominant in the liver, skeletal muscle and placenta. {ECO:0000269|PubMed:9890973}. | Kinase | Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322. {ECO:0000269|PubMed:21690388, ECO:0000269|PubMed:9890973}. | 15.11 | ||||
| dpcMAP11 | Methionine aminopeptidase 1 {ECO:0000255|HAMAP-Rule:MF_03174} | 0 | 187 | 74.59 | ND | 94.08 | 0.56 | ND | 0.6 | Mammalian | Protease | Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Required for normal progression through the cell cycle. {ECO:0000255|HAMAP- Rule:MF_03174, ECO:0000269|PubMed:16274222, ECO:0000269|PubMed:17114291}. | 15.11 | |||||
| dpcMAPK2 | MAP kinase-activated protein kinase 2 | 0 | 909 | 83.17 | ND | 96.79 | 0.72 | ND | 0.6 | Mammalian | Expressed in all tissues examined. | Kinase | Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, ELAVL1, HNRNPA0, HSF1, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat- shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilize GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:11844797, ECO:0000269|PubMed:12456657, ECO:0000269|PubMed:12565831, ECO:0000269|PubMed:14499342, ECO:0000269|PubMed:14517288, ECO:0000269|PubMed:15014438, ECO:0000269|PubMed:15629715, ECO:0000269|PubMed:16278218, ECO:0000269|PubMed:16456544, ECO:0000269|PubMed:17481585, ECO:0000269|PubMed:18021073, ECO:0000269|PubMed:20932473, ECO:0000269|PubMed:8093612, ECO:0000269|PubMed:8280084, ECO:0000269|PubMed:8774846}. | 15.11 | ||||
| dpcMAPK3 | MAP kinase-activated protein kinase 3 | 0 | 48 | 87.36 | ND | 89.60 | 0.40 | ND | 0.5 | Mammalian | Widely expressed, with a higher expression level observed in heart and skeletal muscle. No expression in brain. {ECO:0000269|PubMed:8622688, ECO:0000269|PubMed:8626550}. | Kinase | Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38- alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression. {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:15563468, ECO:0000269|PubMed:18021073, ECO:0000269|PubMed:20599781, ECO:0000269|PubMed:8626550, ECO:0000269|PubMed:8774846}. | 15.11 | ||||
| dpcMCL1 | Induced myeloid leukemia cell differentiation protein Mcl-1 | 0 | 1005 | 75.41 | ND | 82.02 | 0.15 | ND | 0.6 | Mammalian | Other cytosolic protein | Leukemia, Lymphoid
Lymphoma, Non-Hodgkin's Prostate cancer | Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis. {ECO:0000269|PubMed:10766760, ECO:0000269|PubMed:16543145}. | 15.11 | ||||
| dpcMDM2 | E3 ubiquitin-protein ligase Mdm2 | 0 | 457 | 88.55 | ND | 96.15 | 0.86 | ND | 0.6 | Mammalian | Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues. | Other nuclear protein | Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. | E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation. {ECO:0000269|PubMed:12821780, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:15195100, ECO:0000269|PubMed:15632057, ECO:0000269|PubMed:16337594, ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:19098711, ECO:0000269|PubMed:19219073, ECO:0000269|PubMed:19837670, ECO:0000269|PubMed:19965871, ECO:0000269|PubMed:20173098, ECO:0000269|PubMed:20385133, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:22128911}. | 15.11 | |||
| dpcMELK | Maternal embryonic leucine zipper kinase | 0 | 218 | 83.80 | ND | 89.52 | 0.22 | ND | 0.8 | Mammalian | Expressed in placenta, kidney, thymus, testis, ovary and intestine. {ECO:0000269|PubMed:8724849}. | Kinase | Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation. | Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis. {ECO:0000269|PubMed:11802789, ECO:0000269|PubMed:12400006, ECO:0000269|PubMed:14699119, ECO:0000269|PubMed:15908796, ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:17280616}. | 15.11 | |||
| dpcMERTK | Tyrosine-protein kinase Mer | 0 | 185 | 95.71 | ND | 96.28 | 0.45 | ND | 0.8 | Mammalian | Not expressed in normal B- and T-lymphocytes but is expressed in numerous neoplastic B- and T-cell lines. Highly expressed in testis, ovary, prostate, lung, and kidney, with lower expression in spleen, small intestine, colon, and liver. | Kinase | Retinitis pigmentosa 38 (RP38) [MIM:613862]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:11062461}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll- like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:17005688}. | 15.11 | |||
| dpcMET | Hepatocyte growth factor receptor | 0 | 1715 | 85.58 | ND | 95.99 | 0.67 | ND | 0.6 | Mammalian | Expressed in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Found also in basal keratinocytes of esophagus and skin. High levels are found in liver, gastrointestinal tract, thyroid and kidney. Also present in the brain. {ECO:0000269|PubMed:1719465, ECO:0000269|PubMed:1917129}. | Kinase | Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. Note=Defects in MET may be associated with gastric cancer. Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:9927037}. Note=The disease is caused by mutations affecting the gene represented in this entry. Renal cell carcinoma papillary (RCCP) [MIM:605074]: A subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. {ECO:0000269|PubMed:10327054, ECO:0000269|PubMed:10417759, ECO:0000269|PubMed:10433944, ECO:0000269|PubMed:9140397, ECO:0000269|PubMed:9563489}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes. Note=MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies. | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells. | Hepatocyte growth factor receptor antagonist: Cabozantinib Hepatocyte growth factor receptor inhibitor: Crizotinib | 15.11 | ||
| dpcMGA | Maltase-glucoamylase, intestinal | 0 | 85 | 88.01 | ND | 96.42 | 0.55 | ND | 0.5 | Mammalian | Expressed in small intestine, granulocyte, and kidney but not in salivary gland or pancreas. | Hydrolase | Diabetes mellitus | May serve as an alternate pathway for starch digestion when luminal alpha-amylase activity is reduced because of immaturity or malnutrition. May play a unique role in the digestion of malted dietary oligosaccharides used in food manufacturing. | Maltase-glucoamylase, intestinal antagonist: Miglitol Maltase-glucoamylase, intestinal inhibitor: Acarbose, Voglibose | 15.11 | ||
| dpcMGLL | Monoglyceride lipase {ECO:0000312|HGNC:HGNC:17038} | 0 | 312 | 74.02 | ND | 92.62 | 0.67 | ND | 0.6 | Mammalian | Detected in adipose tissue, lung, liver, kidney, brain and heart. {ECO:0000269|PubMed:11470505}. | Enzyme | Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (By similarity). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth (PubMed:20079333). {ECO:0000250|UniProtKB:O35678, ECO:0000269|PubMed:20079333}. | 15.11 | ||||
| dpcMIF | Macrophage migration inhibitory factor | 0 | 150 | 87.01 | ND | 87.64 | 0.10 | ND | 0.8 | Mammalian | Enzyme | Rheumatoid arthritis systemic juvenile (RASJ) [MIM:604302]: An inflammatory articular disorder with systemic- onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. {ECO:0000269|PubMed:11508429}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. {ECO:0000305}. | Pro-inflammatory cytokine. Involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. Counteracts the anti- inflammatory activity of glucocorticoids. Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known. It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity. {ECO:0000269|PubMed:15908412, ECO:0000269|PubMed:17443469, ECO:0000269|PubMed:23776208}. | 15.11 | ||||
| dpcMK01 | Mitogen-activated protein kinase 1 | 0 | 1563 | 81.96 | ND | 85.89 | 0.66 | ND | 0.5 | Mammalian | Kinase | Neurodegenerative diseases
Proliferative diseases | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in respons to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity. | Mitogen-activated protein kinase 1 inducer: Arsenic trioxide, Isoprenaline | 15.11 | |||
| dpcMK07 | Mitogen-activated protein kinase 7 | 0 | 86 | 97.08 | ND | 92.63 | 0.01 | ND | 1.2 | Mammalian | Expressed in many adult tissues. Abundant in heart, placenta, lung, kidney and skeletal muscle. Not detectable in liver. {ECO:0000269|PubMed:7759517}. | Kinase | Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras- independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction. {ECO:0000269|PubMed:11254654, ECO:0000269|PubMed:11278431, ECO:0000269|PubMed:22869143, ECO:0000269|PubMed:9384584, ECO:0000269|PubMed:9790194}. | 15.11 | ||||
| dpcMK08 | Mitogen-activated protein kinase 8 | 0 | 1096 | 89.35 | ND | 94.79 | 0.60 | ND | 0.6 | Mammalian | Kinase | Cancer, unspecific
Crohn's disease, unspecified Hearing Loss Inflammatory Disorders, Unspecified Insulin resistance Obesity | Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:22441692}. JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta- 2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. | 15.11 | ||||
| dpcMK09 | Mitogen-activated protein kinase 9 | 0 | 794 | 77.68 | ND | 89.24 | 0.43 | ND | 0.9 | Mammalian | Kinase | Not Available | Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:22441692}. MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it. | 15.11 | ||||
| dpcMK10 | Mitogen-activated protein kinase 10 | 0 | 832 | 88.62 | ND | 92.14 | 0.58 | ND | 0.7 | Mammalian | Specific to a subset of neurons in the nervous system. Present in the hippocampus and areas, cerebellum, striatum, brain stem, and weakly in the spinal cord. Very weak expression in testis and kidney. | Kinase | Note=A chromosomal aberration involving MAPK10 has been found in a single patient with pharmacoresistant epileptic encephalopathy. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. {ECO:0000269|PubMed:16249883}. | Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress- activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the photic regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:11718727, ECO:0000269|PubMed:22441692}. | 15.11 | |||
| dpcMK11 | Mitogen-activated protein kinase 11 | 0 | 223 | 86.19 | ND | 97.70 | 0.53 | ND | 0.7 | Mammalian | Highest levels in the brain and heart. Also expressed in the placenta, lung, liver, skeletal muscle, kidney and pancreas. | Kinase | Inflammation
Psoriasis Rheumatoid arthritis, unspecified | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK11 functions are mostly redundant with those of MAPK14. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane- associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. {ECO:0000269|PubMed:10330143, ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:15356147, ECO:0000269|PubMed:9430721, ECO:0000269|PubMed:9687510}. | Mitogen-activated protein kinase 11 inhibitor: Regorafenib | 15.11 | ||
| dpcMK12 | Mitogen-activated protein kinase 12 | 0 | 183 | 71.61 | ND | 82.64 | 0.36 | ND | 0.6 | Mammalian | Highly expressed in skeletal muscle and heart. {ECO:0000269|PubMed:11991731, ECO:0000269|PubMed:8633070}. | Kinase | Note=MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma- radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration. {ECO:0000269|PubMed:10848581, ECO:0000269|PubMed:14592936, ECO:0000269|PubMed:17724032, ECO:0000269|PubMed:20605917, ECO:0000269|PubMed:21172807, ECO:0000269|PubMed:8633070, ECO:0000269|PubMed:9430721}. | 15.11 | |||
| dpcMK13 | Mitogen-activated protein kinase 13 | 0 | 213 | 75.82 | ND | 85.74 | 0.61 | ND | 0.7 | Mammalian | Expressed in testes, pancreas, small intestine, lung and kidney. Abundant in macrophages, also present in neutrophils, CD4+ T-cells, and endothelial cells. {ECO:0000269|PubMed:10201954, ECO:0000269|PubMed:9374491}. | Kinase | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells. {ECO:0000269|PubMed:11500363, ECO:0000269|PubMed:11943212, ECO:0000269|PubMed:15632108, ECO:0000269|PubMed:17256148, ECO:0000269|PubMed:18006338, ECO:0000269|PubMed:18367666, ECO:0000269|PubMed:20478268, ECO:0000269|PubMed:9731215}. | 15.11 | ||||
| dpcMK14 | Mitogen-activated protein kinase 14 | 0 | 3356 | 85.97 | ND | 95.35 | 0.58 | ND | 0.7 | Mammalian | Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney. | Abdominal pain upper | Kinase | Adult respiratory distress syndrome
Alzheimer's disease Crescentic glomerulonephritis Crohn's disease, unspecified Cytokine-mediated diseases Endotoxemia Inflammation Insulin resistance Multiple myeloma Psoriasis Rheumatoid arthritis, unspecified Skin diseases Thrombosis | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF- induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14- mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF- kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'. {ECO:0000269|PubMed:10330143, ECO:0000269|PubMed:10747897, ECO:0000269|PubMed:10943842, ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:11333986, ECO:0000269|PubMed:15905572, ECO:0000269|PubMed:16932740, ECO:0000269|PubMed:17003045, ECO:0000269|PubMed:17724032, ECO:0000269|PubMed:19893488, ECO:0000269|PubMed:20188673, ECO:0000269|PubMed:20932473, ECO:0000269|PubMed:9430721, ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9792677, ECO:0000269|PubMed:9858528}. | 15.11 | ||
| dpcMKNK2 | MAP kinase-interacting serine/threonine-protein kinase 2 | 0 | 332 | 88.48 | ND | 87.86 | 0.11 | ND | 0.7 | Mammalian | Ubiquitously expressed in all tissues examined. Isoform 2 is expressed at higher levels in the ovary than is isoform 1. {ECO:0000269|PubMed:11013076}. | Kinase | Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal. {ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:11463832, ECO:0000269|PubMed:12897141, ECO:0000269|PubMed:16111636, ECO:0000269|PubMed:17965020, ECO:0000269|PubMed:18299328, ECO:0000269|PubMed:20823271, ECO:0000269|PubMed:20927323, ECO:0000269|PubMed:21149447}. | 15.11 | ||||
| dpcMMP1 | Interstitial collagenase | 0 | 2529 | 83.95 | ND | 96.66 | 0.68 | ND | 0.6 | Mammalian | Protease | Cancer, unspecific
Chondrosarcoma Emphysema Hormone-refractory Prostate cancer Kaposi's Sarcoma Lung Cancer Myocardial infarction (MI) Non-small Cell Lung Cancer Osteoarthritis Pancreatic Cancer | Cleaves collagens of types I, II, and III at one site in the helical domain. Also cleaves collagens of types VII and X. In case of HIV infection, interacts and cleaves the secreted viral Tat protein, leading to a decrease in neuronal Tat's mediated neurotoxicity. {ECO:0000269|PubMed:1645757}. | Interstitial collagenase inhibitor: Marimastat | 15.11 | |||
| dpcMMP3 | Stromelysin-1 | 0 | 1279 | 71.78 | ND | 95.54 | 0.63 | ND | 0.7 | Mammalian | Protease | Coronary heart disease 6 (CHDS6) [MIM:614466]: A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. {ECO:0000269|PubMed:12477941, ECO:0000269|PubMed:8662692}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions. | Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase. | Stromelysin-1 antagonist: Marimastat | 15.11 | |||
| dpcMMP8 | Neutrophil collagenase | 0 | 749 | 72.57 | ND | 96.27 | 0.69 | ND | 0.8 | Mammalian | Neutrophils. | Protease | Inflammatory diseases
Osteoarthritis Osteoporosis, unspecified Rheumatoid arthritis, unspecified Tumors | Can degrade fibrillar type I, II, and III collagens. | Neutrophil collagenase inhibitor: Marimastat | 15.11 | ||
| dpcMRCKA | Serine/threonine-protein kinase MRCK alpha | 0 | 262 | 76.56 | ND | 84.92 | 0.25 | ND | 0.7 | Mammalian | Highly expressed in the brain and lung and present in lower levels in all other tissues tested. {ECO:0000269|PubMed:9418861}. | Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates: PPP1R12A, LIMK1 and LIMK2. May play a role in TFRC-mediated iron uptake. {ECO:0000269|PubMed:18854160, ECO:0000269|PubMed:21457715, ECO:0000269|PubMed:9418861}. | 15.11 | |||||
| dpcMTAP | S-methyl-5'-thioadenosine phosphorylase {ECO:0000255|HAMAP-Rule:MF_03155} | 0 | 66 | 94.12 | ND | 99.98 | 0.39 | ND | 0.9 | Mammalian | Ubiquitously expressed. | Enzyme | Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) [MIM:112250]: An autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. Some patients show a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. {ECO:0000269|PubMed:22464254}. Note=The disease is caused by mutations affecting the gene represented in this entry. DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254). {ECO:0000269|PubMed:22464254}. Note=Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer. | Catalyzes the reversible phosphorylation of S-methyl-5'- thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S- adenosylmethionine. Has broad substrate specificity with 6- aminopurine nucleosides as preferred substrates. {ECO:0000255|HAMAP-Rule:MF_03155, ECO:0000269|PubMed:3091600}. | 15.11 | |||
| dpcMTOR | Serine/threonine-protein kinase mTOR | 0 | 1816 | 79.57 | ND | 92.45 | 0.75 | ND | 0.7 | Mammalian | Expressed in numerous tissues, with highest levels in testis. {ECO:0000269|PubMed:12408816, ECO:0000269|PubMed:7809080}. | Enzyme | Smith-Kingsmore syndrome (SKS) [MIM:616638]: An autosomal dominant syndrome characterized by intellectual disability, macrocephaly, seizures, umbilical hernia, and facial dysmorphic features. {ECO:0000269|PubMed:25851998, ECO:0000269|PubMed:26542245}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1- mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1- pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser- 758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. Regulates osteoclastogensis by adjusting the expression of CEBPB isoforms (By similarity). {ECO:0000250|UniProtKB:Q9JLN9, ECO:0000269|PubMed:12087098, ECO:0000269|PubMed:12150925, ECO:0000269|PubMed:12150926, ECO:0000269|PubMed:12231510, ECO:0000269|PubMed:12718876, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15268862, ECO:0000269|PubMed:15467718, ECO:0000269|PubMed:15545625, ECO:0000269|PubMed:15718470, ECO:0000269|PubMed:18497260, ECO:0000269|PubMed:18762023, ECO:0000269|PubMed:18925875, ECO:0000269|PubMed:20516213, ECO:0000269|PubMed:20537536, ECO:0000269|PubMed:21659604, ECO:0000269|PubMed:23429703, ECO:0000269|PubMed:23429704}. | Serine/threonine-protein kinase mTOR inhibitor: Everolimus, Sirolimus, Temsirolimus Serine/threonine-protein kinase mTOR potentiator: Pimecrolimus | 15.11 | ||
| dpcMYLK4 | Myosin light chain kinase family member 4 | 0 | 65 | 99.80 | ND | 97.19 | 0.12 | ND | 0.5 | Mammalian | Kinase | 15.11 | ||||||
| dpcNAMPT | Nicotinamide phosphoribosyltransferase | 0 | 309 | 96.17 | ND | 99.71 | 0.48 | ND | 0.9 | Mammalian | Expressed in large amounts in bone marrow, liver tissue, and muscle. Also present in heart, placenta, lung, and kidney tissues. | Enzyme | Catalyzes the condensation of nicotinamide with 5- phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway. The secreted form behaves both as a cytokine with immunomodulating properties and an adipokine with anti-diabetic properties, it has no enzymatic activity, partly because of lack of activation by ATP, which has a low level in extracellular space and plasma. Plays a role in the modulation of circadian clock function. NAMPT-dependent oscillatory production of NAD regulates oscillation of clock target gene expression by releasing the core clock component: CLOCK-ARNTL/BMAL1 heterodimer from NAD-dependent SIRT1-mediated suppression (By similarity). {ECO:0000250|UniProtKB:Q99KQ4, ECO:0000269|PubMed:24130902}. | 15.11 | ||||
| dpcNEK2 | Serine/threonine-protein kinase Nek2 | 0 | 332 | 87.15 | ND | 85.55 | 0.27 | ND | 0.7 | Mammalian | Isoform 1 and isoform 2 are expressed in peripheral blood T-cells and a wide variety of transformed cell types. Isoform 1 and isoform 4 are expressed in the testis. Up- regulated in various cancer cell lines, as well as primary breast tumors. {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:15659832}. | Kinase | Retinitis pigmentosa 67 (RP67) [MIM:615565]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:24043777}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGOL1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Phosphorylates CEP68 and CNTLN directly or indirectly (PubMed:24554434). NEK2-mediated phosphorylation of CEP68 promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis (PubMed:25704143). Involved in the regulation of centrosome disjunction (PubMed:26220856). {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:12857871, ECO:0000269|PubMed:14978040, ECO:0000269|PubMed:15358203, ECO:0000269|PubMed:15388344, ECO:0000269|PubMed:17283141, ECO:0000269|PubMed:17621308, ECO:0000269|PubMed:17626005, ECO:0000269|PubMed:18086858, ECO:0000269|PubMed:18297113, ECO:0000269|PubMed:20034488, ECO:0000269|PubMed:21076410, ECO:0000269|PubMed:24554434, ECO:0000269|PubMed:25704143, ECO:0000269|PubMed:26220856}. Isoform 1: Phosphorylates and activates NEK11 in G1/S- arrested cells. {ECO:0000269|PubMed:15161910}. Isoform 2: Not present in the nucleolus and, in contrast to isoform 1, does not phosphorylate and activate NEK11 in G1/S- arrested cells. {ECO:0000269|PubMed:15161910}. | 15.11 | |||
| dpcNMDE2 | Glutamate receptor ionotropic, NMDA 2B | 0 | 330 | 82.81 | ND | 97.29 | 0.44 | ND | 0.9 | Mammalian | Ligand-gated ion channel | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. In concert with DAPK1 at extrasynaptic sites, acts as a central mediator for stroke damage. Its phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity inducing injurious Ca2+ influx through them, resulting in an irreversible neuronal death (By similarity). {ECO:0000250}. | 15.11 | |||||
| dpcNMDZ1 | Glutamate receptor ionotropic, NMDA 1 | 0 | 606 | 76.40 | ND | 93.11 | 0.55 | ND | 0.8 | Mammalian | Respiratory depression | Ligand-gated ion channel | Mental retardation, autosomal dominant 8 (MRD8) [MIM:614254]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21376300}. Note=The disease is caused by mutations affecting the gene represented in this entry. | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity). {ECO:0000250}. | Glutamate receptor ionotropic, NMDA 1 : Gabapentin Glutamate receptor ionotropic, NMDA 1 activator: Acetylcysteine Glutamate receptor ionotropic, NMDA 1 antagonist: Acamprosate, Ifenprodil, Ketobemidone, Orphenadrine, Pentobarbital, Pethidine, Phenobarbital, Secobarbital Glutamate receptor ionotropic, NMDA 1 binder: Memantine Glutamate receptor ionotropic, NMDA 1 blocker: Atomoxetine Glutamate receptor ionotropic, NMDA 1 inhibitor: Milnacipran | 15.11 | ||
| dpcNPC1 | Niemann-Pick C1 protein | 0 | 6046 | 70.36 | ND | 80.68 | 0.04 | ND | 0.4 | Mammalian | Niemann-Pick disease C1 (NPC1) [MIM:257220]: A lysosomal storage disorder that affects the viscera and the central nervous system. It is due to defective intracellular processing and transport of low-density lipoprotein derived cholesterol. It causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Niemann-Pick disease type C1 has a highly variable clinical phenotype. Clinical features include variable hepatosplenomegaly and severe progressive neurological dysfunction such as ataxia, dystonia and dementia. The age of onset can vary from infancy to late adulthood. An allelic variant of Niemann-Pick disease type C1 is found in people with Nova Scotia ancestry. Patients with the Nova Scotian clinical variant are less severely affected. {ECO:0000269|PubMed:10480349, ECO:0000269|PubMed:10521290, ECO:0000269|PubMed:10521297, ECO:0000269|PubMed:11182931, ECO:0000269|PubMed:11333381, ECO:0000269|PubMed:11349231, ECO:0000269|PubMed:11479732, ECO:0000269|PubMed:11545687, ECO:0000269|PubMed:11754101, ECO:0000269|PubMed:12401890, ECO:0000269|PubMed:12408188, ECO:0000269|PubMed:12554680, ECO:0000269|PubMed:12955717, ECO:0000269|PubMed:15774455, ECO:0000269|PubMed:16098014, ECO:0000269|PubMed:16126423, ECO:0000269|PubMed:16802107, ECO:0000269|PubMed:9211849, ECO:0000269|PubMed:9634529}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. Both NPC1 and NPC2 function as the cellular 'tag team duo' (TTD) to catalyze the mobilization of cholesterol within the multivesicular environment of the late endosome (LE) to effect egress through the limiting bilayer of the LE. NPC2 binds unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes and transfers it to the cholesterol-binding pocket of the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket and is exported from the limiting membrane of late endosomes/ lysosomes to the ER and plasma membrane by an unknown mechanism. Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals. {ECO:0000269|PubMed:18772377, ECO:0000269|PubMed:19563754}. (Microbial infection) Acts as an endosomal entry receptor for ebolavirus. {ECO:0000269|PubMed:21866103, ECO:0000269|PubMed:25855742}. | 15.11 | |||||
| dpcNR1H2 | Oxysterols receptor LXR-beta | 0 | 583 | 87.75 | ND | 96.89 | 0.66 | ND | 0.6 | VirtualToxLab | Mammalian | Ubiquitous. | Nuclear receptor | Atherosclerosis
Dyslipidemia | Nuclear receptor. Binds preferentially to double- stranded oligonucleotide direct repeats having the consensus half- site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8; DLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Exhibits a ligand-dependent transcriptional activation activity (PubMed:25661920). {ECO:0000250|UniProtKB:Q60644, ECO:0000269|PubMed:25661920}. | 15.11 | ||
| dpcNR1H3 | Oxysterols receptor LXR-alpha | 0 | 521 | 83.57 | ND | 95.27 | 0.60 | ND | 0.6 | VirtualToxLab | Mammalian | Visceral organs specific expression. Strong expression was found in liver, kidney and intestine followed by spleen and to a lesser extent the adrenals. | Nuclear receptor | Atherosclerosis
Cancer, unspecific | Nuclear receptor. Interaction with RXR shifts RXR from its role as a silent DNA-binding partner to an active ligand- binding subunit in mediating retinoid responses through target genes defined by LXRES. LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half- sites spaced by four nucleotides. Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Exhibits a ligand-dependent transcriptional activation activity (PubMed:25661920). {ECO:0000250|UniProtKB:Q9Z0Y9, ECO:0000269|PubMed:25661920}. | 15.11 | ||
| dpcNR1H4 | Bile acid receptor | 0 | 506 | 82.64 | ND | 96.17 | 0.63 | ND | 0.5 | Mammalian | Liver and hepatocyte-related cells express mainly FXRalpha1-type isoforms with isoform 3 and isoform 4 in approximative equal proportions. In intestine and kidney mainly FXRalpha2-type isoforms are expressed with isoform 1 and isoform 2 in approximative equal proportions. Expressed in pancreatic beta cells and macrophages. {ECO:0000269|PubMed:19393742, ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:23928191}. | Nuclear receptor | Note=May be involved in intrahepatic cholestasis of pregnancy. {ECO:0000305|PubMed:17681172}. Note=May be involved in cholesterol cholelithiasis. {ECO:0000305|PubMed:17931734}. | Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'- AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homoestasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12660231, PubMed:12554753, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down- regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays a anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity). {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q62735, ECO:0000269|PubMed:10334992, ECO:0000269|PubMed:10334993, ECO:0000269|PubMed:10514450, ECO:0000269|PubMed:11579204, ECO:0000269|PubMed:11927623, ECO:0000269|PubMed:12554753, ECO:0000269|PubMed:12660231, ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12754200, ECO:0000269|PubMed:12806625, ECO:0000269|PubMed:12815072, ECO:0000269|PubMed:12891557, ECO:0000269|PubMed:14684751, ECO:0000269|PubMed:15239098, ECO:0000269|PubMed:15337761, ECO:0000269|PubMed:15471871, ECO:0000269|PubMed:16269519, ECO:0000269|PubMed:16946559, ECO:0000269|PubMed:17895379, ECO:0000269|PubMed:18621523, ECO:0000269|PubMed:19085950, ECO:0000269|PubMed:19410460, ECO:0000269|PubMed:19586769, ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:21242261, ECO:0000269|PubMed:21804189, ECO:0000269|PubMed:23928191, ECO:0000305|PubMed:21383957, ECO:0000305|PubMed:22820415}. Isoform 1: Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. Isoform 2: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA), NR0B2/SHP (inducible by unconjugated CDCA DCA and ACA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. Isoform 3: Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. Isoform 4: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, ACA and DCA), NR0B2/SHP (inducible by unconjugated CDCA, ACA and DCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; most efficient isoform compared to isoforms 1 to 3; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. | Bile acid receptor other: Chenodeoxycholic acid | 15.11 | ||
| dpcNR1I2 | Nuclear receptor subfamily 1 group I member 2 | 0 | 305 | 79.24 | ND | 83.17 | 0.42 | ND | 0.7 | Nature11159 | Mammalian | Expressed in liver, colon and small intestine. | Hepatitis | Nuclear receptor | Anxiety disorder, unspecified
Depression Eye inflammation Multiple Sclerosis | Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes. {ECO:0000269|PubMed:11297522, ECO:0000269|PubMed:11668216, ECO:0000269|PubMed:12578355, ECO:0000269|PubMed:18768384, ECO:0000269|PubMed:19297428, ECO:0000269|PubMed:9727070}. | Nuclear receptor subfamily 1 group I member 2 : Estradiol, Vitamin E Nuclear receptor subfamily 1 group I member 2 agonist: Erlotinib, Ethinyl Estradiol, Rifampicin, Rifaximin, Rilpivirine Nuclear receptor subfamily 1 group I member 2 binder: Docetaxel Nuclear receptor subfamily 1 group I member 2 inducer: Paclitaxel | 15.11 |
| dpcNR5A2 | Nuclear receptor subfamily 5 group A member 2 | 0 | 112 | 81.53 | ND | 86.16 | 0.39 | ND | 0.7 | Mammalian | Abundantly expressed in pancreas, less in liver, very low levels in heart and lung. Expressed in the Hep-G2 cell line. Isoform 1 and isoform 2 seem to be present in fetal and adult liver and Hep-G2 cells. | Nuclear receptor | Binds to the sequence element 5'-AACGACCGACCTTGAG-3' of the enhancer II of hepatitis B virus genes, a critical cis-element of their expression and regulation. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development. | 15.11 | ||||
| dpcNTRK1 | High affinity nerve growth factor receptor | 0 | 501 | 81.85 | ND | 94.02 | 0.40 | ND | 0.8 | Mammalian | Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors. {ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:8325889}. | Kinase | Congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]: Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II. {ECO:0000269|PubMed:10090906, ECO:0000269|PubMed:10233776, ECO:0000269|PubMed:10330344, ECO:0000269|PubMed:10567924, ECO:0000269|PubMed:10861667, ECO:0000269|PubMed:10982191, ECO:0000269|PubMed:11310631, ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:8696348}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Chromosomal aberrations involving NTRK1 are found in papillary thyroid carcinomas (PTCs) (PubMed:2869410, PubMed:7565764, PubMed:1532241). Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1 (PubMed:7565764). A rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1 (PubMed:2869410). An intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein (PubMed:1532241). {ECO:0000269|PubMed:1532241, ECO:0000269|PubMed:2869410, ECO:0000269|PubMed:7565764}. | Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras- PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras- MAPK signaling cascade. Antagonizes the anti-proliferative NGF- NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed. | High affinity nerve growth factor receptor agonist: Amitriptyline High affinity nerve growth factor receptor antagonist: Imatinib High affinity nerve growth factor receptor inhibitor: Regorafenib | 15.11 | ||
| dpcNTRK2 | BDNF/NT-3 growth factors receptor | 0 | 291 | 86.50 | ND | 86.10 | 0.49 | ND | 0.7 | Mammalian | Isoform TrkB is expressed in the central and peripheral nervous system. In the central nervous system (CNS), expression is observed in the cerebral cortex, hippocampus, thalamus, choroid plexus, granular layer of the cerebellum, brain stem, and spinal cord. In the peripheral nervous system, it is expressed in many cranial ganglia, the ophthalmic nerve, the vestibular system, multiple facial structures, the submaxillary glands, and dorsal root ganglia. Isoform TrkB-T1 is mainly expressed in the brain but also detected in other tissues including pancreas, kidney and heart. Isoform TrkB-T-Shc is predominantly expressed in the brain. {ECO:0000269|PubMed:11798182, ECO:0000269|PubMed:7936202}. | Kinase | Obesity, hyperphagia, and developmental delay (OBHD) [MIM:613886]: A disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language. {ECO:0000269|PubMed:15494731}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin- 4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin- dependent calcium signaling in glial cells and mediate communication between neurons and glia. {ECO:0000269|PubMed:15494731}. | BDNF/NT-3 growth factors receptor agonist: Amitriptyline | 15.11 | ||
| dpcNTRK3 | NT-3 growth factor receptor | 0 | 269 | 86.38 | ND | 84.23 | 0.30 | ND | 0.9 | Mammalian | Widely expressed but mainly in nervous tissue. Isoform 2 is expressed at higher levels in adult brain than in fetal brain. | Kinase | Note=Defects in NTRK3 are associated with susceptibility to congenital heart defects (CHD). A disease characterized by congenital developmental abnormalities involving structures of the heart. CHD are the most common major birth defects and the leading cause of death from congenital malformations. {ECO:0000269|PubMed:25196463}. | Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation. {ECO:0000269|PubMed:25196463}. | 15.11 | |||
| dpcOX2R | Orexin receptor type 2 | 0 | 464 | 73.08 | ND | 92.09 | 0.45 | ND | 0.8 | Mammalian | Family A G protein-coupled receptor | Gastrointestinal motility disorders
Nausea and vomiting | Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides. | Orexin receptor type 2 antagonist: Suvorexant | 15.11 | |||
| dpcOXDA | D-amino-acid oxidase | 0 | 139 | 74.15 | ND | 87.68 | 0.30 | ND | 1.2 | Mammalian | Enzyme | Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D- amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids. | D-amino-acid oxidase : Benzoic Acid, Flavin adenine dinucleotide | 15.11 | ||||
| dpcOXSR1 | Serine/threonine-protein kinase OSR1 | 0 | 59 | 71.30 | ND | 99.06 | 0.37 | ND | 0.5 | Mammalian | Ubiquitously expressed in all tissue examined. {ECO:0000269|PubMed:10083736}. | Kinase | Regulates downstream kinases in response to environmental stress. May also have a function in regulating the actin cytoskeleton. {ECO:0000269|PubMed:14707132, ECO:0000303|PubMed:14707132}. | 15.11 | ||||
| dpcP2RY1 | P2Y purinoceptor 1 | 0 | 287 | 78.85 | ND | 98.75 | 0.46 | ND | 0.7 | Mammalian | Family A G protein-coupled receptor | Thrombosis | Receptor for extracellular adenine nucleotides such as ATP and ADP. In platelets binding to ADP leads to mobilization of intracellular calcium ions via activation of phospholipase C, a change in platelet shape, and probably to platelet aggregation. {ECO:0000269|PubMed:9442040}. | 15.11 | ||||
| dpcP2Y12 | P2Y purinoceptor 12 | 0 | 445 | 77.93 | ND | 98.67 | 0.60 | ND | 0.6 | Mammalian | Highly expressed in the platelets, lower levels in the brain. Lowest levels in the lung, appendix, pituitary and adrenal gland. Expressed in the spinal cord and in the fetal brain. {ECO:0000269|PubMed:11104774, ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:11502873}. | Family A G protein-coupled receptor | Bleeding disorder, platelet-type 8 (BDPLT8) [MIM:609821]: A condition characterized by mild to moderate mucocutaneous bleeding, and excessive bleeding after surgery or trauma. The defect is due to severe impairment of platelet response to ADP resulting in defective platelet aggregation. {ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:12578987, ECO:0000269|PubMed:25428217}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation. {ECO:0000269|PubMed:11104774, ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:11502873, ECO:0000269|PubMed:12578987, ECO:0000269|PubMed:24670650, ECO:0000269|PubMed:24784220}. | P2Y purinoceptor 12 agonist: Epoprostenol, Treprostinil P2Y purinoceptor 12 antagonist: Clopidogrel, Prasugrel, Ticlopidine P2Y purinoceptor 12 inhibitor: Cangrelor, Ticagrelor | 15.11 | ||
| dpcPA21B | Phospholipase A2, major isoenzyme | 0 | 331 | 75.49 | ND | 81.88 | 0.46 | ND | 0.8 | Mammalian | Enzyme | PA2 catalyzes the calcium-dependent hydrolysis of the 2- acyl groups in 3-sn-phosphoglycerides, this releases glycerophospholipids and arachidonic acid that serve as the precursors of signal molecules. {ECO:0000250}. | 15.11 | |||||
| dpcPA2GA | Phospholipase A2, membrane associated | 0 | 238 | 78.60 | ND | 95.41 | 0.52 | ND | 0.7 | Mammalian | Enzyme | Atherosclerosis
Coronary Artery Disease | Thought to participate in the regulation of the phospholipid metabolism in biomembranes including eicosanoid biosynthesis. Catalyzes the calcium-dependent hydrolysis of the 2- acyl groups in 3-sn-phosphoglycerides. | Phospholipase A2, membrane associated : Isopropyl Alcohol Phospholipase A2, membrane associated inhibitor: Diclofenac, Ginkgo biloba, Indomethacin, Suramin | 15.11 | |||
| dpcPAFA | Platelet-activating factor acetylhydrolase | 0 | 208 | 78.00 | ND | 96.75 | 0.72 | ND | 0.6 | Mammalian | Plasma. | Enzyme | Platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:614278]: An enzymatic deficiency that results in exacerbated bodily response to inflammatory agents. It can be associated with several disease states including inflammatory gastrointestinal disorders, asthma and atopy. Asthmatic individuals with PAFAD may manifest aggravated respiratory symptoms. {ECO:0000269|PubMed:8675689, ECO:0000269|PubMed:9245731, ECO:0000269|PubMed:9412624, ECO:0000269|PubMed:9472966, ECO:0000269|PubMed:9759612}. Note=The disease is caused by mutations affecting the gene represented in this entry. Asthma (ASTHMA) [MIM:600807]: The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with wheezing due to spasmodic contraction of the bronchi. {ECO:0000269|PubMed:10733466}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Atopic hypersensitivity (ATOPY) [MIM:147050]: A condition characterized by predisposition to develop hypersensitivity reactions. Atopic individuals can develop eczema, allergic rhinitis and allergic asthma. {ECO:0000269|PubMed:10733466}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Modulates the action of platelet-activating factor (PAF) by hydrolyzing the sn-2 ester bond to yield the biologically inactive lyso-PAF. Has a specificity for substrates with a short residue at the sn-2 position. It is inactive against long-chain phospholipids. | 15.11 | |||
| dpcPAK1 | Serine/threonine-protein kinase PAK 1 | 0 | 192 | 81.13 | ND | 90.40 | 0.66 | ND | 0.5 | Mammalian | Overexpressed in gastric cancer cells and tissues (at protein level) (PubMed:25766321). {ECO:0000269|PubMed:25766321}. | Kinase | Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2- induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F- actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion (PubMed:25766321). {ECO:0000269|PubMed:10551809, ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:12624090, ECO:0000269|PubMed:12876277, ECO:0000269|PubMed:14585966, ECO:0000269|PubMed:15611088, ECO:0000269|PubMed:15831477, ECO:0000269|PubMed:15833848, ECO:0000269|PubMed:16278681, ECO:0000269|PubMed:17726028, ECO:0000269|PubMed:17989089, ECO:0000269|PubMed:22669945, ECO:0000269|PubMed:23633677, ECO:0000269|PubMed:25766321, ECO:0000269|PubMed:8805275, ECO:0000269|PubMed:9032240, ECO:0000269|PubMed:9395435, ECO:0000269|PubMed:9528787}. | 15.11 | ||||
| dpcPAK4 | Serine/threonine-protein kinase PAK 4 | 0 | 351 | 84.73 | ND | 90.60 | 0.49 | ND | 0.6 | Mammalian | Highest expression in prostate, testis and colon. | Kinase | Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN. {ECO:0000269|PubMed:11278822, ECO:0000269|PubMed:11313478, ECO:0000269|PubMed:14560027, ECO:0000269|PubMed:15660133, ECO:0000269|PubMed:20507994, ECO:0000269|PubMed:20631255, ECO:0000269|PubMed:20805321}. | 15.11 | ||||
| dpcPAK6 | Serine/threonine-protein kinase PAK 6 | 0 | 66 | 89.17 | ND | 81.39 | 0.00 | ND | 0.6 | Mammalian | Selectively expressed in brain and testis, with lower levels in multiple tissues including prostate and breast. {ECO:0000269|PubMed:11278661, ECO:0000269|PubMed:11773441}. | Kinase | Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Inhibits also ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. May protect cells from apoptosis through phosphorylation of BAD. {ECO:0000269|PubMed:14573606, ECO:0000269|PubMed:20054820}. | 15.11 | ||||
| dpcPAR1 | Proteinase-activated receptor 1 | 0 | 359 | 91.92 | ND | 99.62 | 0.60 | ND | 0.5 | Mammalian | Platelets and vascular endothelial cells. | Family A G protein-coupled receptor | Acute Coronary Syndrome
Analgesics Cardiovascular Disorders Inflammation Ischemic Stroke Pain, unspecified Vascular disease | High affinity receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis. May play a role in platelets activation and in vascular development. {ECO:0000269|PubMed:10079109}. | Proteinase-activated receptor 1 antagonist: Vorapaxar Proteinase-activated receptor 1 cleavage: Streptokinase | 15.11 | ||
| dpcPARP1 | Poly [ADP-ribose] polymerase 1 | 0 | 1321 | 94.88 | ND | 97.86 | 0.64 | ND | 0.6 | Mammalian | Enzyme | Asthma
Cancer, unspecific Chronic obstructive pulmonary disease Diabetic cardiovascular dysfunction Diabetic endothelial dysfunction Multiple sclerosis Traumatic brain injury Tumors | Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP- ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Required for PARP9 and DTX3L recruitment to DNA damage sites. PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. {ECO:0000269|PubMed:17177976, ECO:0000269|PubMed:18172500, ECO:0000269|PubMed:19344625, ECO:0000269|PubMed:19661379, ECO:0000269|PubMed:23230272}. | Poly [ADP-ribose] polymerase 1 binder: Nicotinamide Poly [ADP-ribose] polymerase 1 inhibitor: Olaparib | 15.11 | |||
| dpcPARP2 | Poly [ADP-ribose] polymerase 2 | 0 | 81 | 92.36 | ND | 91.34 | 0.87 | ND | 0.6 | Mammalian | Widely expressed, mainly in actively dividing tissues. The highest levels are in the brain, heart, pancreas, skeletal muscle and testis; also detected in kidney, liver, lung, placenta, ovary and spleen; levels are low in leukocytes, colon, small intestine, prostate and thymus. | Enzyme | Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. | Poly [ADP-ribose] polymerase 2 Inhibitor: Olaparib | 15.11 | |||
| dpcPDE10 | cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A | 0 | 871 | 80.99 | ND | 95.32 | 0.50 | ND | 0.7 | Mammalian | Abundant in the putamen and caudate nucleus regions of brain and testis, moderately expressed in the thyroid gland, pituitary gland, thalamus and cerebellum. | Phosphodiesterase | Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate. {ECO:0000269|PubMed:17389385}. | cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A antagonist: Triflusal cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A inhibitor: Dipyridamole, Papaverine, Tofisopam | 15.11 | |||
| dpcPDE2A | cGMP-dependent 3',5'-cyclic phosphodiesterase | 0 | 264 | 83.78 | ND | 97.63 | 0.90 | ND | 0.5 | Mammalian | Expressed in brain and to a lesser extent in heart, placenta, lung, skeletal muscle, kidney and pancreas. | Dyspepsia Flushing Headache | Phosphodiesterase | Colorectal cancer
Erectile dysfunction | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Isoform PDE2A2: Regulates Mitochondrial cAMP Levels and Respiration. | cGMP-dependent 3',5'-cyclic phosphodiesterase inhibitor: Tofisopam | 15.11 | |
| dpcPDE4D | cAMP-specific 3',5'-cyclic phosphodiesterase 4D | 0 | 489 | 70.51 | ND | 95.42 | 0.68 | ND | 0.8 | Nature11159 | Mammalian | Expressed in colonic epithelial cells (at protein level). Widespread; most abundant in skeletal muscle. Isoform 6 is detected in brain. Isoform 8 is detected in brain, placenta, lung and kidney. Isoform 7 is detected in heart and skeletal muscle. {ECO:0000269|PubMed:12834813, ECO:0000269|PubMed:17244609}. | Dyspepsia Flushing | Phosphodiesterase | Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. {ECO:0000269|PubMed:17006457}. Acrodysostosis 2, with or without hormone resistance (ACRDYS2) [MIM:614613]: A pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems. {ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:23033274, ECO:0000269|PubMed:23043190}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4D antagonist: Apremilast cAMP-specific 3',5'-cyclic phosphodiesterase 4D inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4D inhibitor: Dyphylline, Ibudilast, Ketotifen, Roflumilast cAMP-specific 3',5'-cyclic phosphodiesterase 4D product of: Adenosine monophosphate | 15.11 |
| dpcPDE5A | cGMP-specific 3',5'-cyclic phosphodiesterase | 0 | 1400 | 82.19 | ND | 95.30 | 0.69 | ND | 0.8 | Mammalian | Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung. | Diarrhoea Dyspepsia Flushing Palpitations | Phosphodiesterase | Erectile dysfunction
Injury to spine and spinal cord Pulmonary hypertension Vascular disease | Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'- GMP (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334). {ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9714779}. | cGMP-specific 3',5'-cyclic phosphodiesterase inhibitor: Avanafil, Dipyridamole, Pentoxifylline, Sildenafil, Tadalafil, Theophylline, Udenafil, Vardenafil | 15.11 | |
| dpcPDE7A | High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A | 0 | 281 | 79.58 | ND | 88.49 | 0.71 | ND | 0.5 | Mammalian | PDE7A1 is found at high levels in skeletal muscle and at low levels in a variety of tissues including brain and heart. It is expressed as well in two T-cell lines. PDE7A2 is found abundantly in skeletal muscle and at low levels in heart. | Phosphodiesterase | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May have a role in muscle signal transduction. {ECO:0000269|PubMed:19350606}. | High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A inhibitor: Dyphylline, Ketotifen | 15.11 | |||
| dpcPDE9A | High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305} | 0 | 95 | 93.40 | ND | 99.98 | 0.64 | ND | 0.7 | Mammalian | Expressed in all tissues examined (testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary and prostate) except blood (PubMed:9624146). Highest levels in brain, heart, kidney, spleen, prostate and colon. Isoform PDE9A12 is found in prostate (PubMed:12565835). In brain, present in the cortex, cerebellum, and subiculum (at protein level) (PubMed:22328573). In heart, primarily localizes to myocytes (PubMed:25799991). {ECO:0000269|PubMed:12565835, ECO:0000269|PubMed:22328573, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146}. | Phosphodiesterase | Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP (PubMed:9624146, PubMed:18757755, PubMed:21483814). Specifically regulates natriuretic-peptide- dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart (PubMed:25799991). Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory (By similarity). {ECO:0000250|UniProtKB:Q8QZV1, ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146, ECO:0000305}. | 15.11 | ||||
| dpcPDK1 | [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial | 0 | 79 | 80.84 | ND | 96.12 | 0.79 | ND | 0.4 | Mammalian | Expressed predominantly in the heart. Detected at lower levels in liver, skeletal muscle and pancreas. {ECO:0000269|PubMed:7499431}. | Kinase | Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress. {ECO:0000269|PubMed:17683942, ECO:0000269|PubMed:18541534, ECO:0000269|PubMed:22195962, ECO:0000269|PubMed:7499431}. | 15.11 | ||||
| dpcPDPK1 | 3-phosphoinositide-dependent protein kinase 1 | 0 | 427 | 91.51 | ND | 95.48 | 0.64 | ND | 0.7 | Mammalian | Appears to be expressed ubiquitously. The Tyr- 9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast. {ECO:0000269|PubMed:18024423}. | Kinase | Cancer, unspecific
Diabetes mellitus | Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF- kappa-B activation in macrophages. Isoform 3 is catalytically inactive. {ECO:0000269|PubMed:10226025, ECO:0000269|PubMed:10480933, ECO:0000269|PubMed:10995762, ECO:0000269|PubMed:12167717, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:14604990, ECO:0000269|PubMed:16207722, ECO:0000269|PubMed:16251192, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:17371830, ECO:0000269|PubMed:18835241, ECO:0000269|PubMed:9094314, ECO:0000269|PubMed:9445476, ECO:0000269|PubMed:9707564, ECO:0000269|PubMed:9768361}. | 3-phosphoinositide-dependent protein kinase 1 inhibitor: Celecoxib | 15.11 | ||
| dpcPGES2 | Prostaglandin E synthase 2 | 0 | 40 | 90.35 | ND | 90.57 | 0.94 | ND | 0.3 | Mammalian | Isomerase that catalyzes the conversion of PGH2 into the more stable prostaglandin E2 (PGE2). {ECO:0000269|PubMed:11866447, ECO:0000269|PubMed:17585783}. | 15.11 | ||||||
| dpcPGH1 | Prostaglandin G/H synthase 1 | 0 | 3050 | 70.10 | ND | 89.17 | 0.34 | ND | 0.6 | Nature11159 | Mammalian | Abdominal pain upper Aplastic anaemia Asthma Dyspepsia Erythema multiforme Gastrointestinal haemorrhage Haematuria Haemorrhagic diathesis Hepatitis Nephropathy Oedema Peptic ulcer Pruritus Rash Renal failure Renal tubular disorder Thrombocytopenia Tinnitus Toxic epidermal necrolysis | Enzyme | Cardiovascular disease, unspecified
Chronic inflammatory diseases | Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells. {ECO:0000269|PubMed:10438452}. | 15.11 | ||
| dpcPGH2 | Prostaglandin G/H synthase 2 | 0 | 3317 | 75.12 | ND | 89.60 | 0.44 | ND | 0.8 | Nature11159 | Mammalian | Following colon injury, expressed in the wound bed mesenchyme during the first phase of repair, probably by colonic mesenchymal stem cells (at protein level). {ECO:0000269|PubMed:22465430}. | Abdominal pain upper Aplastic anaemia Dyspepsia Erythema multiforme Flatulence Gastrointestinal haemorrhage Haematuria Haemorrhagic diathesis Hepatitis Nephropathy Oedema Oliguria Peptic ulcer Pruritus Renal failure Thrombocytopenia Tinnitus | Enzyme | Abdominal aortic aneurysm
Adenomatous polyposis Alzheimer's disease Analgesics Arthritis Bladder cancer Breast cancer Cancer, unspecific Carcinoma in situ, unspecified Carpal tunnel syndrome Colorectal cancer Dysmenorrhea, unspecified Endometriosis Genitourinary tumors Gestational hypertension Inflammation Inflammatory diseases Lung cancer Malignant mesothelioma Meningioma Myocardial infarction Oropharyngeal squamous cell carcinoma Osteoarthritis Pain, unspecified Pathological angiogenesis Peutz-Jeghers syndrome Prostate cancer Pyresis Renal cell carcinoma Rheumatoid arthritis, unspecified Stroke Vascular lesion regression | Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis. {ECO:0000269|PubMed:12925531, ECO:0000269|PubMed:20463020, ECO:0000269|PubMed:20810665, ECO:0000269|PubMed:21489986, ECO:0000269|PubMed:22465430}. | Cyclooxygenase inhibitor: Acetaminophen, Aminosalicylic Acid, Aspirin, Balsalazide, Bismuth Subsalicylate, Bromfenac, Diclofenac, Diflunisal, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamic Acid, Mefenamic Acid, Mesalamine, Naproxen, Nepafenac, Olsalazine, Oxaprozin, Oxyphenbutazone, Phenylbutazone, Piroxicam, Sulfasalazine, Sulindac, Suprofen, Tolmetin Cyclooxygenase-2 inhibitor: Carprofen, Celecoxib, Etodolac, Meloxicam, Nabumetone, Rofecoxib, Valdecoxib | 15.11 |
| dpcPHKG2 | Phosphorylase b kinase gamma catalytic chain, liver/testis isoform | 0 | 164 | 86.40 | ND | 86.42 | 0.07 | ND | 0.7 | Mammalian | Kinase | Glycogen storage disease 9C (GSD9C) [MIM:613027]: A metabolic disorder manifesting in infancy with hepatomegaly, growth retardation, hypotonia, liver dysfunction, and elevated plasma aminotransferases and lipids. These symptoms improve with age in most cases; however, some patients may develop hepatic fibrosis or cirrhosis. {ECO:0000269|PubMed:12930917, ECO:0000269|PubMed:8896567, ECO:0000269|PubMed:9245685}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. May regulate glycogeneolysis in the testis. In vitro, phosphorylates PYGM (By similarity). {ECO:0000250, ECO:0000269|PubMed:10487978}. | 15.11 | ||||
| dpcPIM1 | Serine/threonine-protein kinase pim-1 | 0 | 1191 | 84.69 | ND | 93.93 | 0.63 | ND | 0.6 | Mammalian | Expressed primarily in cells of the hematopoietic and germline lineages. Isoform 1 and isoform 2 are both expressed in prostate cancer cell lines. {ECO:0000269|PubMed:16186805}. | Kinase | Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl- X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post- translational levels. Phosphorylation of CDKN1B,induces 14-3-3- proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis. {ECO:0000269|PubMed:10664448, ECO:0000269|PubMed:12431783, ECO:0000269|PubMed:15528381, ECO:0000269|PubMed:16356754, ECO:0000269|PubMed:1825810, ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:19749799}. | Serine/threonine-protein kinase pim-1 product of: Adenosine monophosphate | 15.11 | |||
| dpcPIM2 | Serine/threonine-protein kinase pim-2 | 0 | 561 | 86.17 | ND | 95.72 | 0.60 | ND | 0.7 | Mammalian | Highly expressed in hematopoietic tissues, in leukemic and lymphoma cell lines, testis, small intestine, colon and colorectal adenocarcinoma cells. Weakly expressed in normal liver, but highly expressed in hepatocellular carcinoma tissues. {ECO:0000269|PubMed:18675992}. | Kinase | Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti- apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate. {ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:18675992, ECO:0000269|PubMed:20307683}. | 15.11 | ||||
| dpcPIN1 | Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 | 0 | 160 | 86.71 | ND | 91.72 | 0.36 | ND | 0.7 | Mammalian | The phosphorylated form at Ser-71 is expressed in normal breast tissue cells but not in breast cancer cells. {ECO:0000269|PubMed:17828269, ECO:0000269|PubMed:21497122}. | Enzyme | Alzheimer's disease
Cancer, unspecific Hepatocellular carcinoma | Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr- Pro) motifs in a subset of proteins, resulting in conformational changes in the proteins (PubMed:21497122, PubMed:22033920). Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923). {ECO:0000269|PubMed:15664191, ECO:0000269|PubMed:16644721, ECO:0000269|PubMed:17828269, ECO:0000269|PubMed:21497122, ECO:0000269|PubMed:22033920, ECO:0000269|PubMed:22608923}. | 15.11 | |||
| dpcPK3CA | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform | 0 | 2208 | 90.72 | ND | 97.53 | 0.61 | ND | 0.7 | Mammalian | Enzyme | Note=PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. {ECO:0000269|PubMed:15016963, ECO:0000269|PubMed:15289301, ECO:0000269|PubMed:15520168, ECO:0000269|PubMed:15712344, ECO:0000269|PubMed:15784156, ECO:0000269|PubMed:15924253, ECO:0000269|PubMed:15930273, ECO:0000269|PubMed:15994075, ECO:0000269|PubMed:16114017, ECO:0000269|PubMed:16322209, ECO:0000269|PubMed:16353168, ECO:0000269|PubMed:16432179, ECO:0000269|PubMed:16533766, ECO:0000269|PubMed:17673550, ECO:0000269|PubMed:19805105, ECO:0000269|PubMed:21708979, ECO:0000269|PubMed:22658544, ECO:0000269|PubMed:22729224}. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:15930273, ECO:0000269|PubMed:15994075}. Note=The gene represented in this entry may be involved in disease pathogenesis. Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:16353168}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. {ECO:0000269|PubMed:15520168}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:15608678}. Note=The gene represented in this entry may be involved in disease pathogenesis. Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:17673550}. Note=The disease is caused by mutations affecting the gene represented in this entry. Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) [MIM:602501]: A syndrome characterized by a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria. {ECO:0000269|PubMed:22729224, ECO:0000269|PubMed:26593112}. Note=The disease is caused by mutations affecting the gene represented in this entry. Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:612918]: A sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth. {ECO:0000269|PubMed:22658544}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cowden syndrome 5 (CWS5) [MIM:615108]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. {ECO:0000269|PubMed:23246288}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Also has serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity). {ECO:0000250|UniProtKB:P42337, ECO:0000269|PubMed:21708979, ECO:0000269|PubMed:26593112}. | 15.11 | ||||
| dpcPK3CB | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform | 0 | 986 | 80.70 | ND | 93.31 | 0.60 | ND | 0.7 | Mammalian | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors. {ECO:0000269|PubMed:18544649, ECO:0000269|PubMed:18594509, ECO:0000269|PubMed:19515725, ECO:0000269|PubMed:19940148, ECO:0000269|PubMed:20065293, ECO:0000269|PubMed:21059846}. | 15.11 | ||||||
| dpcPK3CD | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform | 0 | 1048 | 81.64 | ND | 93.59 | 0.58 | ND | 0.6 | Mammalian | Isoform 1 is expressed in spleen and lung (at protein level). Isoform 1 is expressed predominantly in leukocytes. {ECO:0000269|PubMed:22020336}. | Enzyme | Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. {ECO:0000269|PubMed:12130661, ECO:0000269|PubMed:12235209, ECO:0000269|PubMed:15496927, ECO:0000269|PubMed:16116162, ECO:0000269|PubMed:18259608, ECO:0000269|PubMed:18809712, ECO:0000269|PubMed:19297623}. | 15.11 | ||||
| dpcPK3CG | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform | 0 | 1183 | 88.15 | ND | 96.18 | 0.68 | ND | 0.6 | Mammalian | Pancreas, skeletal muscle, liver and heart. {ECO:0000269|PubMed:7624799}. | Enzyme | Angioedema
Cancer, unspecific Heart failure Myocardial infarction Solid tumors | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin- based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B- lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis. {ECO:0000269|PubMed:12163475, ECO:0000269|PubMed:15294162, ECO:0000269|PubMed:16094730, ECO:0000269|PubMed:21393242, ECO:0000269|PubMed:7624799}. | 15.11 | |||
| dpcPLK1 | Serine/threonine-protein kinase PLK1 | 0 | 761 | 89.03 | ND | 94.85 | 0.72 | ND | 0.7 | Mammalian | Placenta and colon. | Kinase | Note=Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis. | Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, CENPU, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, CENPU, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, CENPU, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGOL1: required for spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis. Phosphorylates MISP, leading to stabilization of cortical and astral microtubule attachments required for proper spindle positioning (PubMed:8991084, PubMed:11202906, PubMed:12207013, PubMed:12447691, PubMed:12524548, PubMed:12738781, PubMed:12852856, PubMed:12939256, PubMed:14532005, PubMed:14734534, PubMed:15070733, PubMed:15148369, PubMed:15469984, PubMed:16198290, PubMed:16247472, PubMed:16980960, PubMed:17081991, PubMed:17351640, PubMed:17376779, PubMed:17617734, PubMed:18174154, PubMed:18331714, PubMed:18418051, PubMed:18477460, PubMed:18521620, PubMed:18615013, PubMed:19160488, PubMed:19351716, PubMed:19468300, PubMed:19468302, PubMed:19473992, PubMed:19509060, PubMed:19597481, PubMed:23455478, PubMed:23509069). Together with MEIKIN, acts as a regulator of kinetochore function during meiosis I: required both for mono- orientation of kinetochores on sister chromosomes and protection of centromeric cohesin from separase-mediated cleavage (By similarity). Phosphorylates CEP68 and is required for its degradation (PubMed:25503564). {ECO:0000250|UniProtKB:Q5F2C3, ECO:0000269|PubMed:11202906, ECO:0000269|PubMed:12207013, ECO:0000269|PubMed:12447691, ECO:0000269|PubMed:12524548, ECO:0000269|PubMed:12738781, ECO:0000269|PubMed:12852856, ECO:0000269|PubMed:12939256, ECO:0000269|PubMed:14532005, ECO:0000269|PubMed:14734534, ECO:0000269|PubMed:15070733, ECO:0000269|PubMed:15148369, ECO:0000269|PubMed:15469984, ECO:0000269|PubMed:16198290, ECO:0000269|PubMed:16247472, ECO:0000269|PubMed:16980960, ECO:0000269|PubMed:17081991, ECO:0000269|PubMed:17351640, ECO:0000269|PubMed:17376779, ECO:0000269|PubMed:17617734, ECO:0000269|PubMed:18174154, ECO:0000269|PubMed:18331714, ECO:0000269|PubMed:18418051, ECO:0000269|PubMed:18477460, ECO:0000269|PubMed:18521620, ECO:0000269|PubMed:18615013, ECO:0000269|PubMed:19160488, ECO:0000269|PubMed:19351716, ECO:0000269|PubMed:19468300, ECO:0000269|PubMed:19468302, ECO:0000269|PubMed:19473992, ECO:0000269|PubMed:19509060, ECO:0000269|PubMed:19597481, ECO:0000269|PubMed:23455478, ECO:0000269|PubMed:23509069, ECO:0000269|PubMed:25503564, ECO:0000269|PubMed:8991084}. | 15.11 | |||
| dpcPLK2 | Serine/threonine-protein kinase PLK2 | 0 | 160 | 83.99 | ND | 89.80 | 0.65 | ND | 0.6 | Mammalian | Expressed at higher level in the fetal lung, kidney, spleen and heart. {ECO:0000269|PubMed:11696980}. | Kinase | Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress. {ECO:0000269|PubMed:15242618, ECO:0000269|PubMed:19001868, ECO:0000269|PubMed:20352051, ECO:0000269|PubMed:20531387}. | 15.11 | ||||
| dpcPLK3 | Serine/threonine-protein kinase PLK3 | 0 | 339 | 88.12 | ND | 92.35 | 0.55 | ND | 0.6 | Mammalian | Transcripts are highly detected in placenta, lung, followed by skeletal muscle, heart, pancreas, ovaries and kidney and weakly detected in liver and brain. May have a short half-live. In cells of hematopoietic origin, strongly and exclusively detected in terminally differentiated macrophages. Transcript expression appears to be down-regulated in primary lung tumor. | Kinase | Serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates ATF2, BCL2L1, CDC25A, CDC25C, CHEK2, HIF1A, JUN, p53/TP53, p73/TP73, PTEN, TOP2A and VRK1. Involved in cell cycle regulation: required for entry into S phase and cytokinesis. Phosphorylates BCL2L1, leading to regulate the G2 checkpoint and progression to cytokinesis during mitosis. Plays a key role in response to stress: rapidly activated upon stress stimulation, such as ionizing radiation, reactive oxygen species (ROS), hyperosmotic stress, UV irradiation and hypoxia. Involved in DNA damage response and G1/S transition checkpoint by phosphorylating CDC25A, p53/TP53 and p73/TP73. Phosphorylates p53/TP53 in response to reactive oxygen species (ROS), thereby promoting p53/TP53-mediated apoptosis. Phosphorylates CHEK2 in response to DNA damage, promoting the G2/M transition checkpoint. Phosphorylates the transcription factor p73/TP73 in response to DNA damage, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates HIF1A and JUN is response to hypoxia. Phosphorylates ATF2 following hyperosmotic stress in corneal epithelium. Also involved in Golgi disassembly during the cell cycle: part of a MEK1/MAP2K1-dependent pathway that induces Golgi fragmentation during mitosis by mediating phosphorylation of VRK1. May participate in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation, via its interaction with CIB1. {ECO:0000269|PubMed:10557092, ECO:0000269|PubMed:11156373, ECO:0000269|PubMed:11447225, ECO:0000269|PubMed:11551930, ECO:0000269|PubMed:11971976, ECO:0000269|PubMed:12242661, ECO:0000269|PubMed:14968113, ECO:0000269|PubMed:14980500, ECO:0000269|PubMed:15021912, ECO:0000269|PubMed:16478733, ECO:0000269|PubMed:16481012, ECO:0000269|PubMed:17264206, ECO:0000269|PubMed:17804415, ECO:0000269|PubMed:18062778, ECO:0000269|PubMed:18650425, ECO:0000269|PubMed:19103756, ECO:0000269|PubMed:19490146, ECO:0000269|PubMed:20889502, ECO:0000269|PubMed:20940307, ECO:0000269|PubMed:20951827, ECO:0000269|PubMed:21098032, ECO:0000269|PubMed:21264284, ECO:0000269|PubMed:21376736, ECO:0000269|PubMed:21840391, ECO:0000269|PubMed:9353331}. | 15.11 | ||||
| dpcPLK4 | Serine/threonine-protein kinase PLK4 | 0 | 357 | 77.35 | ND | 86.53 | 0.35 | ND | 0.8 | Mammalian | Kinase | Microcephaly and chorioretinopathy, autosomal recessive, 2 (MCCRP2) [MIM:616171]: A severe disorder characterized by microcephaly, delayed psychomotor development, growth retardation with dwarfism, and ocular abnormalities. {ECO:0000269|PubMed:25344692}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2. {ECO:0000269|PubMed:16244668, ECO:0000269|PubMed:16326102, ECO:0000269|PubMed:17681131, ECO:0000269|PubMed:18239451, ECO:0000269|PubMed:19164942, ECO:0000269|PubMed:21725316}. | 15.11 | ||||
| dpcPLMN | Plasminogen | 0 | 673 | 77.23 | ND | 94.60 | 0.48 | ND | 0.6 | Mammalian | Present in plasma and many other extracellular fluids. It is synthesized in the liver. | Protease | Plasminogen deficiency (PLGD) [MIM:217090]: A disorder characterized by decreased serum plasminogen activity. Two forms of the disorder are distinguished: type 1 deficiency is additionally characterized by decreased plasminogen antigen levels and clinical symptoms, whereas type 2 deficiency, also known as dysplasminogenemia, is characterized by normal, or slightly reduced antigen levels, and absence of clinical manifestations. Plasminogen deficiency type 1 results in markedly impaired extracellular fibrinolysis and chronic mucosal pseudomembranous lesions due to subepithelial fibrin deposition and inflammation. The most common clinical manifestation of type 1 deficiency is ligneous conjunctivitis in which pseudomembranes formation on the palpebral surfaces of the eye progresses to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. {ECO:0000269|PubMed:10233898, ECO:0000269|PubMed:1427790, ECO:0000269|PubMed:1986355, ECO:0000269|PubMed:6216475, ECO:0000269|PubMed:6238949, ECO:0000269|PubMed:8392398, ECO:0000269|PubMed:9242524, ECO:0000269|PubMed:9858247}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells. {ECO:0000269|PubMed:14699093}. Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. {ECO:0000269|PubMed:14699093}. | Plasminogen activator: Alteplase, Anistreplase, Reteplase, Streptokinase, Tenecteplase, Urokinase Plasminogen inhibitor: Aminocaproic Acid, Tranexamic Acid | 15.11 | ||
| dpcPNMT | Phenylethanolamine N-methyltransferase | 0 | 248 | 93.86 | ND | 99.32 | 0.35 | ND | 0.6 | Mammalian | Enzyme | Converts noradrenaline to adrenaline. | 15.11 | |||||
| dpcPNPH | Purine nucleoside phosphorylase | 0 | 252 | 94.29 | ND | 95.92 | 0.10 | ND | 1.5 | Mammalian | Expressed in red blood cells; overexpressed in red blood cells (cytoplasm) of patients with hereditary non- spherocytic hemolytic anemia of unknown etiology. {ECO:0000269|PubMed:22509282}. | Enzyme | Purine nucleoside phosphorylase deficiency (PNPD) [MIM:613179]: A disorder that interrupts both the catabolism of inosine into hypoxanthine and guanosine into guanine, and leads to the accumulation of guanosine, inosine, and their deoxified by- products. The main clinical presentation is recurrent infections due to severe T-cell immunodeficiency. Some patients also have neurologic impairment. {ECO:0000269|PubMed:1384322, ECO:0000269|PubMed:3029074, ECO:0000269|PubMed:8931706}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta- (deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate. {ECO:0000269|PubMed:2104852}. | Purine nucleoside phosphorylase inducer: Cladribine | 15.11 | ||
| dpcPPARA | Peroxisome proliferator-activated receptor alpha | 0 | 2130 | 90.48 | ND | 97.47 | 0.53 | ND | 0.7 | Mammalian | Skeletal muscle, liver, heart and kidney. {ECO:0000269|PubMed:7981125, ECO:0000269|PubMed:8993548}. | Myalgia | Nuclear receptor | Hyperglycemia
Hyperinsulinemia Insulin resistance Lipid metabolic disorders Obesity | Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl- 2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2. {ECO:0000269|PubMed:10195690, ECO:0000269|PubMed:24043310, ECO:0000269|PubMed:7629123, ECO:0000269|PubMed:7684926, ECO:0000269|PubMed:9556573}. | Peroxisome proliferator-activated receptor alpha agonist: Bezafibrate, Clofibrate, Fenofibrate, Gemfibrozil, Indomethacin | 15.11 | |
| dpcPPARD | Peroxisome proliferator-activated receptor delta | 0 | 1236 | 88.30 | ND | 98.74 | 0.73 | ND | 0.7 | Mammalian | Ubiquitous with maximal levels in placenta and skeletal muscle. | Nuclear receptor | Atherosclerosis
Hyperlipidemia Inflammation Metabolic Disease Metabolic syndrome X Noninsulin-dependent diabetes mellitus Obesity Skin diseases | Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand. {ECO:0000269|PubMed:1333051, ECO:0000269|PubMed:15604518}. | Peroxisome proliferator-activated receptor delta agonist: Bezafibrate, Icosapent, Treprostinil Peroxisome proliferator-activated receptor delta negative modulator: Sulindac | 15.11 | ||
| dpcPPARG | Peroxisome proliferator-activated receptor gamma | 0 | 2583 | 87.87 | ND | 96.51 | 0.54 | ND | 0.7 | VirtualToxLab | Mammalian | Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary. {ECO:0000269|PubMed:9065481}. | Dyspepsia | Nuclear receptor | Note=Defects in PPARG can lead to type 2 insulin- resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. {ECO:0000269|PubMed:10394368}. Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:9753710}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Lipodystrophy, familial partial, 3 (FPLD3) [MIM:604367]: A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. {ECO:0000269|PubMed:11788685, ECO:0000269|PubMed:12453919}. Note=The disease is caused by mutations affecting the gene represented in this entry. Glioma 1 (GLM1) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:10851250}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility. | Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity). {ECO:0000250|UniProtKB:P37238, ECO:0000269|PubMed:16150867, ECO:0000269|PubMed:20829347, ECO:0000269|PubMed:23525231, ECO:0000269|PubMed:9065481}. | Peroxisome proliferator-activated receptor gamma activator: Ibuprofen, Indomethacin Peroxisome proliferator-activated receptor gamma agonist: Balsalazide, Bezafibrate, Glipizide, Icosapent, Mesalazine, Mitiglinide, Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone, Sulfasalazine Peroxisome proliferator-activated receptor gamma partial agonist: Telmisartan | 15.11 |
| dpcPPCE | Prolyl endopeptidase | 0 | 524 | 96.50 | ND | 98.60 | 0.73 | ND | 0.8 | Mammalian | Protease | Dementia
Neurological diseases | Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. | Prolyl endopeptidase substrate: Oxytocin | 15.11 | |||
| dpcPPIA | Peptidyl-prolyl cis-trans isomerase A | 0 | 80 | 75.61 | ND | 95.71 | 0.07 | ND | 0.7 | Mammalian | Isomerase | PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. | Peptidyl-prolyl cis-trans isomerase A : Cyclosporine Peptidyl-prolyl cis-trans isomerase A binder: L-Proline | 15.11 | ||||
| dpcPRGR | Progesterone receptor | 0 | 1519 | 79.21 | ND | 94.15 | 0.58 | ND | 0.7 | Nature11159 VirtualToxLab | Mammalian | Acne Amenorrhoea Biliary tract disorder Breast pain Depression Fibrocystic breast disease Gynaecomastia Hirsutism Jaundice cholestatic Libido disorder Menstrual disorder Metrorrhagia Migraine Oedema Urticaria Weight increased | Nuclear receptor | Breast cancer | The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation. Isoform A: inactive in stimulating c-Src/MAPK signaling on hormone stimulation. Isoform 4: Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone. | Progesterone receptor agonist: Allylestrenol, Danazol, Desogestrel, Drospirenone, Dydrogesterone, Ethynodiol, Etonogestrel, Fluticasone Propionate, Medroxyprogesterone Acetate, Megestrol acetate, Norelgestromin, Norethindrone, Norgestimate, Progesterone, Spironolactone Progesterone receptor antagonist: Mifepristone Progesterone receptor binder: Levonorgestrel Progesterone receptor modulator: Ulipristal | 15.11 | |
| dpcPTGIS | Prostacyclin synthase | 0 | 57 | 72.61 | ND | 99.75 | 0.69 | ND | 0.5 | Mammalian | Widely expressed; particularly abundant in ovary, heart, skeletal muscle, lung and prostate. | Cytochrome P450 | Essential hypertension (EHT) [MIM:145500]: A condition in which blood pressure is consistently higher than normal with no identifiable cause. {ECO:0000269|PubMed:12372404}. Note=The disease may be caused by mutations affecting the gene represented in this entry. | Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2). | Prostacyclin synthase inducer: Epoprostenol Prostacyclin synthase inhibitor: Phenylbutazone | 15.11 | ||
| dpcPTN1 | Tyrosine-protein phosphatase non-receptor type 1 | 0 | 1669 | 71.78 | ND | 94.10 | 0.71 | ND | 0.5 | Mammalian | Phosphatase | Type 2 Diabetes | Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of MET. {ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:21135139, ECO:0000269|PubMed:22169477}. | Tyrosine-protein phosphatase non-receptor type 1 inhibitor: Tiludronate | 15.11 | |||
| dpcPTN22 | Tyrosine-protein phosphatase non-receptor type 22 | 0 | 210 | 85.64 | ND | 92.62 | 0.45 | ND | 0.5 | Mammalian | Expressed in bone marrow, B and T-cells, PBMCs, natural killer cells, monocytes, dendritic cells and neutrophils (PubMed:15208781). Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells. {ECO:0000269|PubMed:15208781}. | Phosphatase | Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:15273934}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15004560}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269|PubMed:15208781}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Vitiligo (VTLG) [MIM:193200]: A pigmentary disorder of the skin and mucous membranes. It is characterized by circumscribed depigmented macules and patches, commonly on extensor aspects of extremities, on the face or neck and in skin folds. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. It is a multifactorial disorder with a complex etiology probably including autoimmune mechanisms, and is associated with an elevated risk of other autoimmune diseases. {ECO:0000269|PubMed:16015369}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr- 493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro- inflammatory cytokine secretion and autophagy (PubMed:23991106). {ECO:0000250|UniProtKB:P29352, ECO:0000269|PubMed:16461343, ECO:0000269|PubMed:18056643, ECO:0000269|PubMed:19167335, ECO:0000269|PubMed:21719704, ECO:0000269|PubMed:23871208, ECO:0000269|PubMed:23991106}. | 15.11 | |||
| dpcPTPRB | Receptor-type tyrosine-protein phosphatase beta | 0 | 52 | 99.48 | ND | 93.57 | 0.36 | ND | 0.6 | Mammalian | Phosphatase | Plays an important role in blood vessel remodeling and angiogenesis. Not necessary for the initial formation of blood vessels, but is essential for their maintenance and remodeling. Can induce dephosphorylation of TEK/TIE2, CDH5/VE-cadherin and KDR/VEGFR-2. Regulates angiopoietin-TIE2 signaling in endothelial cells. Acts as a negative regulator of TIE2, and controls TIE2 driven endothelial cell proliferation, which in turn affects blood vessel remodeling during embryonic development and determines blood vessel size during perinatal growth. Essential for the maintenance of endothelial cell contact integrity and for the adhesive function of VE-cadherin in endothelial cells and this requires the presence of plakoglobin (By similarity). {ECO:0000250, ECO:0000269|PubMed:19116766, ECO:0000269|PubMed:19136612}. | 15.11 | |||||
| dpcPUR2 | Trifunctional purine biosynthetic protein adenosine-3 | 0 | 99 | 99.79 | ND | 99.90 | 0.59 | ND | 1.0 | Mammalian | Ligase | Solid tumor | Trifunctional purine biosynthetic protein adenosine-3 inhibitor: Pemetrexed | 15.11 | ||||
| dpcPYGL | Glycogen phosphorylase, liver form | 0 | 428 | 93.41 | ND | 98.35 | 0.50 | ND | 0.6 | Mammalian | Enzyme | Glycogen storage disease 6 (GSD6) [MIM:232700]: A metabolic disorder characterized by mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent hepatomegaly. Heart and skeletal muscle are not affected. {ECO:0000269|PubMed:9529348}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. | Glycogen phosphorylase, liver form activator: Adenosine monophosphate | 15.11 | |||
| dpcPYRD | Dihydroorotate dehydrogenase (quinone), mitochondrial | 0 | 526 | 87.43 | ND | 96.72 | 0.68 | ND | 0.8 | Mammalian | Enzyme | Postaxial acrofacial dysostosis (POADS) [MIM:263750]: POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases. {ECO:0000269|PubMed:19915526}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | Dihydroorotate dehydrogenase (quinone), mitochondrial inhibitor: Atovaquone, Leflunomide, Teriflunomide | 15.11 | |||
| dpcRARA | Retinoic acid receptor alpha | 0 | 240 | 95.86 | ND | 99.32 | 0.39 | ND | 0.7 | Mammalian | Nuclear receptor | Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled- coil domain functions in blocking RA-mediated transactivation and cell differentiation. {ECO:0000269|PubMed:12691149, ECO:0000269|PubMed:8302850, ECO:0000269|PubMed:8562957}. | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Regulates expression of target genes in a ligand- dependent manner by recruiting chromatin complexes containing KMT2E/MLL5. Mediates retinoic acid-induced granulopoiesis. {ECO:0000250, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:19377461, ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:20215566}. | Retinoic acid receptor alpha agonist: Acitretin, Adapalene, Alitretinoin, Tamibarotene, Tazarotene Retinoic acid receptor alpha other/unknown: Isotretinoin | 15.11 | |||
| dpcRARB | Retinoic acid receptor beta | 0 | 244 | 92.73 | ND | 99.65 | 0.35 | ND | 0.8 | Mammalian | Nuclear receptor | Microphthalmia, syndromic, 12 (MCOPS12) [MIM:615524]: A form of microphthalmia, a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS12 patients manifest variable features, including diaphragmatic hernia, pulmonary hypoplasia, and cardiac abnormalities. {ECO:0000269|PubMed:24075189}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. {ECO:0000269|PubMed:12554770}. | Retinoic acid receptor beta agonist: Acitretin, Adapalene, Alitretinoin, Tamibarotene, Tazarotene | 15.11 | |||
| dpcRARG | Retinoic acid receptor gamma | 0 | 236 | 78.60 | ND | 97.89 | 0.55 | ND | 0.7 | Mammalian | Nuclear receptor | Acne
Emphysema Photoaging Psoriasis | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). {ECO:0000250}. | Retinoic acid receptor gamma agonist: Acitretin, Adapalene, Alitretinoin, Tazarotene, Tretinoin | 15.11 | |||
| dpcRENI | Renin | 0 | 739 | 80.26 | ND | 98.38 | 0.67 | ND | 0.8 | Mammalian | Protease | Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial juvenile hyperuricemic nephropathy 2 (HNFJ2) [MIM:613092]: A renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia. {ECO:0000269|PubMed:19664745}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney. | Renin inhibitor: Aliskiren, Remikiren | 15.11 | |||
| dpcRET | Proto-oncogene tyrosine-protein kinase receptor Ret | 0 | 571 | 77.68 | ND | 89.23 | 0.30 | ND | 1.0 | Mammalian | Kinase | Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry. Hirschsprung disease 1 (HSCR1) [MIM:142623]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. {ECO:0000269|PubMed:10090908, ECO:0000269|PubMed:10484767, ECO:0000269|PubMed:10618407, ECO:0000269|PubMed:22174939, ECO:0000269|PubMed:7581377, ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:7704557, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8114938, ECO:0000269|PubMed:8114939, ECO:0000269|PubMed:9043870, ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9094028, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9384613, ECO:0000269|Ref.56}. Note=The disease is caused by mutations affecting the gene represented in this entry. Medullary thyroid carcinoma (MTC) [MIM:155240]: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. {ECO:0000269|PubMed:10323403, ECO:0000269|PubMed:10826520, ECO:0000269|PubMed:11692159, ECO:0000269|PubMed:7784092, ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:7849720, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8557249, ECO:0000269|PubMed:8625130, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9223675, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9398735, ECO:0000269|PubMed:9452077, ECO:0000269|PubMed:9506724, ECO:0000269|PubMed:9621513, ECO:0000269|PubMed:9677065}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple neoplasia 2B (MEN2B) [MIM:162300]: Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. {ECO:0000269|PubMed:7906417, ECO:0000269|PubMed:7906866, ECO:0000269|PubMed:7911697, ECO:0000269|PubMed:8595427, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9294615, ECO:0000269|PubMed:9360560}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pheochromocytoma (PCC) [MIM:171300]: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:12000816}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. {ECO:0000269|PubMed:10522989, ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8099202, ECO:0000269|PubMed:8626834, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9097963, ECO:0000269|PubMed:9384613, ECO:0000269|PubMed:9452064}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene (PubMed:2406025). Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene (PubMed:2734021). Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916). Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene (PubMed:3037315). {ECO:0000269|PubMed:10439047, ECO:0000269|PubMed:10980597, ECO:0000269|PubMed:12787916, ECO:0000269|PubMed:2406025, ECO:0000269|PubMed:2734021, ECO:0000269|PubMed:3037315}. Note=Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis. Congenital central hypoventilation syndrome (CCHS) [MIM:209880]: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. {ECO:0000269|PubMed:12086152, ECO:0000269|PubMed:14566559, ECO:0000269|PubMed:9497256}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut- associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. {ECO:0000269|PubMed:20064382, ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698}. | Proto-oncogene tyrosine-protein kinase receptor Ret antagonist: Cabozantinib Proto-oncogene tyrosine-protein kinase receptor Ret inhibitor: Ponatinib, Regorafenib, Sorafenib | 15.11 | |||
| dpcRIPK2 | Receptor-interacting serine/threonine-protein kinase 2 | 0 | 75 | 86.31 | ND | 91.07 | 0.39 | ND | 0.5 | Mammalian | Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node. | Kinase | Not Available | Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. {ECO:0000269|PubMed:14638696, ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:18079694, ECO:0000269|PubMed:21123652, ECO:0000269|PubMed:21887730}. | 15.11 | |||
| dpcRK | Rhodopsin kinase | 0 | 60 | 88.84 | ND | 86.79 | 0.68 | ND | 0.4 | Mammalian | Rod outer segments of retina photoreceptor cells (at protein level) (PubMed:1656454, PubMed:1730692, PubMed:1527025). Retina (PubMed:1656454). {ECO:0000269|PubMed:1527025, ECO:0000269|PubMed:1656454, ECO:0000269|PubMed:1730692}. | Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade. This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination. {ECO:0000303|PubMed:1656454, ECO:0000303|PubMed:1730692}. | 15.11 | |||||
| dpcROCK1 | Rho-associated protein kinase 1 | 0 | 873 | 79.17 | ND | 91.45 | 0.55 | ND | 0.7 | Mammalian | Detected in blood platelets. {ECO:0000269|PubMed:8617235}. | Kinase | Asthma
Atherosclerotic cardiovascular disease Cardiac allograft vasculopathy Glaucoma Hepatic fibrosis Hypertensive vascular disease Intimal hyperplasia Liver fibrogenesis Primary pulmonary hypertension Pulmonary hypertension Restenosis Vascular disease Ventricular hypertrophy | Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A. Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress. Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Required for centrosome positioning and centrosome-dependent exit from mitosis. Plays a role in terminal erythroid differentiation. May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles. Promotes keratinocyte terminal differentiation. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization. {ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:10652353, ECO:0000269|PubMed:11018042, ECO:0000269|PubMed:11283607, ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:18573880, ECO:0000269|PubMed:18694941, ECO:0000269|PubMed:19036714, ECO:0000269|PubMed:19131646, ECO:0000269|PubMed:19181962, ECO:0000269|PubMed:19997641, ECO:0000269|PubMed:21072057, ECO:0000269|PubMed:8617235, ECO:0000269|PubMed:9722579}. | 15.11 | |||
| dpcROCK2 | Rho-associated protein kinase 2 | 0 | 989 | 76.59 | ND | 92.16 | 0.50 | ND | 0.7 | Mammalian | Kinase | Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation. {ECO:0000269|PubMed:10579722, ECO:0000269|PubMed:15699075, ECO:0000269|PubMed:16574662, ECO:0000269|PubMed:17015463, ECO:0000269|PubMed:19131646, ECO:0000269|PubMed:19997641, ECO:0000269|PubMed:21084279, ECO:0000269|PubMed:21147781}. | 15.11 | |||||
| dpcRORA | Nuclear receptor ROR-alpha | 0 | 66 | 76.10 | ND | 87.34 | 0.31 | ND | 0.2 | Mammalian | Widely expressed in a number of tissues. Expressed in both regulatory T-cells (Treg) and effector T-cells (Teff). {ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:7916608}. | Nuclear receptor | Cholesterol-related diseases
Chronic inflammatory diseases | Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium- mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti- inflammatory role by inducing CHUK expression and inhibiting NF- kappa-B signaling. {ECO:0000269|PubMed:10478845, ECO:0000269|PubMed:11053433, ECO:0000269|PubMed:11252722, ECO:0000269|PubMed:11554739, ECO:0000269|PubMed:12467577, ECO:0000269|PubMed:14570920, ECO:0000269|PubMed:15781255, ECO:0000269|PubMed:15790933, ECO:0000269|PubMed:16462772, ECO:0000269|PubMed:17512500, ECO:0000269|PubMed:18005000, ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19965867, ECO:0000269|PubMed:21499262, ECO:0000269|PubMed:7926749, ECO:0000269|PubMed:9328355, ECO:0000269|PubMed:9862959}. | 15.11 | |||
| dpcRXRA | Retinoic acid receptor RXR-alpha | 0 | 463 | 91.67 | ND | 95.89 | 0.71 | ND | 0.6 | Mammalian | Highly expressed in liver, also found in lung, kidney and heart. | Arthralgia | Nuclear receptor | Prostate cancer | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes. {ECO:0000269|PubMed:10195690, ECO:0000269|PubMed:11162439, ECO:0000269|PubMed:11915042, ECO:0000269|PubMed:20215566}. | Retinoic acid receptor RXR-alpha agonist: Acitretin, Alitretinoin, Bexarotene Retinoic acid receptor RXR-alpha other: Etodolac Retinoic acid receptor RXR-alpha other/unknown: Adapalene | 15.11 | |
| dpcRXRB | Retinoic acid receptor RXR-beta | 0 | 165 | 99.34 | ND | 99.90 | 0.60 | ND | 0.4 | Mammalian | Expressed in a variety of tumor cell lines. {ECO:0000269|PubMed:8381386}. | Nuclear receptor | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (By similarity). Specifically binds 9-cis retinoic acid (9C-RA). {ECO:0000250}. | Retinoic acid receptor RXR-beta agonist: Acitretin, Adapalene, Alitretinoin, Bexarotene, Tazarotene, Tretinoin | 15.11 | |||
| dpcSAHH | Adenosylhomocysteinase | 0 | 126 | 88.00 | ND | 99.94 | 0.37 | ND | 0.7 | Mammalian | Enzyme | Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:613752]: A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy. {ECO:0000269|PubMed:15024124, ECO:0000269|PubMed:16736098, ECO:0000269|PubMed:19177456, ECO:0000269|PubMed:20852937}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Adenosylhomocysteine is a competitive inhibitor of S- adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine. {ECO:0000269|PubMed:12590576}. | 15.11 | ||||
| dpcSGK1 | Serine/threonine-protein kinase Sgk1 | 0 | 117 | 84.13 | ND | 90.64 | 0.96 | ND | 0.2 | Mammalian | Expressed in most tissues with highest levels in the pancreas, followed by placenta, kidney and lung. Isoform 2 is strongly expressed in brain and pancreas, weaker in heart, placenta, lung, liver and skeletal muscle. {ECO:0000269|PubMed:10548550, ECO:0000269|PubMed:18753299}. | Kinase | Leukemia, Myeloid
Myelodysplastic Syndrome Solid tumors | Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cellular enzymes, transcription factors, neuronal excitability, cell growth, proliferation, survival, migration and apoptosis. Plays an important role in cellular stress response. Contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Up-regulates Na(+) channels: SCNN1A/ENAC, SCN5A and ASIC1/ACCN2, K(+) channels: KCNJ1/ROMK1, KCNA1-5, KCNQ1-5 and KCNE1, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channels: BSND, CLCN2 and CFTR, glutamate transporters: SLC1A3/EAAT1, SLC1A2 /EAAT2, SLC1A1/EAAT3, SLC1A6/EAAT4 and SLC1A7/EAAT5, amino acid transporters: SLC1A5/ASCT2, SLC38A1/SN1 and SLC6A19, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, glutamate receptor: GRIK2/GLUR6. Up-regulates carriers: SLC9A3/NHE3, SLC12A1/NKCC2, SLC12A3/NCC, SLC5A3/SMIT, SLC2A1/GLUT1, SLC5A1/SGLT1 and SLC15A2/PEPT2. Regulates enzymes: GSK3A/B, PMM2 and Na(+)/K(+) ATPase, and transcription factors: CTNNB1 and nuclear factor NF-kappa-B. Stimulates sodium transport into epithelial cells by enhancing the stability and expression of SCNN1A/ENAC. This is achieved by phosphorylating the NEDD4L ubiquitin E3 ligase, promoting its interaction with 14-3-3 proteins, thereby preventing it from binding to SCNN1A/ENAC and targeting it for degradation. Regulates store-operated Ca(+2) entry (SOCE) by stimulating ORAI1 and STIM1. Regulates KCNJ1/ROMK1 directly via its phosphorylation or indirectly via increased interaction with SLC9A3R2/NHERF2. Phosphorylates MDM2 and activates MDM2-dependent ubiquitination of p53/TP53. Phosphorylates MAPT/TAU and mediates microtubule depolymerization and neurite formation in hippocampal neurons. Phosphorylates SLC2A4/GLUT4 and up-regulates its activity. Phosphorylates APBB1/FE65 and promotes its localization to the nucleus. Phosphorylates MAPK1/ERK2 and activates it by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Phosphorylates FBXW7 and plays an inhibitory role in the NOTCH1 signaling. Phosphorylates FOXO1 resulting in its relocalization from the nucleus to the cytoplasm. Phosphorylates FOXO3, promoting its exit from the nucleus and interference with FOXO3-dependent transcription. Phosphorylates BRAF and MAP3K3/MEKK3 and inhibits their activity. Phosphorylates SLC9A3/NHE3 in response to dexamethasone, resulting in its activation and increased localization at the cell membrane. Phosphorylates CREB1. Necessary for vascular remodeling during angiogenesis. Sustained high levels and activity may contribute to conditions such as hypertension and diabetic nephropathy. Isoform 2 exhibited a greater effect on cell plasma membrane expression of SCNN1A/ENAC and Na(+) transport than isoform 1. {ECO:0000269|PubMed:11154281, ECO:0000269|PubMed:11410590, ECO:0000269|PubMed:11696533, ECO:0000269|PubMed:12397388, ECO:0000269|PubMed:12590200, ECO:0000269|PubMed:12634932, ECO:0000269|PubMed:12650886, ECO:0000269|PubMed:12761204, ECO:0000269|PubMed:12911626, ECO:0000269|PubMed:14623317, ECO:0000269|PubMed:14706641, ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:15044175, ECO:0000269|PubMed:15234985, ECO:0000269|PubMed:15319523, ECO:0000269|PubMed:15496163, ECO:0000269|PubMed:15733869, ECO:0000269|PubMed:15737648, ECO:0000269|PubMed:15845389, ECO:0000269|PubMed:15888551, ECO:0000269|PubMed:16036218, ECO:0000269|PubMed:16443776, ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:17382906, ECO:0000269|PubMed:18005662, ECO:0000269|PubMed:18304449, ECO:0000269|PubMed:18753299, ECO:0000269|PubMed:19447520, ECO:0000269|PubMed:19756449, ECO:0000269|PubMed:20511718, ECO:0000269|PubMed:20730100, ECO:0000269|PubMed:21865597}. | 15.11 | |||
| dpcSHBG | Sex hormone-binding globulin | 0 | 96 | 96.93 | ND | 95.59 | 0.58 | ND | 0.7 | Mammalian | Isoform 1 and isoform 2 are present in liver and testis. | Secreted protein | Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol. Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentration. | Sex hormone-binding globulin : Danazol, Drostanolone, Estradiol, Estropipate, Fluoxymesterone, Hydrocortisone, Methyltestosterone, Mitotane, Oxymetholone, transdermal testosterone gel Sex hormone-binding globulin binder: Spironolactone Sex hormone-binding globulin other/unknown: Testosterone Sex hormone-binding globulin substrate: Norethindrone | 15.11 | |||
| dpcSIR1 | NAD-dependent protein deacetylase sirtuin-1 | 0 | 262 | 81.87 | ND | 95.73 | 0.56 | ND | 0.7 | Mammalian | Widely expressed. {ECO:0000269|PubMed:10381378}. | Eraser | Diabetes Mellitus Type 2
Neurologic Disorders | NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A- mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insulin-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys-542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1- dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transactivation and contributes to its stability. Deacteylates MECOM/EVI1. Deacetylates PML at 'Lys-487' and this deacetylation promotes PML control of PER2 nuclear localization. During the neurogenic transition, repress selective NOTCH1-target genes through histone deacetylation in a BCL6-dependent manner and leading to neuronal differentiation. Regulates the circadian expression of several core clock genes, including ARNTL/BMAL1, RORC, PER2 and CRY1 and plays a critical role in maintaining a controlled rhythmicity in histone acetylation, thereby contributing to circadian chromatin remodeling. Deacetylates ARNTL/BMAL1 and histones at the circadian gene promoters in order to facilitate repression by inhibitory components of the circadian oscillator. Deacetylates PER2, facilitating its ubiquitination and degradation by the proteosome. Protects cardiomyocytes against palmitate-induced apoptosis (PubMed:11672523, PubMed:12006491, PubMed:14976264, PubMed:14980222, PubMed:15126506, PubMed:15152190, PubMed:15205477, PubMed:15469825, PubMed:15692560, PubMed:16079181, PubMed:16166628, PubMed:16892051, PubMed:16998810, PubMed:17283066, PubMed:17334224, PubMed:17505061, PubMed:17612497, PubMed:17620057, PubMed:17936707, PubMed:18203716, PubMed:18296641, PubMed:18662546, PubMed:18687677, PubMed:19188449, PubMed:19220062, PubMed:19364925, PubMed:19690166, PubMed:19934257, PubMed:20097625, PubMed:20100829, PubMed:20203304, PubMed:20375098, PubMed:20620956, PubMed:20670893, PubMed:20817729, PubMed:21149730, PubMed:21245319, PubMed:21471201, PubMed:21504832, PubMed:21555002, PubMed:21698133, PubMed:21701047, PubMed:21775285, PubMed:21807113, PubMed:21841822, PubMed:21890893, PubMed:21909281, PubMed:21947282, PubMed:22274616). Deacetylates XBP1 isoform 2; deacetylation decreases protein stability of XBP1 isoform 2 and inhibits its transcriptional activity (PubMed:20955178). Involved in the CCAR2- mediated regulation of PCK1 and NR1D1 (PubMed:24415752). Deacetylates CTNB1 at 'Lys-49' (PubMed:24824780). In POMC (pro- opiomelanocortin) neurons, required for leptin-induced activation of PI3K signaling (By similarity). {ECO:0000250|UniProtKB:Q923E4, ECO:0000269|PubMed:11672523, ECO:0000269|PubMed:12006491, ECO:0000269|PubMed:14976264, ECO:0000269|PubMed:14980222, ECO:0000269|PubMed:15126506, ECO:0000269|PubMed:15152190, ECO:0000269|PubMed:15205477, ECO:0000269|PubMed:15469825, ECO:0000269|PubMed:15692560, ECO:0000269|PubMed:16079181, ECO:0000269|PubMed:16166628, ECO:0000269|PubMed:16892051, ECO:0000269|PubMed:16998810, ECO:0000269|PubMed:17283066, ECO:0000269|PubMed:17290224, ECO:0000269|PubMed:17334224, ECO:0000269|PubMed:17505061, ECO:0000269|PubMed:17612497, ECO:0000269|PubMed:17620057, ECO:0000269|PubMed:17936707, ECO:0000269|PubMed:18203716, ECO:0000269|PubMed:18296641, ECO:0000269|PubMed:18662546, ECO:0000269|PubMed:18687677, ECO:0000269|PubMed:19188449, ECO:0000269|PubMed:19220062, ECO:0000269|PubMed:19364925, ECO:0000269|PubMed:19690166, ECO:0000269|PubMed:19934257, ECO:0000269|PubMed:20097625, ECO:0000269|PubMed:20100829, ECO:0000269|PubMed:20203304, ECO:0000269|PubMed:20375098, ECO:0000269|PubMed:20620956, ECO:0000269|PubMed:20670893, ECO:0000269|PubMed:20817729, ECO:0000269|PubMed:20955178, ECO:0000269|PubMed:21149730, ECO:0000269|PubMed:21245319, ECO:0000269|PubMed:21471201, ECO:0000269|PubMed:21504832, ECO:0000269|PubMed:21555002, ECO:0000269|PubMed:21698133, ECO:0000269|PubMed:21701047, ECO:0000269|PubMed:21775285, ECO:0000269|PubMed:21807113, ECO:0000269|PubMed:21841822, ECO:0000269|PubMed:21890893, ECO:0000269|PubMed:21909281, ECO:0000269|PubMed:21947282, ECO:0000269|PubMed:22274616, ECO:0000269|PubMed:24415752, ECO:0000269|PubMed:24824780}. Isoform 2: Isoform 2 is shown to deacetylate 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop. {ECO:0000269|PubMed:20975832}. (Microbial infection) In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. The viral Tat protein inhibits SIRT1 deacetylation activity toward RELA/NF- kappa-B p65, thereby potentiates its transcriptional activity and SIRT1 is proposed to contribute to T-cell hyperactivation during infection. {ECO:0000269|PubMed:18329615}. SirtT1 75 kDa fragment: catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly. {ECO:0000269|PubMed:21987377}. | 15.11 | |||
| dpcSIR2 | NAD-dependent protein deacetylase sirtuin-2 | 0 | 269 | 73.09 | ND | 93.51 | 0.35 | ND | 0.8 | Mammalian | Isoform 1 is expressed in heart, liver and skeletal muscle, weakly expressed in the cortex. Isoform 2 is strongly expressed in the cortex, weakly expressed in heart and liver. Weakly expressed in several malignancies including breast, liver, brain, kidney and prostate cancers compared to normal tissues. Weakly expressed in glioma cell lines compared to normal brain tissues (at protein level). Widely expressed. Highly expressed in heart, brain and skeletal muscle, while it is weakly expressed in placenta and lung. Down-regulated in many gliomas suggesting that it may act as a tumor suppressor gene in human gliomas possibly through the regulation of microtubule network. {ECO:0000269|PubMed:10381378, ECO:0000269|PubMed:10393250, ECO:0000269|PubMed:12963026, ECO:0000269|PubMed:16909107, ECO:0000269|PubMed:21791548, ECO:0000269|PubMed:22014574}. | Eraser | NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors. Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes. Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis. Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by SETD8 leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression. Deacetylates SETD8 modulating SETD8 chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys- 57' (H3K56ac) during the mitotic G2/M transition. Upon bacterium Listeria monocytogenes infection, deacetylates 'Lys-18' of histone H3 in a receptor tyrosine kinase MET- and PI3K/Akt-dependent manner, thereby inhibiting transcriptional activity and promoting late stages of listeria infection. During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function. Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1- mediated autophagy. Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation. Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia. Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation. Inhibits transcriptional activation by deacetylating p53/TP53 and EP300. Deacetylates also EIF5A. Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions. Plays a role as tumor suppressor. Isoform 1: Deacetylates EP300, alpha-tubulin and histone H3 and H4. Isoform 2: Deacetylates EP300, alpha-tubulin and histone H3 and H4. Isoform 5: Lacks deacetylation activity. | 15.11 | ||||
| dpcSLK | STE20-like serine/threonine-protein kinase | 0 | 300 | 82.62 | ND | 86.85 | 0.16 | ND | 0.7 | Mammalian | Ubiquitously expressed. Highest expression is found in heart and in skeletal muscle. {ECO:0000269|PubMed:10699464}. | Kinase | Mediates apoptosis and actin stress fiber dissolution. {ECO:0000250}. | 15.11 | ||||
| dpcSMO | Smoothened homolog | 0 | 400 | 87.72 | ND | 97.51 | 0.41 | ND | 0.7 | Mammalian | Frizzled family G protein-coupled receptor | Cancers | G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia. {ECO:0000269|PubMed:19592253}. | Smoothened homolog agonist: Fluocinonide Smoothened homolog antagonist: Sonidegib, Vismodegib | 15.11 | |||
| dpcSPHK1 | Sphingosine kinase 1 | 0 | 132 | 90.90 | ND | 95.93 | 0.67 | ND | 0.5 | Mammalian | Widely expressed with highest levels in adult liver, kidney, heart and skeletal muscle. {ECO:0000269|PubMed:10802064}. | Enzyme | Late-Stage Ovarian cancer
Prostate cancer | Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol. {ECO:0000269|PubMed:20577214, ECO:0000269|PubMed:23602659}. | Sphingosine kinase 1 substrate: Fingolimod | 15.11 | ||
| dpcSRC | Proto-oncogene tyrosine-protein kinase Src | 0 | 2502 | 88.60 | ND | 95.66 | 0.57 | ND | 0.7 | Mammalian | Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues. | Diarrhoea | Kinase | Note=SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells. | Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein- coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin- 43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1. Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors. Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation. Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr- 1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of ADRBK1, leading to beta- arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor. Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus. Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase. Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr- 128'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Required for podosome formation (By similarity). {ECO:0000250|UniProtKB:P05480, ECO:0000269|PubMed:11389730, ECO:0000269|PubMed:12615910, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:16186108, ECO:0000269|PubMed:18586953, ECO:0000269|PubMed:19419966, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20525694, ECO:0000269|PubMed:21309750, ECO:0000269|PubMed:21411625, ECO:0000269|PubMed:22710723, ECO:0000269|PubMed:2498394, ECO:0000269|PubMed:3093483, ECO:0000269|PubMed:7853507, ECO:0000269|PubMed:8755529, ECO:0000269|PubMed:8759729}. | Proto-oncogene tyrosine-protein kinase Src Inhibitor: Nintedanib Proto-oncogene tyrosine-protein kinase Src inhibitor: Bosutinib, Ponatinib Proto-oncogene tyrosine-protein kinase Src multitarget: Dasatinib | 15.11 | |
| dpcSRPK1 | SRSF protein kinase 1 | 0 | 220 | 79.86 | ND | 87.37 | 0.03 | ND | 0.7 | Mammalian | Isoform 2 is predominantly expressed in the testis but is also present at lower levels in heart, ovary, small intestine, liver, kidney, pancreas and skeletal muscle. Isoform 1 is only seen in the testis, at lower levels than isoform 2. Highly expressed in different erythroid and lymphoid cell lines, with isoform 2 being far more abundant than isoform 1. {ECO:0000269|PubMed:10390541, ECO:0000269|PubMed:11509566, ECO:0000269|PubMed:20708644}. | Kinase | Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation. {ECO:0000269|PubMed:10049757, ECO:0000269|PubMed:10390541, ECO:0000269|PubMed:11509566, ECO:0000269|PubMed:12134018, ECO:0000269|PubMed:14555757, ECO:0000269|PubMed:15034300, ECO:0000269|PubMed:16122776, ECO:0000269|PubMed:16209947, ECO:0000269|PubMed:18155240, ECO:0000269|PubMed:18687337, ECO:0000269|PubMed:19240134, ECO:0000269|PubMed:19477182, ECO:0000269|PubMed:19886675, ECO:0000269|PubMed:20708644, ECO:0000269|PubMed:8208298, ECO:0000269|PubMed:9237760}. | 15.11 | ||||
| dpcST14 | Suppressor of tumorigenicity 14 protein | 0 | 145 | 99.12 | ND | 99.97 | 0.42 | ND | 0.6 | Mammalian | Protease | Ichthyosis, congenital, autosomal recessive 11 (ARCI11) [MIM:602400]: A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. {ECO:0000269|PubMed:17273967, ECO:0000269|PubMed:18843291}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Degrades extracellular matrix. Proposed to play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Involved in the terminal differentiation of keratinocytes through prostasin (PRSS8) activation and filaggrin (FLG) processing. {ECO:0000269|PubMed:18843291}. | 15.11 | ||||
| dpcST17B | Serine/threonine-protein kinase 17B | 0 | 67 | 94.05 | ND | 99.46 | 0.67 | ND | 0.7 | Mammalian | Highly expressed in placenta, lung, pancreas. Lower levels in heart, brain, liver, skeletal muscle and kidney. {ECO:0000269|PubMed:9786912}. | Kinase | Phosphorylates myosin light chains (By similarity). Acts as a positive regulator of apoptosis. {ECO:0000250, ECO:0000269|PubMed:9786912}. | 15.11 | ||||
| dpcSTK10 | Serine/threonine-protein kinase 10 | 0 | 66 | 90.48 | ND | 93.50 | 0.16 | ND | 0.6 | Mammalian | Highly expressed in rapidly proliferating tissues (spleen, placenta, and peripheral blood leukocytes). Also expressed in brain, heart, skeletal muscle, colon, thymus, kidney, liver, small intestine and lung. {ECO:0000269|PubMed:12639966}. | Kinase | Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:16175573}. Note=The disease may be caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase involved in regulation of lymphocyte migration. Phosphorylates MSN, and possibly PLK1. Involved in regulation of lymphocyte migration by mediating phosphorylation of ERM proteins such as MSN. Acts as a negative regulator of MAP3K1/MEKK1. May also act as a cell cycle regulator by acting as a polo kinase kinase: mediates phosphorylation of PLK1 in vitro; however such data require additional evidences in vivo. {ECO:0000269|PubMed:11903060, ECO:0000269|PubMed:12639966, ECO:0000269|PubMed:19255442}. | 15.11 | |||
| dpcSTK16 | Serine/threonine-protein kinase 16 | 0 | 68 | 87.59 | ND | 88.35 | 0.28 | ND | 0.6 | Mammalian | Ubiquitously expressed at very low levels. {ECO:0000269|PubMed:10364453}. | Kinase | Membrane-associated protein kinase that phosphorylates on serine and threonine residues. In vitro substrates include DRG1, ENO1 and EIF4EBP1. Also autophosphorylates. May be involved in secretory vesicle trafficking or intracellular signaling. May have a role in regulating stromal-epithelial interactions that occur during ductal morphogenesis in the mammary gland. May be involved in TGF-beta signaling. Able to autophosphorylate on Tyr residue; it is however unclear whether it has tyrosine-protein kinase toward other proteins. {ECO:0000269|PubMed:10364453}. | 15.11 | ||||
| dpcSTK24 | Serine/threonine-protein kinase 24 | 0 | 64 | 98.65 | ND | 99.08 | 0.30 | ND | 0.4 | Mammalian | Isoform A is ubiquitous. Isoform B is expressed in brain with high expression in hippocampus and cerebral cortex. | Kinase | Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress- induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase- independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve. {ECO:0000269|PubMed:16314523, ECO:0000269|PubMed:17046825, ECO:0000269|PubMed:19604147, ECO:0000269|PubMed:19782762, ECO:0000269|PubMed:19855390}. | 15.11 | ||||
| dpcSTK25 | Serine/threonine-protein kinase 25 | 0 | 64 | 70.72 | ND | 83.39 | 0.03 | ND | 0.8 | Mammalian | Ubiquitously expressed. Highest levels are found in testis, large intestine, brain and stomach followed by heart and lung. | Kinase | Oxidant stress-activated serine/threonine kinase that may play a role in the response to environmental stress. Targets to the Golgi apparatus where it appears to regulate protein transport events, cell adhesion, and polarity complexes important for cell migration. {ECO:0000269|PubMed:15037601}. | 15.11 | ||||
| dpcSTK26 | Serine/threonine-protein kinase 26 {ECO:0000305} | 0 | 83 | 80.99 | ND | 89.15 | 0.31 | ND | 1.0 | Mammalian | Kinase | Mediator of cell growth. Modulates apoptosis. {ECO:0000269|PubMed:11641781, ECO:0000269|PubMed:17360971}. | 15.11 | |||||
| dpcSYMC | Methionine--tRNA ligase, cytoplasmic | 0 | 70 | 70.86 | ND | 99.59 | 0.89 | ND | 0.3 | Mammalian | Enzyme | Interstitial lung and liver disease (ILLD) [MIM:615486]: An autosomal recessive, life-threatening disorder characterized by respiratory insufficiency and progressive liver disease with onset in infancy or early childhood. Clinical features include failure to thrive, hypotonia, intermittent lactic acidosis, aminoaciduria, hypothyroidism, interstitial lung disease, pulmonary alveolar proteinosis, anemia, and liver canalicular cholestasis, steatosis, and iron deposition. {ECO:0000269|PubMed:24103465, ECO:0000269|PubMed:25913036}. Note=The disease is caused by mutations affecting the gene represented in this entry. Charcot-Marie-Tooth disease 2U (CMT2U) [MIM:616280]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2U is a slowly progressive, autosomal dominant form characterized by late-adult onset. {ECO:0000269|PubMed:23729695, ECO:0000269|PubMed:24354524}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Methionine--tRNA ligase, cytoplasmic substrate: L-Methionine | 15.11 | ||||
| dpcTAOK2 | Serine/threonine-protein kinase TAO2 | 0 | 60 | 88.10 | ND | 96.58 | 0.06 | ND | 0.9 | Mammalian | Serine/threonine-protein kinase involved in different processes such as membrane blebbing and apoptotic bodies formation DNA damage response and MAPK14/p38 MAPK stress-activated MAPK cascade. Phosphorylates itself, MBP, activated MAPK8, MAP2K3, MAP2K6 and tubulins. Activates the MAPK14/p38 MAPK signaling pathway through the specific activation and phosphorylation of the upstream MAP2K3 and MAP2K6 kinases. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of upstream MAP2K3 and MAP2K6 kinases. May affect microtubule organization and stability. May play a role in the osmotic stress-MAPK8 pathway. Prevents MAP3K7- mediated activation of CHUK, and thus NF-kappa-B activation. Isoform 2, but not isoform 1, is required for PCDH8 endocytosis. Following homophilic interactions between PCDH8 extracellular domains, isoform 2 phosphorylates and activates MAPK14/p38 MAPK which in turn phosphorylates isoform 2. This process leads to PCDH8 endocytosis and CDH2 cointernalization. Both isoforms are involved in MAPK14/p38 MAPK activation. {ECO:0000269|PubMed:10497253, ECO:0000269|PubMed:17988630}. | 15.11 | ||||||
| dpcTBK1 | Serine/threonine-protein kinase TBK1 | 0 | 226 | 86.85 | ND | 90.96 | 0.48 | ND | 0.8 | Mammalian | Ubiquitous with higher expression in testis. Expressed in the ganglion cells, nerve fiber layer and microvasculature of the retina. {ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:21447600}. | Kinase | Glaucoma 1, open angle, P (GLC1P) [MIM:177700]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1P is characterized by early onset, thin central corneas and low intraocular pressure. {ECO:0000269|PubMed:21447600, ECO:0000269|PubMed:22306015}. Note=The disease may be caused by mutations affecting the gene represented in this entry. A copy number variation on chromosome 12q14 consisting of a 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been found in individuals affected by glaucoma. TBK1 is the most likely candidate for the disorder (PubMed:21447600). {ECO:0000269|PubMed:21447600}. Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (FTDALS4) [MIM:616439]: A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. {ECO:0000269|PubMed:25803835, ECO:0000269|PubMed:25943890}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser- 177', thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates and activates AKT1. Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates Borna disease virus (BDV) P protein. {ECO:0000269|PubMed:10581243, ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:11839743, ECO:0000269|PubMed:12692549, ECO:0000269|PubMed:12702806, ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:15485837, ECO:0000269|PubMed:15489227, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:21931631, ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23453972, ECO:0000269|PubMed:23746807}. | 15.11 | |||
| dpcTGFR1 | TGF-beta receptor type-1 | 0 | 642 | 92.48 | ND | 99.20 | 0.67 | ND | 0.5 | Mammalian | Found in all tissues examined, most abundant in placenta and least abundant in brain and heart. Expressed in a variety of cancer cell lines (PubMed:25893292). {ECO:0000269|PubMed:25893292}. | Kinase | Loeys-Dietz syndrome 1 (LDS1) [MIM:609192]: An aortic aneurysm syndrome with widespread systemic involvement, characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. Some patients have craniosynostosis, exotropy, micrognathia and retrognathia, structural brain abnormalities, and intellectual deficit. {ECO:0000269|PubMed:15731757, ECO:0000269|PubMed:16596670, ECO:0000269|PubMed:16791849, ECO:0000269|PubMed:16928994, ECO:0000269|PubMed:19883511, ECO:0000269|PubMed:22113417}. Note=The disease is caused by mutations affecting the gene represented in this entry. TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS1 by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS1 by the OMIM resource. {ECO:0000269|PubMed:16791849}. Multiple self-healing squamous epithelioma (MSSE) [MIM:132800]: A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars. {ECO:0000269|PubMed:21358634}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non- canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation. {ECO:0000269|PubMed:15761148, ECO:0000269|PubMed:16754747, ECO:0000269|PubMed:18758450, ECO:0000269|PubMed:7774578, ECO:0000269|PubMed:8752209, ECO:0000269|PubMed:8980228, ECO:0000269|PubMed:9346908}. | 15.11 | |||
| dpcTGM2 | Protein-glutamine gamma-glutamyltransferase 2 | 0 | 241 | 71.02 | ND | 97.19 | 0.46 | ND | 0.6 | Mammalian | Enzyme | Burns and Burn Infections
Coeliac disease Fibrosis Neurodegenerative diseases Renal fibrosis Scar Tissue | Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. | Protein-glutamine gamma-glutamyltransferase 2 substrate: L-Glutamine | 15.11 | |||
| dpcTHA | Thyroid hormone receptor alpha | 0 | 376 | 83.46 | ND | 95.96 | 0.78 | ND | 0.7 | VirtualToxLab | Mammalian | Nuclear receptor | Hypothyroidism, congenital, non-goitrous, 6 (CHNG6) [MIM:614450]: A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance. {ECO:0000269|PubMed:22168587, ECO:0000269|PubMed:24969835, ECO:0000269|PubMed:25670821, ECO:0000269|PubMed:26037512}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Isoform Alpha-1: Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:19926848}. Isoform Alpha-2: Does not bind thyroid hormone and functions as a weak dominant negative inhibitor of thyroid hormone action. {ECO:0000269|PubMed:8910441}. | Thyroid hormone receptor alpha agonist: Dextrothyroxine, Levothyroxine, Liothyronine, Liotrix | 15.11 | ||
| dpcTHB | Thyroid hormone receptor beta | 0 | 1254 | 76.47 | ND | 89.03 | 0.69 | ND | 0.8 | VirtualToxLab | Mammalian | Nuclear receptor | Generalized thyroid hormone resistance (GTHR) [MIM:188570]: A disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). {ECO:0000269|PubMed:10660344, ECO:0000269|PubMed:1314846, ECO:0000269|PubMed:1324420, ECO:0000269|PubMed:1563081, ECO:0000269|PubMed:1587388, ECO:0000269|PubMed:1619012, ECO:0000269|PubMed:1661299, ECO:0000269|PubMed:16804041, ECO:0000269|PubMed:1846005, ECO:0000269|PubMed:19268523, ECO:0000269|PubMed:2153155, ECO:0000269|PubMed:2510172, ECO:0000269|PubMed:7833659, ECO:0000269|PubMed:8175986, ECO:0000269|PubMed:8514853, ECO:0000269|PubMed:8664910, ECO:0000269|PubMed:8889584}. Note=The disease is caused by mutations affecting the gene represented in this entry. Generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:274300]: An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. {ECO:0000269|PubMed:1653889}. Note=The disease is caused by mutations affecting the gene represented in this entry. Selective pituitary thyroid hormone resistance (PRTH) [MIM:145650]: Variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established. {ECO:0000269|PubMed:7528740, ECO:0000269|PubMed:8381821}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, ECO:0000269|PubMed:16781732, ECO:0000269|PubMed:17418816, ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:18798561, ECO:0000269|PubMed:19926848}. | Thyroid hormone receptor beta agonist: Dextrothyroxine, Levothyroxine, Liothyronine, Liotrix | 15.11 | ||
| dpcTHRB | Prothrombin | 0 | 4674 | 88.23 | ND | 95.71 | 0.61 | ND | 0.9 | Mammalian | Expressed by the liver and secreted in plasma. | Protease | Factor II deficiency (FA2D) [MIM:613679]: A very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels. {ECO:0000269|PubMed:1349838, ECO:0000269|PubMed:1354985, ECO:0000269|PubMed:1421398, ECO:0000269|PubMed:14962227, ECO:0000269|PubMed:2719946, ECO:0000269|PubMed:3242619, ECO:0000269|PubMed:3567158, ECO:0000269|PubMed:3771562, ECO:0000269|PubMed:3801671, ECO:0000269|PubMed:6405779, ECO:0000269|PubMed:7792730, ECO:0000269|PubMed:7865694}. Note=The disease is caused by mutations affecting the gene represented in this entry. Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Thrombophilia due to thrombin defect (THPH1) [MIM:188050]: A multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. {ECO:0000269|PubMed:2825773}. Note=The disease is caused by mutations affecting the gene represented in this entry. A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Pregnancy loss, recurrent, 2 (RPRGL2) [MIM:614390]: A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions. {ECO:0000269|PubMed:11506076}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing. {ECO:0000269|PubMed:2856554}. | Prothrombin : ART-123, Coagulation Factor IX, Drotrecogin alfa Prothrombin activator: Antihemophilic Factor (Recombinant), Menadione Prothrombin inhibitor: Argatroban, Bivalirudin, Dabigatran etexilate, Lepirudin, Suramin, Ximelagatran Prothrombin other/unknown: Proflavine | 15.11 | ||
| dpcTIE2 | Angiopoietin-1 receptor | 0 | 669 | 89.41 | ND | 97.05 | 0.60 | ND | 0.7 | Mammalian | Detected in umbilical vein endothelial cells. Proteolytic processing gives rise to a soluble extracellular domain that is detected in blood plasma (at protein level). Predominantly expressed in endothelial cells and their progenitors, the angioblasts. Has been directly found in placenta and lung, with a lower level in umbilical vein endothelial cells, brain and kidney. {ECO:0000269|PubMed:11806244, ECO:0000269|PubMed:8382358}. | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Mental disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Dominantly inherited venous malformations (VMCM) [MIM:600195]: An error of vascular morphogenesis characterized by dilated, serpiginous channels. {ECO:0000269|PubMed:10369874, ECO:0000269|PubMed:19888299, ECO:0000269|PubMed:8980225}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation. | Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post- natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1. {ECO:0000269|PubMed:12816861, ECO:0000269|PubMed:14665640, ECO:0000269|PubMed:15284220, ECO:0000269|PubMed:15851516, ECO:0000269|PubMed:18366015, ECO:0000269|PubMed:18425119, ECO:0000269|PubMed:18425120, ECO:0000269|PubMed:19223473, ECO:0000269|PubMed:20651738, ECO:0000269|PubMed:9204896}. | Angiopoietin-1 receptor : Ampicillin Angiopoietin-1 receptor inhibitor: Ponatinib, Regorafenib, Vandetanib | 15.11 | |
| dpcTNIK | TRAF2 and NCK-interacting protein kinase | 0 | 78 | 82.58 | ND | 93.58 | 0.63 | ND | 0.4 | Mammalian | Expressed ubiquitously. Highest levels observed in heart, brain and skeletal muscle. Expressed in normal colonic epithelia and colorectal cancer tissues. {ECO:0000269|PubMed:10521462, ECO:0000269|PubMed:19816403}. | Kinase | Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway. Recruited to promoters of Wnt target genes and required to activate their expression. May act by phosphorylating TCF4/TCF7L2. Appears to act upstream of the JUN N-terminal pathway. May play a role in the response to environmental stress. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it may play a role in cytoskeletal rearrangements and regulate cell spreading. Phosphorylates SMAD1 on Thr-322. {ECO:0000269|PubMed:10521462, ECO:0000269|PubMed:15342639, ECO:0000269|PubMed:19061864, ECO:0000269|PubMed:19816403, ECO:0000269|PubMed:20159449, ECO:0000269|PubMed:21690388}. | 15.11 | ||||
| dpcTNKS1 | Tankyrase-1 | 0 | 130 | 82.31 | ND | 94.06 | 0.56 | ND | 0.8 | Mammalian | Ubiquitous; highest levels in testis. | Enzyme | Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1. Stimulates 26S proteasome activity. {ECO:0000269|PubMed:10988299, ECO:0000269|PubMed:11739745, ECO:0000269|PubMed:16076287, ECO:0000269|PubMed:19759537, ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:22864114, ECO:0000269|PubMed:23622245}. | 15.11 | ||||
| dpcTNKS2 | Tankyrase-2 | 0 | 147 | 82.31 | ND | 85.20 | 0.43 | ND | 0.7 | Mammalian | Highly expressed in placenta, skeletal muscle, liver, brain, kidney, heart, thymus, spinal cord, lung, peripheral blood leukocytes, pancreas, lymph nodes, spleen, prostate, testis, ovary, small intestine, colon, mammary gland, breast and breast carcinoma, and in common-type meningioma. Highly expressed in fetal liver, heart and brain. | Enzyme | Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP- ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. Stimulates 26S proteasome activity. {ECO:0000269|PubMed:11739745, ECO:0000269|PubMed:11802774, ECO:0000269|PubMed:19759537, ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:23622245}. | 15.11 | ||||
| dpcTOP2B | DNA topoisomerase 2-beta | 0 | 47 | 86.28 | ND | 99.80 | 0.85 | ND | 0.3 | Mammalian | Alopecia Anaemia Bone marrow failure Haemorrhagic diathesis Mucosal inflammation Stomatitis | Isomerase | Cancer, unspecific | Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. {ECO:0000269|PubMed:10684600}. | DNA topoisomerase 2-beta : Dexrazoxane DNA topoisomerase 2-beta inhibitor: Daunorubicin, Etoposide | 15.11 | ||
| dpcTPA | Tissue-type plasminogen activator | 0 | 401 | 84.99 | ND | 94.78 | 0.60 | ND | 0.4 | Mammalian | Synthesized in numerous tissues (including tumors) and secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, and milk. | Protease | Note=Increased activity of TPA results in increased fibrinolysis of fibrin blood clots that is associated with excessive bleeding. Defective release of TPA results in hypofibrinolysis that can lead to thrombosis or embolism. {ECO:0000269|PubMed:1762144}. | Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. Plays a direct role in facilitating neuronal migration. | Tissue-type plasminogen activator : Urokinase Tissue-type plasminogen activator antagonist: Aminocaproic Acid Tissue-type plasminogen activator negative modulator: Ibuprofen Tissue-type plasminogen activator other/unknown: Iloprost | 15.11 | ||
| dpcTPH1 | Tryptophan 5-hydroxylase 1 | 0 | 47 | 99.99 | ND | 99.96 | 0.30 | ND | 0.3 | Mammalian | Isoform 2 seems to be less widely expressed than isoform 1. | Enzyme | Tryptophan 5-hydroxylase 1 cofactor: Tetrahydrobiopterin Tryptophan 5-hydroxylase 1 substrate: L-Tryptophan | 15.11 | ||||
| dpcTRY1 | Cationic trypsin | 0 | 1445 | 95.28 | ND | 97.82 | 0.59 | ND | 0.7 | Mammalian | Synthesized in the acinar cells of the pancreas. | Protease | 15.11 | |||||
| dpcTRYB1 | Tryptase alpha/beta-1 | 0 | 107 | 92.03 | ND | 99.71 | 0.72 | ND | 0.5 | Mammalian | Isoform 1 and isoform 2 are expressed in lung, stomach, spleen, heart and skin; in these tissues, isoform 1 is predominant. Isoform 2 is expressed in aorta, spleen, and breast tumor, with highest levels in the endothelial cells of some blood vessels surrounding the aorta, as well as those surrounding the tumor and low levels, if any, in mast cells (at protein level). {ECO:0000269|PubMed:18854315}. | Protease | Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type. May play a role in innate immunity. Isoform 2 cleaves large substrates, such as fibronectin, more efficiently than isoform 1, but seems less efficient toward small substrates (PubMed:18854315). {ECO:0000250, ECO:0000250|UniProtKB:P21845, ECO:0000269|PubMed:18854315}. | 15.11 | ||||
| dpcTTHY | Transthyretin | 0 | 78 | 83.91 | ND | 85.15 | 0.15 | ND | 1.9 | Mammalian | Detected in plasma (at protein level). Detected in liver. | Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain. | 15.11 | |||||
| dpcTTK | Dual specificity protein kinase TTK | 0 | 188 | 92.05 | ND | 91.57 | 0.70 | ND | 0.6 | Mammalian | Present in rapidly proliferating cell lines. | Kinase | Cancer, unspecific | Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint. {ECO:0000269|PubMed:18243099}. | 15.11 | |||
| dpcTYK2 | Non-receptor tyrosine-protein kinase TYK2 | 0 | 375 | 92.26 | ND | 94.12 | 0.44 | ND | 0.7 | Mammalian | Observed in all cell lines analyzed. Expressed in a variety of lymphoid and non-lymphoid cell lines. {ECO:0000269|PubMed:2156206}. | Kinase | Immunodeficiency 35 (IMD35) [MIM:611521]: A primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE. {ECO:0000269|PubMed:17088085}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. {ECO:0000269|PubMed:7526154}. | 15.11 | |||
| dpcTYPH | Thymidine phosphorylase | 0 | 143 | 86.20 | ND | 95.70 | 0.70 | ND | 0.5 | Mammalian | Enzyme | Mitochondrial DNA depletion syndrome 1, MNGIE type (MTDPS1) [MIM:603041]: A multisystem disease associated with mitochondrial dysfunction. It is clinically characterized by onset between the second and fifth decades of life, ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), diffuse leukoencephalopathy, cachexia, peripheral neuropathy, and myopathy. {ECO:0000269|PubMed:12177387, ECO:0000269|PubMed:9924029}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro. {ECO:0000269|PubMed:1590793}. Catalyzes the reversible phosphorolysis of thymidine. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis. {ECO:0000269|PubMed:1590793}. | Thymidine phosphorylase inhibitor: Cidofovir Thymidine phosphorylase substrate: Capecitabine, Floxuridine, Fluorouracil, Trifluridine | 15.11 | |||
| dpcTYRO3 | Tyrosine-protein kinase receptor TYRO3 | 0 | 397 | 90.19 | ND | 92.39 | 0.41 | ND | 0.7 | Mammalian | Abundant in the brain and lower levels in other tissues. | Kinase | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:20546121}. (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:25277499, PubMed:22156524, PubMed:22673088). Acts as a receptor for ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:17005688). {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:22156524, ECO:0000269|PubMed:22673088, ECO:0000269|PubMed:25277499}. | 15.11 | ||||
| dpcTYSY | Thymidylate synthase | 0 | 707 | 78.90 | ND | 95.44 | 0.45 | ND | 0.6 | Mammalian | Enzyme | Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. {ECO:0000250}. | 15.11 | |||||
| dpcUPP1 | Uridine phosphorylase 1 | 0 | 46 | 95.28 | ND | 99.23 | 0.68 | ND | 0.5 | Mammalian | Enzyme | Catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1- phosphate (PubMed:7488099). The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis. {ECO:0000269|PubMed:7488099, ECO:0000305}. | Uridine phosphorylase 1 substrate: Fluorouracil | 15.11 | ||||
| dpcUROK | Urokinase-type plasminogen activator | 0 | 823 | 95.81 | ND | 97.41 | 0.66 | ND | 0.6 | Mammalian | Expressed in the prostate gland and prostate cancers. {ECO:0000269|PubMed:15988036}. | Protease | Quebec platelet disorder (QPD) [MIM:601709]: An autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. {ECO:0000269|PubMed:20007542}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. | Urokinase-type plasminogen activator : Urokinase Urokinase-type plasminogen activator inhibitor: Amiloride | 15.11 | ||
| dpcVDR | Vitamin D3 receptor | 0 | 3360 | 75.47 | ND | 84.51 | 0.78 | ND | 0.5 | Mammalian | Nuclear receptor | Rickets vitamin D-dependent 2A (VDDR2A) [MIM:277440]: A disorder of vitamin D metabolism resulting in severe rickets, hypocalcemia and secondary hyperparathyroidism. Most patients have total alopecia in addition to rickets. {ECO:0000269|PubMed:1652893, ECO:0000269|PubMed:2177843, ECO:0000269|PubMed:2849209, ECO:0000269|PubMed:7828346, ECO:0000269|PubMed:8106618, ECO:0000269|PubMed:8381803, ECO:0000269|PubMed:8392085, ECO:0000269|PubMed:8675579, ECO:0000269|PubMed:8961271, ECO:0000269|PubMed:9005998}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Recruited to promoters via its interaction with BAZ1B/WSTF which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis. {ECO:0000269|PubMed:10678179, ECO:0000269|PubMed:15728261, ECO:0000269|PubMed:16252006, ECO:0000269|PubMed:16913708}. | Vitamin D3 receptor agonist: Alfacalcidol, Calcidiol, Cholecalciferol, Dihydrotachysterol, Ergocalciferol, Paricalcitol Vitamin D3 receptor antagonist: Calcipotriol, Calcitriol | 15.11 | |||
| dpcVGFR1 | Vascular endothelial growth factor receptor 1 | 0 | 1048 | 86.89 | ND | 92.26 | 0.44 | ND | 1.0 | Mammalian | Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform 2 is strongly expressed in placenta. Isoform 3 is expressed in corneal epithelial cells (at protein level). Isoform 3 is expressed in vascular smooth muscle cells (VSMC). {ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:20512933}. | Kinase | Note=Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages. Note=Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia. | Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion. {ECO:0000269|PubMed:11141500, ECO:0000269|PubMed:11312102, ECO:0000269|PubMed:11811792, ECO:0000269|PubMed:12796773, ECO:0000269|PubMed:14633857, ECO:0000269|PubMed:15735759, ECO:0000269|PubMed:16685275, ECO:0000269|PubMed:18079407, ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:18583712, ECO:0000269|PubMed:18593464, ECO:0000269|PubMed:20512933, ECO:0000269|PubMed:20551949, ECO:0000269|PubMed:21752276, ECO:0000269|PubMed:7824266, ECO:0000269|PubMed:8248162, ECO:0000269|PubMed:8605350, ECO:0000269|PubMed:9299537}. | Vascular endothelial growth factor receptor 1 Inhibitor: Lenvatinib, Nintedanib Vascular endothelial growth factor receptor 1 antagonist: Sunitinib Vascular endothelial growth factor receptor 1 inhibitor: Axitinib, Pazopanib, Regorafenib, Sorafenib | 15.11 | ||
| dpcVGFR2 | Vascular endothelial growth factor receptor 2 | 0 | 4578 | 84.34 | ND | 95.32 | 0.45 | ND | 0.9 | Mammalian | Detected in cornea (at protein level). Widely expressed. {ECO:0000269|PubMed:19668192}. | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Hemangioma, capillary infantile (HCI) [MIM:602089]: A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. {ECO:0000269|PubMed:11807987, ECO:0000269|PubMed:18931684}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. | Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC. {ECO:0000269|PubMed:10102632, ECO:0000269|PubMed:10368301, ECO:0000269|PubMed:10600473, ECO:0000269|PubMed:11387210, ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:1417831, ECO:0000269|PubMed:15026417, ECO:0000269|PubMed:15215251, ECO:0000269|PubMed:15962004, ECO:0000269|PubMed:16966330, ECO:0000269|PubMed:17303569, ECO:0000269|PubMed:18529047, ECO:0000269|PubMed:19668192, ECO:0000269|PubMed:19834490, ECO:0000269|PubMed:20080685, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20705758, ECO:0000269|PubMed:21893193, ECO:0000269|PubMed:7929439, ECO:0000269|PubMed:9160888, ECO:0000269|PubMed:9804796, ECO:0000269|PubMed:9837777}. | Vascular endothelial growth factor receptor 2 Inhibitor: Lenvatinib, Nintedanib Vascular endothelial growth factor receptor 2 antagonist: Cabozantinib, Ramucirumab, Sorafenib Vascular endothelial growth factor receptor 2 inhibitor: Axitinib, Pazopanib, Ponatinib, Regorafenib Vascular endothelial growth factor receptor 2 multitarget: Sunitinib | 15.11 | |
| dpcWEE1 | Wee1-like protein kinase | 0 | 315 | 97.03 | ND | 96.15 | 0.72 | ND | 0.5 | Mammalian | Kinase | Cancer | Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation. | 15.11 | ||||
| dpcXDH | Xanthine dehydrogenase/oxidase | 0 | 441 | 79.88 | ND | 94.90 | 0.64 | ND | 0.7 | Mammalian | Detected in milk (at protein level). {ECO:0000269|PubMed:11005854, ECO:0000269|PubMed:12421831, ECO:0000269|PubMed:15148401}. | Enzyme | Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. | 15.11 | ||||
| dpcXIAP | E3 ubiquitin-protein ligase XIAP | 0 | 381 | 95.58 | ND | 99.86 | 0.67 | ND | 0.5 | Mammalian | Ubiquitous, except peripheral blood leukocytes. | Other cytosolic protein | Lymphoproliferative syndrome, X-linked, 2 (XLP2) [MIM:300635]: A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma. {ECO:0000269|PubMed:17080092}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta- catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program. {ECO:0000269|PubMed:11447297, ECO:0000269|PubMed:12121969, ECO:0000269|PubMed:14645242, ECO:0000269|PubMed:14685266, ECO:0000269|PubMed:17560374, ECO:0000269|PubMed:17967870, ECO:0000269|PubMed:19473982, ECO:0000269|PubMed:20154138, ECO:0000269|PubMed:21145488, ECO:0000269|PubMed:22103349, ECO:0000269|PubMed:22304967, ECO:0000269|PubMed:9230442}. | 15.11 | |||
| dpcZAP70 | Tyrosine-protein kinase ZAP-70 | 0 | 282 | 82.95 | ND | 99.45 | 0.43 | ND | 0.7 | Mammalian | Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells. {ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:16467082, ECO:0000269|PubMed:9378960}. | Kinase | Selective T-cell defect (STCD) [MIM:269840]: A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T-cells. {ECO:0000269|PubMed:11123350, ECO:0000269|PubMed:11412303, ECO:0000269|PubMed:18509675, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8202713}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). {ECO:0000269|PubMed:11353765, ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:20135127, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8702662, ECO:0000269|PubMed:9489702}. | 15.11 | |||
| kcc1A03 | HLA class I histocompatibility antigen, A-3 alpha chain | 3 | 121 | 100.00 | ND | 99.98 | 0.07 | ND | 0.5 | Mammalian | Surface antigen | Involved in the presentation of foreign antigens to the immune system. | 15.1 | |||||
| kcc2B11 | HLA class II histocompatibility antigen, DRB1-1 beta chain | 1 | 43 | 99.97 | ND | 100.00 | 0.00 | ND | 0.6 | Mammalian | Surface antigen | Sarcoidosis 1 (SS1) [MIM:181000]: An idiopathic, systemic, inflammatory disease characterized by the formation of immune granulomas in involved organs. Granulomas predominantly invade the lungs and the lymphatic system, but also skin, liver, spleen, eyes and other organs may be involved. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading. (Microbial infection) Acts as a receptor for Epstein- Barr virus on lymphocytes. {ECO:0000269|PubMed:11864610, ECO:0000269|PubMed:9151859}. | 15.1 | ||||
| kcc5HT1A | 5-hydroxytryptamine receptor 1A | 148 | 5517 | 95.71 | ND | 97.22 | 0.55 | ND | 0.8 | Nature11159 | Mammalian | Detected in lymph nodes, thymus and spleen. Detected in activated T-cells, but not in resting T-cells. {ECO:0000269|PubMed:3041227, ECO:0000269|PubMed:8393041}. | Asthenia Cardiac failure congestive Dry eye Dry mouth Insomnia Orthostatic hypotension Peripheral coldness Priapism Psychotic disorder Raynaud's phenomenon | Family A G protein-coupled receptor | Periodic fever, menstrual cycle-dependent (PFMC) [MIM:614674]: A condition characterized by recurrent fevers up to 40 degrees Celsius associated with the luteal phase of the menstrual cycle. Women show menstrual cycle-dependent physiologic changes in relation to sex hormone levels. Because ovulation triggers a significant change in the hormonal milieu that is similar to local inflammation, a 0.5 to 1.0 degree Celsius increase in basal body temperature after ovulation is commonly associated with progesterone secretion and is believed to be triggered by the induction of several inflammatory cytokines. {ECO:0000269|PubMed:21990073}. Note=The disease is caused by mutations affecting the gene represented in this entry. | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of 5- hydroxytryptamine release and in the regulation of dopamine and 5- hydroxytryptamine metabolism. Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior. Plays a role in the response to anxiogenic stimuli. {ECO:0000269|PubMed:22957663, ECO:0000269|PubMed:3138543, ECO:0000269|PubMed:8138923, ECO:0000269|PubMed:8393041}. | 5-hydroxytryptamine receptor 1A activator: Imipramine 5-hydroxytryptamine receptor 1A agonist: Apomorphine, Bromocriptine, Cabergoline, Cinitapride, Eletriptan, Ergotamine, Lisuride, Methysergide, Naratriptan, Pergolide, Ropinirole, Rotigotine, Sumatriptan, Vilazodone, Zolmitriptan 5-hydroxytryptamine receptor 1A antagonist: Acepromazine, Alprenolol, Alverine, Amoxapine, Asenapine, Chlorpromazine, Clozapine, Doxepin, Ergoloid mesylate, Iloperidone, Ketamine, Lurasidone, Molindone, Nefazodone, Nortriptyline, Olanzapine, Paliperidone, Penbutolol, Pindolol, Pipotiazine, Quetiapine, Risperidone, Thioproperazine, Trimipramine, Ziprasidone 5-hydroxytryptamine receptor 1A antagonist;partial agonist: Aripiprazole 5-hydroxytryptamine receptor 1A binder: Desipramine, Dopamine, Loxapine 5-hydroxytryptamine receptor 1A blocker: Mianserin 5-hydroxytryptamine receptor 1A inhibitor: Amitriptyline 5-hydroxytryptamine receptor 1A other/unknown: Ondansetron, Propranolol 5-hydroxytryptamine receptor 1A partial agonist: Buspirone, Trazodone, Yohimbine 5-hydroxytryptamine receptor 1A unknown: Bopindolol, Pramipexole | 15.1 |
| kcc5HT1B | 5-hydroxytryptamine receptor 1B | 60 | 1185 | 95.85 | ND | 96.28 | 0.60 | ND | 0.9 | Mammalian | Detected in cerebral artery smooth muscle cells (at protein level). Detected in brain cortex, striatum, amygdala, medulla, hippocampus, caudate nucleus and putamen. {ECO:0000269|PubMed:1348246, ECO:0000269|PubMed:1351684, ECO:0000269|PubMed:15853772}. | Gestational hypertension Orthostatic hypotension Psychotic disorder | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Migraine Obsessive-compulsive disorder Pulmonary hypertension | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances, such as lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior. Besides, plays a role in vasoconstriction of cerebral arteries. {ECO:0000269|PubMed:10452531, ECO:0000269|PubMed:1315531, ECO:0000269|PubMed:1328844, ECO:0000269|PubMed:1348246, ECO:0000269|PubMed:1351684, ECO:0000269|PubMed:1559993, ECO:0000269|PubMed:1565658, ECO:0000269|PubMed:15853772, ECO:0000269|PubMed:1610347, ECO:0000269|PubMed:23519210, ECO:0000269|PubMed:23519215, ECO:0000269|PubMed:8218242}. | 5-hydroxytryptamine receptor 1B agonist: Almotriptan, Apomorphine, Bromocriptine, Cabergoline, Dihydroergotamine, Eletriptan, Ergotamine, Frovatriptan, Lisuride, Naratriptan, Pergolide, Rizatriptan, Ropinirole, Sumatriptan, Zolmitriptan 5-hydroxytryptamine receptor 1B antagonist: Amoxapine, Aripiprazole, Asenapine, Clozapine, Ergoloid mesylate, Ketamine, Olanzapine, Penbutolol, Yohimbine, Ziprasidone 5-hydroxytryptamine receptor 1B binder: Amitriptyline, Loxapine, Methysergide 5-hydroxytryptamine receptor 1B other/unknown: Ondansetron, Pindolol, Propranolol, Quetiapine 5-hydroxytryptamine receptor 1B unknown: Bopindolol, Pramipexole | 15.1 | |
| kcc5HT1D | 5-hydroxytryptamine receptor 1D | 57 | 1093 | 97.79 | ND | 97.96 | 0.77 | ND | 0.7 | Mammalian | Detected in brain neocortex and caudate nucleus (at protein level). {ECO:0000269|PubMed:1828434}. | Dyskinesia Gestational hypertension Orthostatic hypotension Somnolence Tachycardia | Family A G protein-coupled receptor | Migraine
Obsessive-compulsive disorder Vascular headache Vomiting | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Regulates the release of 5-hydroxytryptamine in the brain, and thereby affects neural activity. May also play a role in regulating the release of other neurotransmitters. May play a role in vasoconstriction. {ECO:0000269|PubMed:10452531, ECO:0000269|PubMed:1565658, ECO:0000269|PubMed:1652050}. | 5-hydroxytryptamine receptor 1D agonist: Almotriptan, Apomorphine, Bromocriptine, Cabergoline, Dihydroergotamine, Eletriptan, Ergotamine, Frovatriptan, Lisuride, Naratriptan, Pergolide, Rizatriptan, Ropinirole, Sumatriptan, Zolmitriptan 5-hydroxytryptamine receptor 1D antagonist: Aripiprazole, Clozapine, Ergoloid mesylate, Ketamine, Olanzapine, Paliperidone, Risperidone, Yohimbine, Ziprasidone 5-hydroxytryptamine receptor 1D binder: Amitriptyline, Loxapine, Trimipramine 5-hydroxytryptamine receptor 1D other/unknown: Quetiapine 5-hydroxytryptamine receptor 1D unknown: Pramipexole | 15.1 | |
| kcc5HT1E | 5-hydroxytryptamine receptor 1E | 2 | 100 | 94.87 | ND | 92.51 | 0.11 | ND | 1.1 | Mammalian | Detected in brain. {ECO:0000269|PubMed:14744596}. | Ejaculation disorder Orthostatic hypotension | Family A G protein-coupled receptor | Neurologic and psychiatric diseases | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various alkaloids and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:14744596, ECO:0000269|PubMed:1513320, ECO:0000269|PubMed:1608964, ECO:0000269|PubMed:1733778, ECO:0000269|PubMed:21422162}. | 5-hydroxytryptamine receptor 1E agonist: Eletriptan 5-hydroxytryptamine receptor 1E antagonist: Aripiprazole, Clozapine, Ergoloid mesylate, Ketamine, Olanzapine, Ziprasidone 5-hydroxytryptamine receptor 1E binder: Loxapine, Methysergide 5-hydroxytryptamine receptor 1E other/unknown: Quetiapine | 15.1 | |
| kcc5HT1F | 5-hydroxytryptamine receptor 1F | 4 | 92 | 98.29 | ND | 96.97 | 0.37 | ND | 0.9 | Mammalian | Family A G protein-coupled receptor | Migraine | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various alkaloids and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:21422162, ECO:0000269|PubMed:8380639, ECO:0000269|PubMed:8384716}. | 5-hydroxytryptamine receptor 1F agonist: Eletriptan, Ergotamine, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan 5-hydroxytryptamine receptor 1F antagonist: Ergoloid mesylate, Ketamine 5-hydroxytryptamine receptor 1F binder: Methysergide, Mianserin | 15.1 | |||
| kcc5HT2A | 5-hydroxytryptamine receptor 2A | 158 | 3650 | 94.01 | ND | 95.02 | 0.62 | ND | 0.7 | Nature11159 | Mammalian | Detected in brain cortex (at protein level). Detected in blood platelets. {ECO:0000269|PubMed:18297054}. | Akathisia Anticholinergic syndrome Corneal pigmentation Dermatitis allergic Dry mouth Dystonia Ejaculation disorder Electrocardiogram change Erectile dysfunction Extrapyramidal disorder Fibrocystic breast disease Galactorrhoea Gynaecomastia Hypercholesterolaemia Hyperprolactinaemia Hyperthermia Insomnia Lenticular opacities Lipid metabolism disorder Mania Miosis Mydriasis Nasal congestion Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tachycardia Tardive dyskinesia Weight increased | Family A G protein-coupled receptor | Acute ureteric colic
Anxiety disorder, unspecified Arterial embolism and thrombosis Cocaine dependence Depression Diabetic nephropathy Diabetic neuropathy Essential (primary) hypertension Migraine Schizophrenia | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5- dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores. Affects neural activity, perception, cognition and mood. Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction. {ECO:0000269|PubMed:1330647, ECO:0000269|PubMed:18297054, ECO:0000269|PubMed:18703043, ECO:0000269|PubMed:19057895, ECO:0000269|PubMed:21645528, ECO:0000269|PubMed:22300836}. (Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV. {ECO:0000269|PubMed:24089568}. | 5-hydroxytryptamine receptor 2A agonist: Apomorphine, Bromocriptine, Cabergoline, Cisapride, Ergotamine, Lisuride, Pergolide, Ropinirole, Trimipramine 5-hydroxytryptamine receptor 2A antagonist: Acepromazine, Amisulpride, Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Butriptyline, Chlorpromazine, Chlorprothixene, Cinitapride, Clomipramine, Clozapine, Cyclobenzaprine, Cyproheptadine, Desipramine, Doxepin, Epinastine, Ergoloid mesylate, Flupentixol, Fluspirilene, Iloperidone, Imipramine, Ketamine, Loxapine, Lurasidone, Mesoridazine, Methotrimeprazine, Methysergide, Mianserin, Minaprine, Mirtazapine, Molindone, Nefazodone, Nortriptyline, Olanzapine, Paliperidone, Pipotiazine, Promazine, Promethazine, Propiomazine, Quetiapine, Risperidone, Sertindole, Thioproperazine, Thioridazine, Thiothixene, Trazodone, Yohimbine, Ziprasidone 5-hydroxytryptamine receptor 2A binder: Maprotiline 5-hydroxytryptamine receptor 2A other/unknown: Donepezil, Haloperidol, Paroxetine, Remoxipride 5-hydroxytryptamine receptor 2A unknown: Pramipexole | 15.1 |
| kcc5HT2B | 5-hydroxytryptamine receptor 2B | 63 | 993 | 88.31 | ND | 92.66 | 0.24 | ND | 1.0 | Nature11159 | Mammalian | Ubiquitous. Detected in liver, kidney, heart, pulmonary artery, and intestine. Detected at lower levels in blood, placenta and brain, especially in cerebellum, occipital cortex and frontal cortex. {ECO:0000269|PubMed:21179162, ECO:0000269|PubMed:7926008, ECO:0000269|PubMed:8078486, ECO:0000269|PubMed:8143856, ECO:0000269|PubMed:8882600}. | Dry mouth Dyskinesia Extrapyramidal disorder Insomnia Nasal congestion Orthostatic hypotension | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Migraine P-chloroamphetamine-induced hyperglycemia | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down- stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of dopamine and 5-hydroxytryptamine release, 5-hydroxytryptamine uptake and in the regulation of extracellular dopamine and 5- hydroxytryptamine levels, and thereby affects neural activity. May play a role in the perception of pain. Plays a role in the regulation of behavior, including impulsive behavior. Required for normal proliferation of embryonic cardiac myocytes and normal heart development. Protects cardiomyocytes against apoptosis. Plays a role in the adaptation of pulmonary arteries to chronic hypoxia. Plays a role in vasoconstriction. Required for normal osteoblast function and proliferation, and for maintaining normal bone density. Required for normal proliferation of the interstitial cells of Cajal in the intestine. {ECO:0000269|PubMed:12970106, ECO:0000269|PubMed:18703043, ECO:0000269|PubMed:23519210, ECO:0000269|PubMed:23519215, ECO:0000269|PubMed:7926008, ECO:0000269|PubMed:8078486, ECO:0000269|PubMed:8143856, ECO:0000269|PubMed:8882600}. | 5-hydroxytryptamine receptor 2B agonist: Apomorphine, Bromocriptine, Cabergoline, Dihydroergotamine, Eletriptan, Pergolide, Ropinirole 5-hydroxytryptamine receptor 2B antagonist: Amoxapine, Asenapine, Chlorprothixene, Clomipramine, Doxepin, Ergoloid mesylate, Ketamine, Lisuride, Methysergide, Minaprine, Olanzapine, Triflupromazine, Yohimbine 5-hydroxytryptamine receptor 2B binder: Chlorpromazine, Mianserin, Mirtazapine 5-hydroxytryptamine receptor 2B unknown: Pramipexole | 15.1 |
| kcc5HT2C | 5-hydroxytryptamine receptor 2C | 144 | 2537 | 93.67 | ND | 94.35 | 0.54 | ND | 0.8 | Nature11159 | Mammalian | Detected in brain. {ECO:0000269|PubMed:8812491}. | Akathisia Dermatitis allergic Dry mouth Dystonia Ejaculation disorder Extrapyramidal disorder Galactorrhoea Hypercholesterolaemia Hyperthermia Insomnia Lipid metabolism disorder Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Psychotic disorder Tachycardia Tardive dyskinesia | Family A G protein-coupled receptor | Acute ureteric colic
Cocaine dependence Motor disorder Schizophrenia | G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1- 2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis. {ECO:0000269|PubMed:12970106, ECO:0000269|PubMed:18703043, ECO:0000269|PubMed:19057895, ECO:0000269|PubMed:7895773}. | 5-hydroxytryptamine receptor 2C agonist: Apomorphine, Bromocriptine, Cabergoline, Dexfenfluramine, Ergotamine, Lisuride, Pergolide, Ropinirole, Trazodone 5-hydroxytryptamine receptor 2C antagonist: Agomelatine, Amoxapine, Aripiprazole, Asenapine, Captodiame, Chlorprothixene, Clomipramine, Clozapine, Cyproheptadine, Doxepin, Ergoloid mesylate, Ketamine, Loxapine, Methotrimeprazine, Methysergide, Mianserin, Minaprine, Mirtazapine, Nefazodone, Nortriptyline, Olanzapine, Paliperidone, Promazine, Propiomazine, Quetiapine, Risperidone, Sertindole, Tramadol, Trimipramine, Yohimbine, Ziprasidone 5-hydroxytryptamine receptor 2C antagonist;binder: Imipramine 5-hydroxytryptamine receptor 2C binder: Amitriptyline, Chlorpromazine, Desipramine, Maprotiline 5-hydroxytryptamine receptor 2C unknown: Pramipexole | 15.1 |
| kcc5HT3A | 5-hydroxytryptamine receptor 3A | 22 | 586 | 97.45 | ND | 97.25 | 0.55 | ND | 1.1 | Nature11159 | Mammalian | Expressed in cerebral cortex, amygdala, hippocampus, and testis. Detected in monocytes of the spleen and tonsil, in small and large intestine, uterus, prostate, ovary and placenta. {ECO:0000269|PubMed:10521471}. | Ligand-gated ion channel | Alcohol dependence
Alcoholism Irritable bowel syndrome Nausea and vomiting Pruritus | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel. {ECO:0000269|PubMed:12867984, ECO:0000269|PubMed:9950429}. | 5-hydroxytryptamine receptor 3A agonist: Cisapride, Metoclopramide 5-hydroxytryptamine receptor 3A antagonist: Alosetron, Amoxapine, Aripiprazole, Chloroprocaine, Clozapine, Dolasetron, Ergoloid mesylate, Granisetron, Memantine, Methadone, Mirtazapine, Olanzapine, Ondansetron, Palonosetron, Procaine, Rocuronium, Tubocurarine, Ziprasidone 5-hydroxytryptamine receptor 3A binder: Loxapine, Trimipramine 5-hydroxytryptamine receptor 3A other/unknown: Quetiapine 5-hydroxytryptamine receptor 3A unknown: Ethanol, Tapentadol | 15.1 | |
| kcc5HT4R | 5-hydroxytryptamine receptor 4 | 20 | 647 | 97.83 | ND | 98.41 | 0.58 | ND | 0.8 | Mammalian | Isoform 5-HT4(A) is expressed in ileum, brain, and atrium, but not in the ventricle. {ECO:0000269|PubMed:15118808}. | Family A G protein-coupled receptor | Alzheimer's disease
Cardiac arrhythmias Dementia Diarrhoea-predominant irritable bowel syndrome Drug dependence Irritable bowel syndrome Psychiatric illness | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. | 5-hydroxytryptamine receptor 4 agonist: Cinitapride, Cisapride, Metoclopramide, Ondansetron 5-hydroxytryptamine receptor 4 antagonist: Ergoloid mesylate | 15.1 | ||
| kcc5HT5A | 5-hydroxytryptamine receptor 5A | 8 | 246 | 89.22 | ND | 95.92 | 0.54 | ND | 0.8 | Mammalian | Family A G protein-coupled receptor | Bipolar affective disorder
Depression Schizophrenia | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins. | 5-hydroxytryptamine receptor 5A antagonist: Asenapine, Olanzapine 5-hydroxytryptamine receptor 5A binder: Loxapine | 15.1 | |||
| kcc5HT6R | 5-hydroxytryptamine receptor 6 | 74 | 1922 | 96.43 | ND | 97.40 | 0.67 | ND | 0.7 | Mammalian | Expressed in several human brain regions, most prominently in the caudate nucleus. | Akathisia Dry mouth Dystonia Extrapyramidal disorder Galactorrhoea Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tardive dyskinesia | Family A G protein-coupled receptor | Irritable bowel syndrome
Nausea and vomiting Pruritus in chronic liver disease Schizophrenia | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. It has a high affinity for tricyclic psychotropic drugs (By similarity). Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity (By similarity). Is an activator of TOR signaling (PubMed:23027611). {ECO:0000250|UniProtKB:P31388, ECO:0000250|UniProtKB:Q9R1C8, ECO:0000269|PubMed:23027611}. | 5-hydroxytryptamine receptor 6 antagonist: Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Clozapine, Ergoloid mesylate, Iloperidone, Olanzapine, Sertindole, Ziprasidone 5-hydroxytryptamine receptor 6 binder: Chlorpromazine, Doxepin, Imipramine, Loxapine, Mianserin, Nortriptyline 5-hydroxytryptamine receptor 6 other/unknown: Quetiapine | 15.1 | |
| kcc5HT7R | 5-hydroxytryptamine receptor 7 | 79 | 1311 | 96.55 | ND | 96.32 | 0.63 | ND | 0.7 | Mammalian | Isoform A is the predominant isoform in spleen, caudate and hippocampus. Isoform B is expressed at lower levels. Isoform D is a minor isoform in term of expression. {ECO:0000269|PubMed:9084407}. | Akathisia Dystonia Ejaculation disorder Hyperthermia Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tardive dyskinesia | Family A G protein-coupled receptor | Migraine
Neuropsychiatric disorders | This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase. | 5-hydroxytryptamine receptor 7 agonist: Eletriptan 5-hydroxytryptamine receptor 7 antagonist: Amisulpride, Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Bromocriptine, Cabergoline, Clozapine, Epinastine, Ergoloid mesylate, Iloperidone, Imipramine, Lurasidone, Maprotiline, Methysergide, Mianserin, Olanzapine, Quetiapine, Ziprasidone 5-hydroxytryptamine receptor 7 binder: Chlorpromazine, Dopamine, Loxapine 5-hydroxytryptamine receptor 7 binding: Mirtazapine | 15.1 | |
| kcc5NTD | 5'-nucleotidase | 2 | 44 | 99.96 | ND | 99.43 | 0.03 | ND | 0.7 | Mammalian | Enzyme | Calcification of joints and arteries (CALJA) [MIM:211800]: A condition characterized by adult-onset calcification of the lower extremity arteries, including the iliac, femoral and tibial arteries, and hand and foot capsule joints. Age of onset has been reported as early as the second decade of life, usually involving intense joint pain or calcification in the hands. {ECO:0000269|PubMed:21288095}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Hydrolyzes extracellular nucleotides into membrane permeable nucleosides. Exhibits AMP-, NAD-, and NMN-nucleosidase activities. {ECO:0000269|PubMed:21933152}. | 5'-nucleotidase inhibitor: Pentoxifylline 5'-nucleotidase substrate: Cytarabine | 15.1 | |||
| kccA4 | Amyloid beta A4 protein | 149 | 3532 | 94.98 | ND | 96.81 | 0.66 | ND | 0.7 | Mammalian | Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex- opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra- striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non- neuronal cells. Isoform APP751 is the most abundant form in T- lymphocytes. Appican is expressed in astrocytes. {ECO:0000269|PubMed:12859342, ECO:0000269|PubMed:1406936}. | Membrane receptor | Alzheimer disease 1 (AD1) [MIM:104300]: A familial early- onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. {ECO:0000269|PubMed:10097173, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10665499, ECO:0000269|PubMed:10867787, ECO:0000269|PubMed:11063718, ECO:0000269|PubMed:11528419, ECO:0000269|PubMed:12034808, ECO:0000269|PubMed:1302033, ECO:0000269|PubMed:1303239, ECO:0000269|PubMed:1303275, ECO:0000269|PubMed:1415269, ECO:0000269|PubMed:15201367, ECO:0000269|PubMed:15365148, ECO:0000269|PubMed:15668448, ECO:0000269|PubMed:1671712, ECO:0000269|PubMed:1678058, ECO:0000269|PubMed:1908231, ECO:0000269|PubMed:1925564, ECO:0000269|PubMed:1944558, ECO:0000269|PubMed:8267572, ECO:0000269|PubMed:8290042, ECO:0000269|PubMed:8476439, ECO:0000269|PubMed:8577393, ECO:0000269|PubMed:9328472, ECO:0000269|PubMed:9754958}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cerebral amyloid angiopathy, APP-related (CAA-APP) [MIM:605714]: A hereditary localized amyloidosis due to amyloid- beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque- like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Note=The disease is caused by mutations affecting the gene represented in this entry. | Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER- dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1. {ECO:0000250}. Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Also binds GPC1 in lipid rafts. Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain. {ECO:0000250}. The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis. N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6). | 5'-nucleotidase inhibitor: Pentoxifylline 5'-nucleotidase substrate: Cytarabine | 15.1 | ||
| kccAA1R | Adenosine receptor A1 | 97 | 5613 | 96.18 | ND | 97.11 | 0.61 | ND | 0.6 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Analgesics
Asthma Cardiac arrhythmias Chronic ileitis Inflammation Inflammatory bowel disease Insulin resistance (obesity-related) Noninsulin-dependent diabetes mellitus Pain Renal failure | Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. | Adenosine receptor A1 agonist: Adenosine, Gabapentin Adenosine receptor A1 antagonist: Aminophylline, Dyphylline, Oxtriphylline, Pentoxifylline, Theobromine, Theophylline Adenosine receptor A1 antagonist;multitarget: Caffeine Adenosine receptor A1 unknown: Enprofylline | 15.1 | ||
| kccAA2AR | Adenosine receptor A2a | 95 | 4634 | 96.42 | ND | 97.40 | 0.69 | ND | 0.7 | Nature11159 | Mammalian | Angina pectoris Flushing Palpitations | Family A G protein-coupled receptor | Analgesics
Brain injury Depression Dyskinesia Inflammation Ischemia reperfusion injuries Neurodegenerative diseases Neuropsychiatric disorders Oxygen-induced retinopathy Pain Parkinson's disease Renal diseases | Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. | Adenosine receptor A2a agonist: Adenosine, Regadenoson Adenosine receptor A2a antagonist: Dyphylline, Mefloquine, Oxtriphylline, Pentoxifylline, Theobromine, Theophylline Adenosine receptor A2a antagonist;multitarget: Caffeine Adenosine receptor A2a unknown: Enprofylline | 15.1 | |
| kccAA2BR | Adenosine receptor A2b | 39 | 1915 | 97.51 | ND | 98.32 | 0.75 | ND | 0.6 | Mammalian | Palpitations | Family A G protein-coupled receptor | Asthma | Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. | Adenosine receptor A2b agonist: Adenosine Adenosine receptor A2b antagonist: Enprofylline, Theophylline | 15.1 | ||
| kccAA3R | Adenosine receptor A3 | 66 | 3089 | 96.49 | ND | 95.90 | 0.65 | ND | 0.7 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Cancer, unspecific
Chronic ileitis Depression Inflammatory bowel disease Myocardial ischemia and reperfusion injury | Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. Possible role in reproduction. | Adenosine receptor A3 agonist: Adenosine Adenosine receptor A3 antagonist: Aminophylline Adenosine receptor A3 unknown: Enprofylline | 15.1 | ||
| kccAAPK1 | 5'-AMP-activated protein kinase catalytic subunit alpha-1 | 12 | 307 | 89.01 | ND | 86.31 | 0.09 | ND | 1.5 | Mammalian | Kinase | Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. {ECO:0000269|PubMed:11518699, ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:18439900, ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641}. | 5'-AMP-activated protein kinase catalytic subunit alpha-1 activator: Acetylsalicylic acid, Adenosine monophosphate, Phenformin 5'-AMP-activated protein kinase catalytic subunit alpha-1 unknown: Adenosine triphosphate | 15.1 | ||||
| kccABC3F | DNA dC->dU-editing enzyme APOBEC-3F | 32 | 1249 | 86.64 | ND | 87.01 | 0.02 | ND | 0.9 | Mammalian | Widely expressed. Highly expressed in ovary. {ECO:0000269|PubMed:11863358, ECO:0000269|PubMed:15152192, ECO:0000269|PubMed:20308164}. | Enzyme | DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits antiviral activity against vif-deficient HIV-1. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination- independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double- stranded RNA. Exhibits antiviral activity also against hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV) and may inhibit the mobility of LTR and non-LTR retrotransposons. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation. {ECO:0000269|PubMed:15152192, ECO:0000269|PubMed:16378963, ECO:0000269|PubMed:16527742, ECO:0000269|PubMed:19458006, ECO:0000269|PubMed:20062055, ECO:0000269|PubMed:20219927, ECO:0000269|PubMed:20335265, ECO:0000269|PubMed:21496894, ECO:0000269|PubMed:21835787, ECO:0000269|PubMed:22807680, ECO:0000269|PubMed:22915799, ECO:0000269|PubMed:23097438, ECO:0000269|PubMed:23152537}. | 15.1 | ||||
| kccABC3G | DNA dC->dU-editing enzyme APOBEC-3G | 45 | 1803 | 85.17 | ND | 85.57 | 0.09 | ND | 0.9 | Mammalian | Expressed in spleen, testes, ovary and peripheral blood leukocytes and CD4+ lymphocytes. Also expressed in non-permissive peripheral blood mononuclear cells, and several tumor cell lines; no expression detected in permissive lymphoid and non-lymphoid cell lines. Exists only in the LMM form in peripheral blood-derived resting CD4 T-cells and monocytes, both of which are refractory to HIV-1 infection. LMM is converted to a HMM complex when resting CD4 T-cells are activated or when monocytes are induced to differentiate into macrophages. This change correlates with increased susceptibility of these cells to HIV-1 infection. {ECO:0000269|PubMed:11863358, ECO:0000269|PubMed:12167863, ECO:0000269|PubMed:20308164}. | Enzyme | DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits potent antiviral activity against vif-deficient HIV-1. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination- independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single-or double- stranded RNA. Exhibits antiviral activity also against simian immunodeficiency viruses (SIVs), hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV). May inhibit the mobility of LTR and non-LTR retrotransposons. {ECO:0000269|PubMed:12167863, ECO:0000269|PubMed:12808465, ECO:0000269|PubMed:12808466, ECO:0000269|PubMed:12809610, ECO:0000269|PubMed:12859895, ECO:0000269|PubMed:12970355, ECO:0000269|PubMed:14528300, ECO:0000269|PubMed:14557625, ECO:0000269|PubMed:15031497, ECO:0000269|PubMed:16378963, ECO:0000269|PubMed:16527742, ECO:0000269|PubMed:18288108, ECO:0000269|PubMed:19458006, ECO:0000269|PubMed:20219927, ECO:0000269|PubMed:20335265, ECO:0000269|PubMed:21123384, ECO:0000269|PubMed:21835787, ECO:0000269|PubMed:22791714, ECO:0000269|PubMed:22807680, ECO:0000269|PubMed:22915799, ECO:0000269|PubMed:23097438, ECO:0000269|PubMed:23152537}. | 15.1 | ||||
| kccABCC9 | ATP-binding cassette sub-family C member 9 | 4 | 47 | 99.91 | ND | 99.88 | 0.69 | ND | 0.2 | Mammalian | Primary active transporter | Cardiomyopathy, dilated 1O (CMD1O) [MIM:608569]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:15034580}. Note=The disease is caused by mutations affecting the gene represented in this entry. Atrial fibrillation, familial, 12 (ATFB12) [MIM:614050]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:17245405}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypertrichotic osteochondrodysplasia (HTOCD) [MIM:239850]: A rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The hypertrichosis leads to thick scalp hair, which extends onto the forehead, and a general increase in body hair. In addition, macrocephaly and coarse facial features, including a broad nasal bridge, epicanthal folds, a wide mouth, and full lips, can be suggestive of a storage disorder. About half of affected individuals are macrosomic and edematous at birth, whereas in childhood they usually have a muscular appearance with little subcutaneous fat. Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones have been reported. Cardiac manifestations such as patent ductus arteriosus, ventricular hypertrophy, pulmonary hypertension, and pericardial effusions are present in approximately 80% of cases. Motor development is usually delayed due to hypotonia. Most patients have a mild speech delay, and a small percentage have learning difficulties or intellectual disability. {ECO:0000269|PubMed:22608503, ECO:0000269|PubMed:22610116}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation. {ECO:0000269|PubMed:9831708}. | ATP-binding cassette sub-family C member 9 modulator: Glyburide ATP-binding cassette sub-family C member 9 unknown: Adenosine triphosphate | 15.1 | |||
| kccABCG2 | ATP-binding cassette sub-family G member 2 | 14 | 371 | 96.56 | ND | 96.41 | 0.44 | ND | 0.5 | Mammalian | Highly expressed in placenta. Low expression in small intestine, liver and colon. {ECO:0000269|PubMed:9850061, ECO:0000269|PubMed:9861027}. | Anaemia Thrombocytopenia | Primary active transporter | High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin. {ECO:0000269|PubMed:12958161, ECO:0000269|PubMed:20705604, ECO:0000269|PubMed:22132962, ECO:0000269|PubMed:23189181}. | ATP-binding cassette sub-family G member 2 Antagonist : Zafirlukast ATP-binding cassette sub-family G member 2 inducer: Venlafaxine ATP-binding cassette sub-family G member 2 inhibitor: Buprenorphine, Cabazitaxel, Cyclosporine, Dexamethasone, Diethylstilbestrol, Dronabinol, Erlotinib, Estradiol, Estrone, Hesperetin, Hydrocortisone, Lansoprazole, Nelfinavir, Novobiocin, Omeprazole, Pantoprazole, Rabeprazole, Regorafenib, Rilpivirine, Ritonavir, Saquinavir, Sunitinib, Telmisartan, Vandetanib, Verapamil, Vismodegib ATP-binding cassette sub-family G member 2 substrate: Apixaban, Carboplatin, Cisplatin, Cladribine, Clofarabine, Conjugated Estrogens, Dactinomycin, Daunorubicin, Docetaxel, Etoposide, Ezetimibe, Fluorouracil, Folic Acid, Idelalisib, Irinotecan, Ivermectin, Lamivudine, Leflunomide, Lenvatinib, Methotrexate, Mycophenolate mofetil, Nitrofurantoin, Oxaliplatin, Paclitaxel, Pazopanib, Pitavastatin, Riluzole, Rosuvastatin, SOFOSBUVIR, Sumatriptan, Tamoxifen, Teniposide, Testosterone, Vemurafenib, Vincristine, Zidovudine ATP-binding cassette sub-family G member 2 substrate;inhibitor: Afatinib, Dabrafenib, Dasatinib, Doxorubicin, Gefitinib, Glyburide, Imatinib, Mitoxantrone, Nilotinib, Ponatinib, Pravastatin, Prazosin, Sorafenib, Sulfasalazine, Topotecan | 15.1 | ||
| kccABL1 | Tyrosine-protein kinase ABL1 | 40 | 1065 | 97.56 | ND | 95.44 | 0.45 | ND | 1.0 | Mammalian | Widely expressed. | Kinase | Leukemia, chronic myeloid (CML) [MIM:608232]: A clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph), involving myeloid, erythroid, megakaryocytic, B-lymphoid, and sometimes T-lymphoid cells, but not marrow fibroblasts. Note=The gene represented in this entry is involved in disease pathogenesis. Note=A chromosomal aberration involving ABL1 has been found in patients with chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). | Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage- induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin- associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. {ECO:0000269|PubMed:10391250, ECO:0000269|PubMed:11971963, ECO:0000269|PubMed:12379650, ECO:0000269|PubMed:12531427, ECO:0000269|PubMed:12672821, ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:15556646, ECO:0000269|PubMed:15657060, ECO:0000269|PubMed:15886098, ECO:0000269|PubMed:16424036, ECO:0000269|PubMed:16678104, ECO:0000269|PubMed:16943190, ECO:0000269|PubMed:17306540, ECO:0000269|PubMed:17623672, ECO:0000269|PubMed:18328268, ECO:0000269|PubMed:18945674, ECO:0000269|PubMed:19891780, ECO:0000269|PubMed:20357770, ECO:0000269|PubMed:20417104, ECO:0000269|PubMed:9037071, ECO:0000269|PubMed:9144171, ECO:0000269|PubMed:9461559}. | Tyrosine-protein kinase ABL1 inhibitor: Adenosine triphosphate, Bosutinib, Imatinib, Nilotinib, Ponatinib, Regorafenib Tyrosine-protein kinase ABL1 multitarget: Dasatinib | 15.1 | ||
| kccACACA | Acetyl-CoA carboxylase 1 | 12 | 321 | 99.24 | ND | 98.88 | 0.51 | ND | 0.7 | Mammalian | Expressed in brain, placental, skeletal muscle, renal, pancreatic and adipose tissues; expressed at low level in pulmonary tissue; not detected in the liver. | Enzyme | Acetyl-CoA carboxylase 1 deficiency (ACACAD) [MIM:613933]: An inborn error of de novo fatty acid synthesis associated with severe brain damage, persistent myopathy and poor growth. {ECO:0000269|PubMed:6114432}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the rate-limiting reaction in the biogenesis of long-chain fatty acids. Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. {ECO:0000269|PubMed:20952656}. | Acetyl-CoA carboxylase 1 unknown: Biotin | 15.1 | ||
| kccACACB | Acetyl-CoA carboxylase 2 | 12 | 307 | 99.90 | ND | 99.91 | 0.32 | ND | 0.6 | Mammalian | Widely expressed with highest levels in heart, skeletal muscle, liver, adipose tissue, mammary gland, adrenal gland and colon (PubMed:9099716). Isoform 3 is expressed in skeletal muscle, adipose tissue and liver (at protein level) (PubMed:19190759). Isoform 3 is detected at high levels in adipose tissue with lower levels in heart, liver, skeletal muscle and testis (PubMed:19190759). {ECO:0000269|PubMed:19190759, ECO:0000269|PubMed:9099716}. | Enzyme | Obesity | Catalyzes the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA. Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. Involved in inhibition of fatty acid and glucose oxidation and enhancement of fat storage (By similarity). May play a role in regulation of mitochondrial fatty acid oxidation through malonyl- CoA-dependent inhibition of carnitine palmitoyltransferase 1 (By similarity). {ECO:0000250|UniProtKB:E9Q4Z2, ECO:0000269|PubMed:20952656}. | Acetyl-CoA carboxylase 2 unknown: Adenine, Biotin | 15.1 | ||
| kccACE | Angiotensin-converting enzyme | 40 | 1219 | 98.38 | ND | 98.94 | 0.38 | ND | 0.9 | Mammalian | Ubiquitously expressed, with highest levels in lung, kidney, heart, gastrointestinal system and prostate. Isoform Testis-specific is expressed in spermatocytes and adult testis. {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:12459472, ECO:0000269|PubMed:15671045}. | Angioedema Cough Dysgeusia Palpitations Pancreatitis | Protease | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry. Microvascular complications of diabetes 3 (MVCD3) [MIM:612624]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end- stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Intracerebral hemorrhage (ICH) [MIM:614519]: A pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke. {ECO:0000269|PubMed:15277638}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. | Angiotensin-converting enzyme inhibitor: Benazepril, Candoxatril, Captopril, Cilazapril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Rescinnamine, Spirapril, Trandolapril | 15.1 | |
| kccACE2 | Angiotensin-converting enzyme 2 | 3 | 62 | 99.89 | ND | 99.60 | 0.72 | ND | 0.8 | Mammalian | Expressed in endothelial cells from small and large arteries, and in arterial smooth muscle cells. Expressed in lung alveolar epithelial cells, enterocytes of the small intestine, Leydig cells and Sertoli cells (at protein level). Expressed in heart, kidney, testis, and gastrointestinal system. {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:12459472, ECO:0000269|PubMed:15141377, ECO:0000269|PubMed:15231706, ECO:0000269|PubMed:15671045}. | Protease | Cardiovascular disease, unspecified | Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin- 13 and dynorphin-13 with high efficiency. May be an important regulator of heart function. {ECO:0000269|PubMed:10924499, ECO:0000269|PubMed:10969042, ECO:0000269|PubMed:14647384, ECO:0000269|PubMed:24227843}. (Microbial infection) Acts as a receptor for SARS coronavirus/SARS-CoV and human coronavirus NL63/HCoV-NL63. {ECO:0000269|PubMed:14647384, ECO:0000269|PubMed:15452268, ECO:0000269|PubMed:15791205, ECO:0000269|PubMed:15897467}. | Angiotensin-converting enzyme 2 inhibitor: Lisinopril, Moexipril | 15.1 | ||
| kccACES | Acetylcholinesterase | 130 | 3484 | 93.38 | ND | 96.22 | 0.72 | ND | 0.7 | Mammalian | Isoform H is highly expressed in erythrocytes. {ECO:0000269|PubMed:2714437}. | Diarrhoea Nausea Salivary hypersecretion | Hydrolase | Alzheimer's disease
Cognitive deficits Hypoxic-ischemic encephalopathy Motor neurone disease Parkinson's disease | Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis. {ECO:0000269|PubMed:11985878, ECO:0000269|PubMed:1517212, ECO:0000269|PubMed:1748670, ECO:0000269|PubMed:2714437}. | Acetylcholinesterase activator: Pralidoxime Acetylcholinesterase antagonist: Dimetacrine Acetylcholinesterase antagonist;inhibitor: Pyridostigmine Acetylcholinesterase inhibitor: Ambenonium, Decamethonium, Demecarium, Donepezil, Edrophonium, Galantamine, Gallamine Triethiodide, Isoflurophate, Mefloquine, Minaprine, Neostigmine, Physostigmine, Rivastigmine, Tubocurarine Acetylcholinesterase product of: Choline Acetylcholinesterase unknown: Dipivefrin, Ephedrine | 15.1 | |
| kccACH10 | Neuronal acetylcholine receptor subunit alpha-10 | 1 | 50 | 96.62 | ND | 93.14 | 0.49 | ND | 0.6 | Nature11159 | Mammalian | Expressed in inner-ear tissue, tonsil, immortalized B-cells, cultured T-cells and peripheral blood lymphocytes. {ECO:0000269|PubMed:11752216, ECO:0000269|PubMed:15531379}. | Apnoea Bradycardia Bronchospasm Cardiac arrest Death Hypotension Lung disorder Muscle twitching Respiratory disorder Respiratory failure Salivary hypersecretion | Ligand-gated ion channel | Analgesics
Neuropathic pain | Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane. In the ear, this may lead to a reduction in basilar membrane motion, altering the activity of auditory nerve fibers and reducing the range of dynamic hearing. This may protect against acoustic trauma. {ECO:0000269|PubMed:11752216}. | Neuronal acetylcholine receptor subunit alpha-10 agonist: Nicotine, Succinylcholine Neuronal acetylcholine receptor subunit alpha-10 allosteric modulator: Galantamine Neuronal acetylcholine receptor subunit alpha-10 antagonist: Chloroprocaine, Methadone, Pentolinium, Trimethaphan Neuronal acetylcholine receptor subunit alpha-10 unknown: Ethanol | 15.1 |
| kccACHA3 | Neuronal acetylcholine receptor subunit alpha-3 | 5 | 130 | 92.28 | ND | 93.15 | 0.67 | ND | 0.9 | Mammalian | Ligand-gated ion channel | After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. | Neuronal acetylcholine receptor subunit alpha-3 agonist: Cytisine, Nicotine Neuronal acetylcholine receptor subunit alpha-3 allosteric modulator: Galantamine Neuronal acetylcholine receptor subunit alpha-3 antagonist: Bupropion, Dextromethorphan, Levomethadyl Acetate, Pentolinium Neuronal acetylcholine receptor subunit alpha-3 partial agonist: Varenicline Neuronal acetylcholine receptor subunit alpha-3 unknown: Ethanol | 15.1 | ||||
| kccACHA4 | Neuronal acetylcholine receptor subunit alpha-4 | 21 | 273 | 98.60 | ND | 98.76 | 0.50 | ND | 1.0 | Mammalian | Agitation Apnoea Bradycardia Bronchospasm Death Hypotension Irritability Laryngospasm Lung disorder Nystagmus Respiratory depression Respiratory disorder Respiratory failure Salivary hypersecretion Shock | Ligand-gated ion channel | Epilepsy, nocturnal frontal lobe, 1 (ENFL1) [MIM:600513]: An autosomal dominant focal epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements. {ECO:0000269|PubMed:10563623, ECO:0000269|PubMed:14623738, ECO:0000269|PubMed:7550350}. Note=The disease is caused by mutations affecting the gene represented in this entry. | After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions. {ECO:0000269|PubMed:22361591}. | Neuronal acetylcholine receptor subunit alpha-4 agonist: Cytisine, Nicotine Neuronal acetylcholine receptor subunit alpha-4 allosteric modulator: Galantamine Neuronal acetylcholine receptor subunit alpha-4 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Dextromethorphan, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Talbutal, Thiopental Neuronal acetylcholine receptor subunit alpha-4 partial agonist: Varenicline Neuronal acetylcholine receptor subunit alpha-4 unknown: Ethanol | 15.1 | ||
| kccACHA7 | Neuronal acetylcholine receptor subunit alpha-7 | 75 | 1434 | 95.13 | ND | 97.60 | 0.64 | ND | 0.8 | Mammalian | Agitation Apnoea Bradycardia Bronchospasm Irritability Laryngospasm Nystagmus Respiratory depression Respiratory disorder Salivary hypersecretion Shock | Ligand-gated ion channel | Alzheimer's disease
Analgesics Drug dependence Neuropsychiatric disorders Pain Schizophrenia | After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is blocked by alpha-bungarotoxin. | Neuronal acetylcholine receptor subunit alpha-7 agonist: Cytisine, Nicotine, Varenicline Neuronal acetylcholine receptor subunit alpha-7 allosteric modulator: Galantamine Neuronal acetylcholine receptor subunit alpha-7 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Dextromethorphan, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Talbutal, Thiopental Neuronal acetylcholine receptor subunit alpha-7 unknown: Ethanol | 15.1 | ||
| kccACK1 | Activated CDC42 kinase 1 | 5 | 288 | 96.32 | ND | 95.28 | 0.41 | ND | 1.5 | Mammalian | The Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. It also shows a significant increase in expression in prostate cancers during the progressive stages. {ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20623637}. | Kinase | Non-receptor tyrosine-protein and serine/threonine- protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr- 287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. {ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:11278436, ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:18262180, ECO:0000269|PubMed:18435854, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20383201}. | Activated CDC42 kinase 1 unknown: Adenosine triphosphate | 15.1 | |||
| kccACLY | ATP-citrate synthase | 4 | 72 | 98.89 | ND | 99.89 | 0.48 | ND | 0.6 | Mammalian | Enzyme | Hyperlipidemia
Obesity | ATP citrate-lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine. {ECO:0000269|PubMed:23932781}. | 15.1 | ||||
| kccACM1 | Muscarinic acetylcholine receptor M1 | 88 | 2288 | 91.88 | ND | 94.18 | 0.58 | ND | 0.9 | Nature11159 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Diabetic eye disease Dry mouth Dry skin Dysphagia Dysuria Extrapyramidal disorder Hyperpyrexia Hyperthermia Hyperventilation Hypohidrosis Intraocular pressure increased Mydriasis Neuroleptic malignant syndrome Photophobia Suppressed lactation Tachycardia Urinary retention Vision blurred | Family A G protein-coupled receptor | Alzheimer's disease
Bronchospasm (histamine induced) Cognitive deficits Schizophrenia | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover. | Muscarinic acetylcholine receptor M1 agonist: Carbachol, Cevimeline, Metoclopramide, Minaprine, Pilocarpine, Succinylcholine Muscarinic acetylcholine receptor M1 antagonist: Aclidinium, Amitriptyline, Amoxapine, Anisotropine Methylbromide, Aripiprazole, Atropine, Benzatropine, Biperiden, Brompheniramine, Buclizine, Chlorprothixene, Clidinium, Clozapine, Cocaine, Cyclopentolate, Cycrimine, Cyproheptadine, Darifenacin, Desipramine, Dicyclomine, Diphenidol, Disopyramide, Doxepin, Doxylamine, Escitalopram, Ethopropazine, Fesoterodine, Flavoxate, Flupentixol, Glycopyrrolate, Homatropine Methylbromide, Hyoscyamine, Imipramine, Ipratropium bromide, Maprotiline, Mepenzolate, Methantheline, Methotrimeprazine, Methylscopolamine bromide, Metixene, Nicardipine, Nortriptyline, Olanzapine, Oxybutynin, Oxyphencyclimine, Oxyphenonium, Paroxetine, Pirenzepine, Procyclidine, Promazine, Promethazine, Propantheline, Propiomazine, Quetiapine, Scopolamine, Solifenacin, Tiotropium, Tolterodine, Triflupromazine, Trihexyphenidyl, Tropicamide, Trospium, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M1 binder: Cinnarizine, Citalopram, Ketamine, Loxapine, Pethidine, Trimipramine Muscarinic acetylcholine receptor M1 other/unknown: Molindone Muscarinic acetylcholine receptor M1 unknown: Chlorpromazine | 15.1 | |
| kccACM2 | Muscarinic acetylcholine receptor M2 | 77 | 1670 | 95.41 | ND | 96.16 | 0.69 | ND | 0.8 | Nature11159 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Diabetic eye disease Dry mouth Dry skin Extrapyramidal disorder Gastric hypomotility Hyperpyrexia Intraocular pressure increased Mydriasis Salivary hypersecretion Tachycardia Urinary incontinence Urinary retention Vision blurred | Family A G protein-coupled receptor | Major depressive disorder (MDD) [MIM:608516]: A common psychiatric disorder. It is a complex trait characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is characterized by at least 2 weeks during which there is a new onset or clear worsening of either depressed mood or loss of interest or pleasure in nearly all activities. Four additional symptoms must also be present including changes in appetite, weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. The episode must be accompanied by distress or impairment in social, occupational, or other important areas of functioning. {ECO:0000269|PubMed:15229186}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol. {ECO:0000269|PubMed:24256733, ECO:0000269|PubMed:3443095}. | Muscarinic acetylcholine receptor M2 agonist: Bethanechol, Carbachol, Pilocarpine, Succinylcholine Muscarinic acetylcholine receptor M2 antagonist: Aclidinium, Amitriptyline, Amoxapine, Anisotropine Methylbromide, Aripiprazole, Atropine, Brompheniramine, Chlorprothixene, Clozapine, Cocaine, Cyproheptadine, Darifenacin, Desipramine, Dicyclomine, Dimetindene, Diphenidol, Disopyramide, Doxacurium chloride, Doxepin, Ethopropazine, Fesoterodine, Flavoxate, Gallamine Triethiodide, Homatropine Methylbromide, Hyoscyamine, Imipramine, Ipratropium bromide, Maprotiline, Methotrimeprazine, Methylscopolamine bromide, Metixene, Metocurine, Nicardipine, Nortriptyline, Olanzapine, Oxybutynin, Oxyphencyclimine, Pancuronium, Paroxetine, Pipecuronium, Procyclidine, Promazine, Promethazine, Propiomazine, Quetiapine, Rocuronium, Scopolamine, Solifenacin, Tiotropium, Tolterodine, Triflupromazine, Trihexyphenidyl, Tropicamide, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M2 antagonist;partial agonist: Mivacurium Muscarinic acetylcholine receptor M2 binder: Cinnarizine, Glycopyrrolate, Ketamine, Loxapine, Pethidine, Trimipramine | 15.1 | |
| kccACM3 | Muscarinic acetylcholine receptor M3 | 66 | 1456 | 94.69 | ND | 95.78 | 0.72 | ND | 0.9 | Nature11159 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Diabetic eye disease Dry mouth Dry skin Dysphagia Extrapyramidal disorder Hyperpyrexia Intraocular pressure increased Mydriasis Salivary hypersecretion Tachycardia Urinary retention Vision blurred | Family A G protein-coupled receptor | Prune belly syndrome (PBS) [MIM:100100]: A syndrome characterized by thin abdominal musculature with overlying lax skin, cryptorchism, megacystis with disorganized detrusor muscle, and urinary tract abnormalities. {ECO:0000269|PubMed:22077972}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover. {ECO:0000269|PubMed:7565628}. | Muscarinic acetylcholine receptor M3 agonist: Cevimeline, Methacholine, Pilocarpine, Succinylcholine Muscarinic acetylcholine receptor M3 antagonist: Aclidinium, Amitriptyline, Amoxapine, Anisotropine Methylbromide, Aripiprazole, Atropine, Brompheniramine, Chlorprothixene, Clozapine, Cyproheptadine, Darifenacin, Desipramine, Diphemanil Methylsulfate, Diphenidol, Disopyramide, Doxepin, Fesoterodine, Glycopyrrolate, Homatropine Methylbromide, Hyoscyamine, Imipramine, Ipratropium bromide, Isopropamide, Maprotiline, Mepenzolate, Methotrimeprazine, Methylscopolamine bromide, Metixene, Mivacurium, Nicardipine, Nortriptyline, Olanzapine, Oxybutynin, Oxyphencyclimine, Pancuronium, Paroxetine, Pipecuronium, Procyclidine, Promazine, Promethazine, Propiomazine, Quetiapine, Scopolamine, Solifenacin, Tiotropium, Tolterodine, Tramadol, Trihexyphenidyl, Tropicamide, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M3 binder: Cinnarizine, Ketamine, Loxapine, Pethidine, Trimipramine Muscarinic acetylcholine receptor M3 unknown: Chlorpromazine | 15.1 | |
| kccACM4 | Muscarinic acetylcholine receptor M4 | 28 | 609 | 91.31 | ND | 91.44 | 0.46 | ND | 0.9 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Dry mouth Dysphagia Extrapyramidal disorder Mydriasis Salivary hypersecretion Tachycardia Throat irritation Urinary incontinence Urinary retention Vision blurred | Family A G protein-coupled receptor | Analgesics
Manic disorder Neurologic and psychiatric diseases Pain, unspecified Parkinsonian symptoms | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase. | Muscarinic acetylcholine receptor M4 antagonist: Aclidinium, Amitriptyline, Amoxapine, Aripiprazole, Atropine, Brompheniramine, Chlorprothixene, Clozapine, Darifenacin, Desipramine, Doxepin, Fesoterodine, Homatropine Methylbromide, Hyoscyamine, Imipramine, Isopropamide, Maprotiline, Methotrimeprazine, Metixene, Nicardipine, Nortriptyline, Olanzapine, Paroxetine, Procyclidine, Promazine, Promethazine, Propiomazine, Quetiapine, Scopolamine, Solifenacin, Tolterodine, Trihexyphenidyl, Tropicamide, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M4 binder: Cinnarizine, Ketamine, Loxapine, Pethidine, Trimipramine | 15.1 | ||
| kccACM5 | Muscarinic acetylcholine receptor M5 | 25 | 559 | 91.81 | ND | 90.49 | 0.40 | ND | 0.7 | Mammalian | Anticholinergic syndrome Constipation Cycloplegia Dry mouth Dry skin Extrapyramidal disorder Mydriasis Orthostatic hypotension Tachycardia Urinary incontinence Urinary retention | Family A G protein-coupled receptor | Opioid dependence
Schizophrenia | The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover. | Muscarinic acetylcholine receptor M5 antagonist: Aclidinium, Amitriptyline, Amoxapine, Aripiprazole, Atropine, Brompheniramine, Chlorprothixene, Clozapine, Darifenacin, Desipramine, Doxepin, Fesoterodine, Homatropine Methylbromide, Imipramine, Maprotiline, Methotrimeprazine, Metixene, Nicardipine, Nortriptyline, Olanzapine, Paroxetine, Promazine, Promethazine, Propiomazine, Quetiapine, Scopolamine, Solifenacin, Tolterodine, Trihexyphenidyl, Umeclidinium, Ziprasidone Muscarinic acetylcholine receptor M5 binder: Cinnarizine, Ketamine, Loxapine, Pethidine, Trimipramine | 15.1 | ||
| kccACOD | Acyl-CoA desaturase | 14 | 324 | 98.44 | ND | 97.82 | 0.36 | ND | 0.8 | Mammalian | Detected in fetal liver, lung and brain. Highly expressed in adult adipose tissue, and at lower levels in adult brain and lung. {ECO:0000269|PubMed:15907797}. | Enzyme | Cardiovascular disease, unspecified
Hyperlipidemia Tuberculosis | Stearyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates (PubMed:15907797, PubMed:18765284). Catalyzes the insertion of a cis double bond at the delta-9 position into fatty acyl-CoA substrates including palmitoyl-CoA and stearoyl-CoA (PubMed:15907797, PubMed:18765284). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:15610069). Plays an important role in lipid biosynthesis. Plays an important role in regulating the expression of genes that are involved in lipogenesis and in regulating mitochondrial fatty acid oxidation (By similarity). Plays an important role in body energy homeostasis (By similarity). Contributes to the biosynthesis of membrane phospholipids, cholesterol esters and triglycerides (By similarity). {ECO:0000250|UniProtKB:P13516, ECO:0000269|PubMed:15610069, ECO:0000269|PubMed:15907797, ECO:0000269|PubMed:18765284}. | 15.1 | |||
| kccACOD1 | Acyl-CoA desaturase 1 {ECO:0000305} | 31 | 532 | 99.65 | ND | 98.95 | 0.37 | ND | 0.7 | Mammalian | Detected in liver (at protein level) (PubMed:10899171, PubMed:11533264). Detected in skin and liver (PubMed:10545940, PubMed:11161812, PubMed:11441127, PubMed:11533264). Detected in sebaceous gland, but not in hair follicle (PubMed:10545940). Detected in white and brown adipose tissue, eyelid, Harderian gland, and at lower levels in Meibomian gland, eyeball and adrenal gland (PubMed:11500518, PubMed:11533264). Highly expressed in liver, and detected at low levels in brain, heart, lung, stomach, skeletal muscle and kidney (PubMed:11161812, PubMed:12815040). {ECO:0000269|PubMed:10545940, ECO:0000269|PubMed:10899171, ECO:0000269|PubMed:11441127, ECO:0000269|PubMed:11500518, ECO:0000269|PubMed:11533264, ECO:0000269|PubMed:12815040}. | Enzyme | Note=Defects is Scd1 are the cause of asebia (ab) (PubMed:17738154, PubMed:10545940, PubMed:10854228, PubMed:10899171, PubMed:15278437). The trait is due to spontaneous autosomal recessive mutations that give rise to deletions or point mutations in Scd1. The ab trait has complete penetrance (PubMed:17738154). Ab mice are characterized by reduced body weight, extreme sebaceous gland hypoplasia leading to nearly complete absence of sebaceous glands, and thickened, scaly skin with hyperkeratosis and alopecia (PubMed:17738154, PubMed:10854228, PubMed:15278437). The hair follicles are abnormally long and extend at a sharp angle into the subcutis, probably due to abnormal persistence of inner root sheath. Frequently the hair shaft ruptures through the base of the hair follicle, giving rise to inflammation that results in scarring alopecia (PubMed:10854228, PubMed:15278437). Besides, ab mice display increased transepithelial water loss (PubMed:10854228). Ab mice present a narrow eye fissure and their eyes are nearly closed (PubMed:10854228, PubMed:15278437). Older mice develop blindness (PubMed:17738154). Scd1 activity is almost absent in liver, and is not compensated by expression of another family member (PubMed:10899171). Liver levels of total cholesterol esters are decreased by 87%, while plasma cholesterol levels are increased by 35% (PubMed:10899171). Likewise, skin sterol esters and diol diesters are strongly reduced (PubMed:10854228). Liver triglyceride levels are decreased by 62%, while plasma triglyceride levels are decreased by 67% (PubMed:10899171). The fatty acid composition of liver triglycerides is altered, with a decrease of about 85% in palmitoleate (C16:1) and oleate (C18:1) levels (PubMed:10899171). These defects cannot be compensated by a diet enriched in unsaturated fatty acids (PubMed:10899171, PubMed:11441127). {ECO:0000269|PubMed:10545940, ECO:0000269|PubMed:10854228, ECO:0000269|PubMed:10899171, ECO:0000269|PubMed:11441127, ECO:0000269|PubMed:11533264, ECO:0000269|PubMed:15278437, ECO:0000269|PubMed:17738154}. | Stearyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates. Catalyzes the insertion of a cis double bond at the delta-9 position into fatty acyl-CoA substrates including palmitoyl-CoA and stearoyl-CoA (PubMed:11500518, PubMed:11533264, PubMed:16275639, PubMed:16443825, PubMed:26098370). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:11500518, PubMed:11533264, PubMed:16443825, PubMed:26098370). Plays an important role in lipid biosynthesis (PubMed:17127673, PubMed:10899171, PubMed:11500518, PubMed:11441127, PubMed:11533264, PubMed:12177411, PubMed:26098370). Plays an important role in regulating the expression of genes that are involved in lipogenesis and in regulating mitochondrial fatty acid oxidation (PubMed:12177411, PubMed:17127673, PubMed:24356954, PubMed:24295027). Plays an important role in body energy homeostasis (PubMed:17127673, PubMed:15210843, PubMed:24295027, PubMed:24356954). Contributes to the biosynthesis of membrane phospholipids, cholesterol esters and triglycerides (PubMed:10899171, PubMed:11500518, PubMed:11441127, PubMed:11533264, PubMed:12177411, PubMed:15210843, PubMed:26098370). Required for normal development of sebaceous glands (PubMed:17738154, PubMed:11533264). Required for the biosynthesis of normal levels of delta-9 unsaturated fatty acids and 1-alkyl-2,3-diacylglycerol in the Harderian gland (PubMed:11500518). Required for normal production of meibum, an oily material that prevents drying of the cornea (PubMed:11533264). {ECO:0000269|PubMed:10899171, ECO:0000269|PubMed:11441127, ECO:0000269|PubMed:11500518, ECO:0000269|PubMed:11533264, ECO:0000269|PubMed:12177411, ECO:0000269|PubMed:15210843, ECO:0000269|PubMed:16275639, ECO:0000269|PubMed:16443825, ECO:0000269|PubMed:17127673, ECO:0000269|PubMed:26098370, ECO:0000305|PubMed:24295027, ECO:0000305|PubMed:24356954}. | 15.1 | |||
| kccACOX1 | Peroxisomal acyl-coenzyme A oxidase 1 | 2 | 52 | 99.99 | ND | 99.99 | 0.02 | ND | 0.3 | Mammalian | Widely expressed with highest levels of isoform 1 and isoform 2 detected in testis. Isoform 1 is expressed at higher levels than isoform 2 in liver and kidney while isoform 2 levels are higher in brain, lung, muscle, white adipose tissue and testis. Levels are almost equal in heart. {ECO:0000269|PubMed:17603022, ECO:0000269|PubMed:20195242}. | acyl-CoA oxidase | Adrenoleukodystrophy, pseudoneonatal (Pseudo-NALD) [MIM:264470]: A peroxisomal single-enzyme disorder of fatty acid beta-oxidation, resulting in clinical manifestations that remind neonatal adrenoleukodystrophy. Clinical features include mental retardation, leukodystrophy, seizures, mild hepatomegaly, hearing deficit. Pseudo-NALD is characterized by increased plasma levels of very-long chain fatty acids, due to decreased or absent peroxisome acyl-CoA oxidase activity. Peroxisomes are intact and functioning. {ECO:0000269|PubMed:11815777, ECO:0000269|PubMed:17458872, ECO:0000269|PubMed:8040306}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the desaturation of acyl-CoAs to 2-trans- enoyl-CoAs. Isoform 1 shows highest activity against medium-chain fatty acyl-CoAs and activity decreases with increasing chain length. Isoform 2 is active against a much broader range of substrates and shows activity towards very long-chain acyl-CoAs. Isoform 2 is twice as active as isoform 1 against 16-hydroxy- palmitoyl-CoA and is 25% more active against 1,16-hexadecanodioyl- CoA. {ECO:0000269|PubMed:17458872, ECO:0000269|PubMed:17603022}. | Peroxisomal acyl-coenzyme A oxidase 1 unknown: Flavin adenine dinucleotide | 15.1 | ||
| kccACRO | Acrosin | 5 | 88 | 99.93 | ND | 99.99 | 0.85 | ND | 0.5 | Mammalian | Protease | Acrosin is the major protease of mammalian spermatozoa. It is a serine protease of trypsin-like cleavage specificity, it is synthesized in a zymogen form, proacrosin and stored in the acrosome. | 15.1 | |||||
| kccACV1B | Activin receptor type-1B | 2 | 79 | 96.16 | ND | 90.68 | 0.47 | ND | 0.9 | Mammalian | Expressed in many tissues, most strongly in kidney, pancreas, brain, lung, and liver. | Kinase | Note=ACVRIB is abundantly expressed in systemic sclerosis patient fibroblasts and production of collagen is also induced by activin-A/INHBA. This suggests that the activin/ACRV1B signaling mechanism is involved in systemic sclerosis. | Transmembrane serine/threonine kinase activin type-1 receptor forming an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating a many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, type-2 receptors (ACVR2A and/or ACVR2B) act as a primary activin receptors whereas the type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine- threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor such as ACVR1B. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C- terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor. ACVR1B also phosphorylates TDP2. {ECO:0000269|PubMed:12364468, ECO:0000269|PubMed:12639945, ECO:0000269|PubMed:18039968, ECO:0000269|PubMed:20226172, ECO:0000269|PubMed:8196624, ECO:0000269|PubMed:9032295, ECO:0000269|PubMed:9892009}. | Activin receptor type-1B unknown: Adenosine triphosphate | 15.1 | ||
| kccACVL1 | Serine/threonine-protein kinase receptor R3 | 1 | 76 | 98.42 | ND | 98.95 | 0.40 | ND | 1.0 | Mammalian | Kinase | Telangiectasia, hereditary hemorrhagic, 2 (HHT2) [MIM:600376]: A multisystemic vascular dysplasia leading to dilation of permanent blood vessels and arteriovenous malformations of skin, mucosa, and viscera. The disease is characterized by recurrent epistaxis and gastro-intestinal hemorrhage. Visceral involvement includes arteriovenous malformations of the lung, liver, and brain. {ECO:0000269|PubMed:10694922, ECO:0000269|PubMed:10767348, ECO:0000269|PubMed:11170071, ECO:0000269|PubMed:11484689, ECO:0000269|PubMed:14684682, ECO:0000269|PubMed:15024723, ECO:0000269|PubMed:15712270, ECO:0000269|PubMed:16525724, ECO:0000269|PubMed:16752392, ECO:0000269|PubMed:20414677, ECO:0000269|PubMed:8640225, ECO:0000269|PubMed:9245985}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. May bind activin as well. {ECO:0000269|PubMed:22718755, ECO:0000269|PubMed:22799562}. | Serine/threonine-protein kinase receptor R3 unknown: Adenosine triphosphate | 15.1 | |||
| kccACVR1 | Activin receptor type-1 | 5 | 188 | 93.71 | ND | 94.51 | 0.47 | ND | 1.3 | Mammalian | Expressed in normal parenchymal cells, endothelial cells, fibroblasts and tumor-derived epithelial cells. | Kinase | Fibrodysplasia ossificans progressiva (FOP) [MIM:135100]: A rare autosomal dominant connective tissue disorder resulting in skeletal malformations and progressive extraskeletal ossification. Heterotopic ossification begins in childhood and can be induced by trauma or may occur without warning. Bone formation is episodic and progressive, leading to a debilitating ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible. {ECO:0000269|PubMed:16642017, ECO:0000269|PubMed:19085907, ECO:0000269|PubMed:19330033}. Note=The disease is caused by mutations affecting the gene represented in this entry. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin. May be involved for left-right pattern formation during embryogenesis (By similarity). {ECO:0000250}. | Activin receptor type-1 unknown: Adenosine triphosphate | 15.1 | ||
| kccADA | Adenosine deaminase | 13 | 437 | 98.24 | ND | 98.82 | 0.68 | ND | 0.7 | Mammalian | Found in all tissues, occurs in large amounts in T-lymphocytes and, at the time of weaning, in gastrointestinal tissues. | Hydrolase | Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-negative/NK-cell-negative due to adenosine deaminase deficiency (ADASCID) [MIM:102700]: An autosomal recessive disorder accounting for about 50% of non-X-linked SCIDs. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell- mediated cellular immunity due to a defect in T-cell development. ADA deficiency has been diagnosed in chronically ill teenagers and adults (late or adult onset). Population and newborn screening programs have also identified several healthy individuals with normal immunity who have partial ADA deficiency. {ECO:0000269|PubMed:10200056, ECO:0000269|PubMed:1284479, ECO:0000269|PubMed:2166947, ECO:0000269|PubMed:2783588, ECO:0000269|PubMed:3182793, ECO:0000269|PubMed:3839802, ECO:0000269|PubMed:6208479, ECO:0000269|PubMed:7599635, ECO:0000269|PubMed:8227344, ECO:0000269|PubMed:8299233}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the hydrolytic deamination of adenosine and 2- deoxyadenosine. Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4. Its interaction with DPP4 regulates lymphocyte- epithelial cell adhesion. {ECO:0000269|PubMed:11772392}. | Adenosine deaminase inhibitor: Dipyridamole, Edetic Acid, Pentostatin Adenosine deaminase inhibitor;inducer: Theophylline Adenosine deaminase substrate: Adenosine, Nelarabine, Vidarabine | 15.1 | ||
| kccADA10 | Disintegrin and metalloproteinase domain-containing protein 10 | 6 | 116 | 97.02 | ND | 91.78 | 0.05 | ND | 1.1 | Mammalian | Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver. {ECO:0000269|PubMed:11511685, ECO:0000269|PubMed:9016778}. | Protease | Reticulate acropigmentation of Kitamura (RAK) [MIM:615537]: A rare cutaneous pigmentation disorder characterized by reticulate, slightly depressed, sharply demarcated brown macules without hypopigmentation, affecting the dorsa of the hands and feet and appearing in the first or second decade of life. The macules gradually darken and extend to the proximal regions of the extremities. The manifestations tend to progress until middle age, after which progression of the eruptions stops. The pigmentary augmentation is found on the flexor aspects of the wrists, neck, patella and olecranon. Other features include breaks in the epidermal ridges on the palms and fingers, palmoplantar pits, occasionally plantar keratoderma, and partial alopecia. {ECO:0000269|PubMed:23666529}. Note=The disease is caused by mutations affecting the gene represented in this entry. Alzheimer disease 18 (AD18) [MIM:615590]: A late-onset form of Alzheimer disease, a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. {ECO:0000269|PubMed:19608551}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth- like factor, ephrin-A2 and for constitutive and regulated alpha- secretase cleavage of amyloid precursor protein (APP). Contributes to the normal cleavage of the cellular prion protein. Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity. Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis. Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form. Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B. May regulate the EFNA5-EPHA3 signaling. {ECO:0000269|PubMed:11477090, ECO:0000269|PubMed:11786905, ECO:0000269|PubMed:12475894, ECO:0000269|PubMed:16239146, ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:19114711, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:21288900}. | 15.1 | |||
| kccADA17 | Disintegrin and metalloproteinase domain-containing protein 17 | 34 | 1423 | 99.57 | ND | 99.47 | 0.73 | ND | 0.6 | Mammalian | Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney. | Protease | Inflammatory skin and bowel disease, neonatal, 1 (NISBD1) [MIM:614328]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269|PubMed:22010916}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2. {ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:24226769, ECO:0000269|PubMed:24227843}. | Adenosine deaminase inhibitor: Dipyridamole, Edetic Acid, Pentostatin Adenosine deaminase inhibitor;inducer: Theophylline Adenosine deaminase substrate: Adenosine, Nelarabine, Vidarabine | 15.1 | ||
| kccADA1A | Alpha-1A adrenergic receptor | 90 | 1591 | 97.07 | ND | 97.54 | 0.59 | ND | 0.9 | Nature11159 | Mammalian | Expressed in heart, brain, liver and prostate, but not in kidney, lung, adrenal, aorta and pituitary. Within the prostate, expressed in the apex, base, periurethral and lateral lobe. Isoform 4 is the most abundant isoform expressed in the prostate with high levels also detected in liver and heart. {ECO:0000269|PubMed:7737411, ECO:0000269|PubMed:8196478, ECO:0000269|PubMed:9490024}. | Anxiety Bradycardia Carbohydrate metabolism disorder Cerebral haemorrhage Dyskinesia Dysuria Ejaculation disorder Fear Gangrene Gestational hypertension Hyperhidrosis Hypertension Insomnia Intranasal paraesthesia Irritability Nasal congestion Nasal discomfort Nasal dryness Nervous system disorder Orthostatic hypotension Pallor Palpitations Psychotic disorder Pulmonary oedema Restlessness Sleep disorder Sneezing Sudden death Tachycardia Vasoconstriction Ventricular arrhythmia | Family A G protein-coupled receptor | Benign prostate hyperplasia
Hypertrophic vascular disease | This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes. {ECO:0000269|PubMed:18802028, ECO:0000269|PubMed:22120526}. | Alpha-1A adrenergic receptor agonist: Amphetamine, Apraclonidine, Benzphetamine, Bromocriptine, Clonidine, Dipivefrin, Droxidopa, Epinephrine, Ergonovine, Isometheptene, Levonordefrin, Mephentermine, Metaraminol, Methoxamine, Midodrine, Naphazoline, Nicergoline, Norepinephrine, Oxymetazoline, Pergolide, Phendimetrazine, Phenylpropanolamine, Pseudoephedrine, Xylometazoline Alpha-1A adrenergic receptor antagonist: Acepromazine, Alfuzosin, Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Bevantolol, Carvedilol, Chlorpromazine, Clozapine, Dapiprazole, Desipramine, Doxazosin, Doxepin, Dronedarone, Droperidol, Ergoloid mesylate, Escitalopram, Flupentixol, Iloperidone, Imipramine, Labetalol, Maprotiline, Methotrimeprazine, Mianserin, Nefazodone, Nicardipine, Nortriptyline, Olanzapine, Paliperidone, Phenoxybenzamine, Phentolamine, Prazosin, Promazine, Propiomazine, Quetiapine, Risperidone, Silodosin, Tamsulosin, Terazosin, Thioproperazine, Thioridazine, Tolazoline, Trazodone, Trifluoperazine, Trimipramine, Ziprasidone Alpha-1A adrenergic receptor binder: Cabergoline, Citalopram, Loxapine, Mirtazapine Alpha-1A adrenergic receptor partial agonist: Ergotamine Alpha-1A adrenergic receptor unknown: Dextroamphetamine, Ephedrine, Epinastine, Fenoldopam, Phenylephrine, Promethazine, Sertindole | 15.1 |
| kccADA1B | Alpha-1B adrenergic receptor | 58 | 1151 | 95.99 | ND | 95.72 | 0.68 | ND | 0.7 | Mammalian | Anxiety Bradycardia Cerebral haemorrhage Depressed level of consciousness Dyskinesia Ejaculation disorder Fear Gangrene Gestational hypertension Hyperhidrosis Intranasal paraesthesia Nasal congestion Nasal discomfort Nasal dryness Nervous system disorder Orthostatic hypotension Pallor Palpitations Pulmonary oedema Respiration abnormal Sneezing Tachycardia Vasoconstriction | Family A G protein-coupled receptor | Shy-Drager syndrome | This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine (PE)-stimulated ERK signaling in cardiac myocytes. {ECO:0000269|PubMed:18802028, ECO:0000269|PubMed:22120526}. | Alpha-1B adrenergic receptor agonist: Amphetamine, Bromocriptine, Clonidine, Droxidopa, Epinephrine, Mephentermine, Methoxamine, Midodrine, Norepinephrine, Oxymetazoline, Pergolide, Phendimetrazine, Xylometazoline Alpha-1B adrenergic receptor antagonist: Acepromazine, Alfuzosin, Amitriptyline, Amoxapine, Aripiprazole, Carvedilol, Chlorpromazine, Clozapine, Dapiprazole, Desipramine, Dextroamphetamine, Doxazosin, Doxepin, Dronedarone, Ergoloid mesylate, Imipramine, Labetalol, Lisdexamfetamine, Maprotiline, Methotrimeprazine, Mianserin, Nicardipine, Nortriptyline, Olanzapine, Paliperidone, Phenoxybenzamine, Prazosin, Promazine, Propericiazine, Propiomazine, Quetiapine, Risperidone, Silodosin, Tamsulosin, Terazosin, Thioproperazine, Thioridazine, Trimipramine, Ziprasidone Alpha-1B adrenergic receptor binder: Cabergoline, Loxapine, Mirtazapine Alpha-1B adrenergic receptor other/unknown: Nefazodone Alpha-1B adrenergic receptor partial agonist: Ergotamine, Modafinil Alpha-1B adrenergic receptor unknown: Fenoldopam, Phenylephrine, Sertindole | 15.1 | ||
| kccADA1D | Alpha-1D adrenergic receptor | 53 | 1159 | 95.85 | ND | 95.94 | 0.68 | ND | 0.8 | Mammalian | Anxiety Bradycardia Cerebral haemorrhage Dyskinesia Fear Gestational hypertension Hyperhidrosis Intranasal paraesthesia Nasal congestion Nasal dryness Neurosis Orthostatic hypotension Pallor Palpitations Tachycardia Vasoconstriction | Family A G protein-coupled receptor | Hypertension | This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium. | Alpha-1D adrenergic receptor agonist: Amphetamine, Bromocriptine, Clonidine, Droxidopa, Mephentermine, Midodrine, Norepinephrine, Oxymetazoline, Pergolide, Xylometazoline Alpha-1D adrenergic receptor antagonist: Alfuzosin, Amitriptyline, Amoxapine, Carvedilol, Dapiprazole, Desipramine, Doxazosin, Doxepin, Epinephrine, Ergoloid mesylate, Imipramine, Labetalol, Maprotiline, Methotrimeprazine, Mianserin, Nicardipine, Nortriptyline, Phenoxybenzamine, Prazosin, Promazine, Propiomazine, Quetiapine, Silodosin, Tamsulosin, Terazosin Alpha-1D adrenergic receptor binder: Cabergoline, Methoxamine, Mirtazapine Alpha-1D adrenergic receptor partial agonist: Ergotamine Alpha-1D adrenergic receptor unknown: Chlorpromazine, Dronedarone, Fenoldopam, Phenylephrine, Sertindole | 15.1 | ||
| kccADA2A | Alpha-2A adrenergic receptor | 48 | 818 | 90.80 | ND | 93.03 | 0.56 | ND | 1.0 | Nature11159 | Mammalian | Bradycardia Cerebral haemorrhage Depressed level of consciousness Dyskinesia Ejaculation disorder Fear Gangrene Gestational hypertension Hallucination Intranasal paraesthesia Nasal congestion Nasal discomfort Nasal dryness Nervous system disorder Neurosis Orthostatic hypotension Pallor Palpitations Priapism Respiration abnormal Sneezing Somnolence Urinary incontinence Vasoconstriction | Family A G protein-coupled receptor | Heart failure
Hypertension Ischemic heart disease | Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol. {ECO:0000269|PubMed:23105096}. | Alpha-2A adrenergic receptor agonist: Amphetamine, Apomorphine, Apraclonidine, Benzphetamine, Bethanidine, Brimonidine, Bromocriptine, Clonidine, Dexmedetomidine, Dihydroergotamine, Dipivefrin, Droxidopa, Epinephrine, Guanabenz, Guanfacine, Lofexidine, Mephentermine, Methamphetamine, Naphazoline, Norepinephrine, Oxymetazoline, Pergolide, Phenylpropanolamine, Pseudoephedrine, Ropinirole, Tizanidine, Xylometazoline Alpha-2A adrenergic receptor antagonist: Amitriptyline, Amoxapine, Aripiprazole, Asenapine, Cabergoline, Carvedilol, Clozapine, Doxepin, Ergoloid mesylate, Fenoldopam, Maprotiline, Methotrimeprazine, Mianserin, Mirtazapine, Nefazodone, Nortriptyline, Olanzapine, Paliperidone, Phenoxybenzamine, Phentolamine, Propericiazine, Quetiapine, Risperidone, Tolazoline, Trazodone, Yohimbine, Ziprasidone Alpha-2A adrenergic receptor binder: Desipramine, Loxapine, Prazosin Alpha-2A adrenergic receptor desensitize the target: Trimipramine Alpha-2A adrenergic receptor other/unknown: Lisuride Alpha-2A adrenergic receptor partial agonist: Ergotamine, Pramipexole Alpha-2A adrenergic receptor unknown: Chlorpromazine, Dronedarone, Epinastine, Flupirtine, Lurasidone, Methyldopa | 15.1 | |
| kccADA2B | Alpha-2B adrenergic receptor | 24 | 420 | 89.43 | ND | 88.66 | 0.26 | ND | 1.3 | Nature11159 | Mammalian | Bradycardia Cerebral haemorrhage Depressed level of consciousness Dyskinesia Fear Gestational hypertension Hallucination Intranasal paraesthesia Nasal congestion Nasal dryness Neurosis Orthostatic hypotension Pallor Respiration abnormal Sneezing Urinary incontinence Vasoconstriction | Family A G protein-coupled receptor | Heart failure
Hypertension Ischemic heart disease | Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine > norepinephrine > epinephrine = oxymetazoline > dopamine > p-tyramine = phenylephrine > serotonin > p-synephrine / p-octopamine. For antagonists, the rank order is yohimbine > chlorpromazine > phentolamine > mianserine > spiperone > prazosin > alprenolol > propanolol > pindolol. {ECO:0000269|PubMed:23105096}. | Alpha-2B adrenergic receptor agonist: Amphetamine, Apomorphine, Apraclonidine, Bethanidine, Brimonidine, Bromocriptine, Clonidine, Droxidopa, Epinephrine, Etomidate, Mephentermine, Methamphetamine, Norepinephrine, Pergolide, Ropinirole, Tizanidine, Xylometazoline Alpha-2B adrenergic receptor agonist;partial agonist: Ergotamine Alpha-2B adrenergic receptor antagonist: Amoxapine, Aripiprazole, Asenapine, Cabergoline, Carvedilol, Clozapine, Doxepin, Ergoloid mesylate, Fenoldopam, Maprotiline, Methotrimeprazine, Mianserin, Nortriptyline, Olanzapine, Paliperidone, Phenoxybenzamine, Quetiapine, Rotigotine, Yohimbine, Ziprasidone Alpha-2B adrenergic receptor antagonist;agonist: Risperidone Alpha-2B adrenergic receptor binder: Desipramine, Guanabenz, Guanfacine, Loxapine, Oxymetazoline, Prazosin, Tolazoline Alpha-2B adrenergic receptor other/unknown: Lisuride, Trimipramine Alpha-2B adrenergic receptor unknown: Chlorpromazine, Dronedarone, Pramipexole | 15.1 | |
| kccADA2C | Alpha-2C adrenergic receptor | 22 | 470 | 90.46 | ND | 90.73 | 0.52 | ND | 1.3 | Nature11159 | Mammalian | Bradycardia Cerebral haemorrhage Depressed level of consciousness Dyskinesia Fear Gestational hypertension Hallucination Intranasal paraesthesia Nasal congestion Nasal dryness Neurosis Orthostatic hypotension Pallor Priapism Respiration abnormal Sneezing Somnolence Urinary incontinence Vasoconstriction | Family A G protein-coupled receptor | Neuropsychiatric disorders
Raynaud's syndrome | Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. | Alpha-2C adrenergic receptor agonist: Amphetamine, Apomorphine, Bethanidine, Brimonidine, Bromocriptine, Clonidine, Droxidopa, Epinephrine, Mephentermine, Methamphetamine, Norepinephrine, Oxymetazoline, Paliperidone, Pergolide, Risperidone, Ropinirole, Tizanidine, Xylometazoline Alpha-2C adrenergic receptor antagonist: Amoxapine, Asenapine, Cabergoline, Carvedilol, Clozapine, Doxepin, Ergoloid mesylate, Fenoldopam, Iloperidone, Lurasidone, Maprotiline, Methotrimeprazine, Mianserin, Nortriptyline, Olanzapine, Phenoxybenzamine, Quetiapine, Yohimbine, Ziprasidone Alpha-2C adrenergic receptor antagonist;other/unknown: Aripiprazole Alpha-2C adrenergic receptor binder: Desipramine, Loxapine, Mirtazapine, Tolazoline Alpha-2C adrenergic receptor other/unknown: Lisuride Alpha-2C adrenergic receptor unknown: Chlorpromazine, Dronedarone, Pramipexole | 15.1 | |
| kccADCY1 | Adenylate cyclase type 1 | 1 | 48 | 99.88 | ND | 99.97 | 0.36 | ND | 0.1 | Mammalian | Detected in zona glomerulosa and zona fasciculata in the adrenal gland (at protein level) (PubMed:11549699). Brain, retina and adrenal medulla. {ECO:0000269|PubMed:11549699, ECO:0000269|PubMed:8314585}. | Enzyme | Deafness, autosomal recessive, 44 (DFNB44) [MIM:610154]: A form of non-syndromic deafness characterized by prelingual profound hearing loss affecting all frequencies. {ECO:0000269|PubMed:24482543}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling. Mediates responses to increased cellular Ca(2+)/calmodulin levels (By similarity). May be involved in regulatory processes in the central nervous system. May play a role in memory and learning. Plays a role in the regulation of the circadian rhythm of daytime contrast sensitivity probably by modulating the rhythmic synthesis of cyclic AMP in the retina (By similarity). {ECO:0000250|UniProtKB:O88444, ECO:0000250|UniProtKB:P19754}. | Adenylate cyclase type 1 product of: Adenosine monophosphate Adenylate cyclase type 1 unknown: Adenosine triphosphate | 15.1 | ||
| kccADCY5 | Adenylate cyclase type 5 | 6 | 55 | 99.70 | ND | 99.65 | 0.68 | ND | 0.6 | Mammalian | Detected in pancreas islets (at protein level). Detected in pancreas islets. {ECO:0000269|PubMed:24740569}. | Enzyme | Dyskinesia, familial, with facial myokymia (FDFM) [MIM:606703]: A disorder characterized by predominantly perioral and periorbital myokymia, and face, neck and upper limb dystonic/choreic movements. Initially paroxysmal and worsened by stress, the dyskinetic episodes become nearly constant by the end of the third decade of life, but in some individuals, they may diminish in frequency and severity at older ages. {ECO:0000269|PubMed:22782511, ECO:0000269|PubMed:24700542}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:15385642, PubMed:26206488, PubMed:24700542). Mediates signaling downstream of ADRB1 (PubMed:24700542). Regulates the increase of free cytosolic Ca(2+) in response to increased blood glucose levels and contributes to the regulation of Ca(2+)-dependent insulin secretion (PubMed:24740569). {ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:24700542, ECO:0000269|PubMed:24740569, ECO:0000269|PubMed:26206488}. | Adenylate cyclase type 1 product of: Adenosine monophosphate Adenylate cyclase type 1 unknown: Adenosine triphosphate | 15.1 | ||
| kccADK | Adenosine kinase | 13 | 436 | 99.46 | ND | 98.63 | 0.75 | ND | 0.6 | Mammalian | Widely expressed. Highest level in placenta, liver, muscle and kidney. | Enzyme | Hypermethioninemia due to adenosine kinase deficiency (HMAKD) [MIM:614300]: A metabolic disorder characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S- adenosylmethionine and S-adenosylhomocysteine. Homocysteine levels are typically normal. {ECO:0000269|PubMed:21963049}. Note=The disease is caused by mutations affecting the gene represented in this entry. | ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives. Serves as a potential regulator of concentrations of extracellular adenosine and intracellular adenine nucleotides. | Adenosine kinase activator: Ribavirin Adenosine kinase product of: Adenosine monophosphate Adenosine kinase substrate: Abacavir, Adenosine, Adenosine triphosphate, Ribavirin | 15.1 | ||
| kccADRB1 | Beta-1 adrenergic receptor | 47 | 1352 | 97.81 | ND | 97.41 | 0.55 | ND | 0.8 | Nature11159 | Mammalian | Angina pectoris Anxiety Arrhythmia Asthenia Atrioventricular block Bradycardia Bronchospasm Cardiac failure Cardiac failure congestive Deafness transitory Dry eye Fear Hallucination Lung disorder Metabolic disorder Neurotoxicity Palpitations Peripheral coldness Psychotic disorder Raynaud's phenomenon Sleep disorder | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Asthma Cardiac arrhythmias Cardiovascular disease, unspecified Coronary heart disease Dilated cardiomyopathy Glaucoma Hypertension | Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. Mediates Ras activation through G(s)-alpha- and cAMP-mediated signaling. {ECO:0000269|PubMed:12391161}. | Beta-1 adrenergic receptor agonist: Amphetamine, Arbutamine, Clenbuterol, Dobutamine, Droxidopa, Epinephrine, Fenoterol, Isoetarine, Isoprenaline, Mephentermine, Norepinephrine, Phenylpropanolamine, Pirbuterol, Salbutamol Beta-1 adrenergic receptor agonist;partial agonist: Pseudoephedrine Beta-1 adrenergic receptor antagonist: Alprenolol, Amiodarone, Asenapine, Atenolol, Betaxolol, Bethanidine, Bevantolol, Bisoprolol, Bupranolol, Carvedilol, Esmolol, Labetalol, Levobunolol, Metipranolol, Metoprolol, Nadolol, Nebivolol, Nortriptyline, Oxprenolol, Practolol, Propranolol, Sotalol, Timolol Beta-1 adrenergic receptor antagonist;partial agonist: Penbutolol Beta-1 adrenergic receptor binder: Amitriptyline, Cabergoline, Loxapine, Mirtazapine, Trimipramine Beta-1 adrenergic receptor other: Desipramine Beta-1 adrenergic receptor partial agonist: Acebutolol, Bopindolol, Carteolol, Pindolol Beta-1 adrenergic receptor unknown: Dronedarone, Olanzapine | 15.1 | |
| kccADRB2 | Beta-2 adrenergic receptor | 73 | 1866 | 92.17 | ND | 94.09 | 0.71 | ND | 0.8 | Nature11159 | Mammalian | Angina pectoris Anxiety Arrhythmia Atrioventricular block Bradycardia Bronchospasm Cardiac arrest Cardiac failure Cardiac failure congestive Dry eye Fear Myocardial infarction Neurotoxicity Palpitations Peripheral coldness Raynaud's phenomenon Sleep disorder Tachycardia Tension Tremor Vasodilatation Ventricular arrhythmia | Family A G protein-coupled receptor | Anxiety disorder, unspecified
Asthma Cardiac arrhythmias Chronic obstructive pulmonary disease, unspecified Depression Glaucoma Hypertension Inflammation Multiple sclerosis Obstructive airway disease Respiratory distress syndrome Skeletal muscle wasting Skeletal muscle weakness | Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine. | Beta-2 adrenergic receptor agonist: Amphetamine, Arbutamine, Arformoterol, Bambuterol, Clenbuterol, Dipivefrin, Dobutamine, Droxidopa, Epinephrine, Fenoterol, Formoterol, Indacaterol, Isoetarine, Isoprenaline, Mephentermine, Norepinephrine, Olodaterol, Orciprenaline, Phenylpropanolamine, Pirbuterol, Procaterol, Ritodrine, Salbutamol, Salmeterol, Terbutaline Beta-2 adrenergic receptor antagonist: Alprenolol, Asenapine, Betaxolol, Bethanidine, Bevantolol, Bisoprolol, Bupranolol, Carteolol, Carvedilol, Desipramine, Labetalol, Levobunolol, Metipranolol, Metoprolol, Nadolol, Nebivolol, Nortriptyline, Oxprenolol, Propranolol, Sotalol, Timolol Beta-2 adrenergic receptor antagonist;partial agonist: Penbutolol Beta-2 adrenergic receptor binder: Amitriptyline, Cabergoline, Mirtazapine, Trimipramine Beta-2 adrenergic receptor partial agonist: Acebutolol, Bopindolol, Pindolol, Pseudoephedrine Beta-2 adrenergic receptor unknown: Atenolol, Olanzapine, Phenoxybenzamine | 15.1 | |
| kccADRB3 | Beta-3 adrenergic receptor | 36 | 1193 | 99.23 | ND | 99.60 | 0.57 | ND | 0.7 | Nature11159 | Mammalian | Expressed mainly in adipose tissues. | Angina pectoris Arrhythmia Atrioventricular block Bradycardia Bronchospasm Cardiac failure Cardiac failure congestive Dry eye Hallucination Palpitations Peripheral coldness Psychotic disorder Raynaud's phenomenon Sleep disorder | Family A G protein-coupled receptor | Cardiac arrhythmias
Erectile dysfunction Gain weight in patients with morbid obesity Hypertension Hypertonicity of bladder Noninsulin-dependent diabetes mellitus Obesity Overactive bladder disorder | Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. Beta-3 is involved in the regulation of lipolysis and thermogenesis. | Beta-3 adrenergic receptor agonist: Amphetamine, Arbutamine, Clenbuterol, Droxidopa, Epinephrine, Fenoterol, Isoprenaline, Mephentermine, Mirabegron, Norepinephrine Beta-3 adrenergic receptor antagonist: Bethanidine, Bupranolol, Nortriptyline, Propranolol Beta-3 adrenergic receptor binder: Amitriptyline, Trimipramine Beta-3 adrenergic receptor unknown: Bopindolol, Olanzapine | 15.1 |
| kccAGTR1 | Type-1 angiotensin II receptor | 40 | 1715 | 97.25 | ND | 97.36 | 0.74 | ND | 0.7 | Nature11159 | Mammalian | Liver, lung, adrenal and adrenocortical adenomas. | Dizziness | Family A G protein-coupled receptor | Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. | Type-1 angiotensin II receptor antagonist: Azilsartan medoxomil, Candesartan, Eprosartan, Forasartan, Irbesartan, Losartan, Olmesartan, Saprisartan, Tasosartan, Telmisartan, Valsartan | 15.1 |
| kccAGTR2 | Type-2 angiotensin II receptor | 18 | 727 | 99.67 | ND | 99.80 | 0.63 | ND | 0.9 | Mammalian | In adult, highly expressed in myometrium with lower levels in adrenal gland and fallopian tube. Expressed in the cerebellum. Very highly expressed in fetal kidney and intestine. {ECO:0000269|PubMed:12089445}. | Family A G protein-coupled receptor | Hypertension | Receptor for angiotensin II. Cooperates with MTUS1 to inhibit ERK2 activation and cell proliferation. {ECO:0000269|PubMed:15123706}. | Type-2 angiotensin II receptor antagonist: Tasosartan | 15.1 | ||
| kccAGTRA | Type-1A angiotensin II receptor | 7 | 137 | 99.85 | ND | 99.78 | 0.46 | ND | 1.1 | Mammalian | Family A G protein-coupled receptor | Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. | 15.1 | |||||
| kccAGTRB | Type-1B angiotensin II receptor | 22 | 334 | 99.76 | ND | 99.63 | 0.46 | ND | 0.7 | Mammalian | G-protein coupled receptor 1 | Receptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. | 15.1 | |||||
| kccAHR | Aryl hydrocarbon receptor | 6 | 245 | 91.24 | ND | 87.23 | 0.40 | ND | 1.4 | Mammalian | Expressed in all tissues tested including blood, brain, heart, kidney, liver, lung, pancreas and skeletal muscle. {ECO:0000269|PubMed:7515333, ECO:0000269|PubMed:8246913}. | Transcription factor | Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1. {ECO:0000269|PubMed:10395741, ECO:0000269|PubMed:7961644}. | Aryl hydrocarbon receptor agonist: Atorvastatin, Flutamide, Leflunomide, Mexiletine, Nimodipine | 15.1 | |||
| kccAK1A1 | Alcohol dehydrogenase [NADP(+)] | 1 | 86 | 94.88 | ND | 99.33 | 0.32 | ND | 0.5 | Mammalian | Widely expressed. Highly expressed in kidney, salivary gland and liver. Detected in trachea, stomach, brain, lung, prostate, placenta, mammary gland, small intestine and lung. {ECO:0000269|PubMed:10510318, ECO:0000269|PubMed:11306097}. | Enzyme | Methanol Poisoning | Catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols. Catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol. Has broad substrate specificity. In vitro substrates include succinic semialdehyde, 4- nitrobenzaldehyde, 1,2-naphthoquinone, methylglyoxal, and D- glucuronic acid. Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs, including the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN). {ECO:0000269|PubMed:10510318, ECO:0000269|PubMed:11306097, ECO:0000269|PubMed:18276838}. | Alcohol dehydrogenase [NADP(+)] substrate: Doxorubicin Alcohol dehydrogenase [NADP(+)] unknown: Ethanol | 15.1 | ||
| kccAK1BA | Aldo-keto reductase family 1 member B10 | 4 | 69 | 98.21 | ND | 95.92 | 0.71 | ND | 0.6 | Mammalian | Found in many tissues. Highly expressed in small intestine, colon and adrenal gland. | Enzyme | Acts as all-trans-retinaldehyde reductase. Can efficiently reduce aliphatic and aromatic aldehydes, and is less active on hexoses (in vitro). May be responsible for detoxification of reactive aldehydes in the digested food before the nutrients are passed on to other organs. {ECO:0000269|PubMed:18087047}. | Alcohol dehydrogenase [NADP(+)] substrate: Doxorubicin Alcohol dehydrogenase [NADP(+)] unknown: Ethanol | 15.1 | |||
| kccAK1C1 | Aldo-keto reductase family 1 member C1 | 3 | 162 | 98.65 | ND | 98.29 | 0.64 | ND | 0.8 | Mammalian | Expressed in all tissues tested including liver, prostate, testis, adrenal gland, brain, uterus, mammary gland and keratinocytes. Highest levels found in liver, mammary gland and brain. {ECO:0000269|PubMed:11013348}. | Enzyme | Converts progesterone to its inactive form, 20-alpha- dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine, may have a role in the transport of bile. May have a role in monitoring the intrahepatic bile acid concentration. Has a low bile-binding ability. May play a role in myelin formation. {ECO:0000269|PubMed:11013348, ECO:0000269|PubMed:8573067}. | Aldo-keto reductase family 1 member C1 inhibitor: Acetylsalicylic acid, Salicylic acid | 15.1 | |||
| kccAK1C2 | Aldo-keto reductase family 1 member C2 | 2 | 270 | 98.66 | ND | 99.36 | 0.57 | ND | 0.5 | Mammalian | Expressed in fetal testes. Expressed in fetal and adult adrenal glands. {ECO:0000269|PubMed:21802064}. | Enzyme | 46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. {ECO:0000269|PubMed:21802064}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha- DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability. {ECO:0000269|PubMed:15929998, ECO:0000269|PubMed:17034817, ECO:0000269|PubMed:17442338, ECO:0000269|PubMed:8573067}. | Aldo-keto reductase family 1 member C2 inducer: Ursodeoxycholic acid | 15.1 | ||
| kccAK1C3 | Aldo-keto reductase family 1 member C3 | 11 | 359 | 98.05 | ND | 97.52 | 0.40 | ND | 0.7 | Mammalian | Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. The dominant HSD in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate. {ECO:0000269|PubMed:10557352, ECO:0000269|PubMed:10622721, ECO:0000269|PubMed:11165022, ECO:0000269|PubMed:7650035, ECO:0000269|PubMed:9415401, ECO:0000269|PubMed:9927279}. | Enzyme | Cancer, unspecific
Head and neck cancer | Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta- PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone. | Aldo-keto reductase family 1 member C3 substrate: Doxorubicin Aldo-keto reductase family 1 member C3 unknown: Bimatoprost | 15.1 | ||
| kccAKT1 | RAC-alpha serine/threonine-protein kinase | 59 | 1451 | 95.87 | ND | 94.76 | 0.69 | ND | 0.8 | Mammalian | Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. {ECO:0000269|PubMed:1718748, ECO:0000269|PubMed:17932490, ECO:0000269|PubMed:20333297}. | Kinase | Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:17611497}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The gene represented in this entry may be involved in disease pathogenesis. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Proteus syndrome (PROTEUSS) [MIM:176920]: A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes. {ECO:0000269|PubMed:21793738}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cowden syndrome 6 (CWS6) [MIM:615109]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. Note=The disease is caused by mutations affecting the gene represented in this entry. | AKT1 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)- response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr- 117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro- apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53. AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation. | RAC-alpha serine/threonine-protein kinase inducer: Arsenic trioxide RAC-alpha serine/threonine-protein kinase unknown: Adenosine triphosphate | 15.1 | ||
| kccAKT2 | RAC-beta serine/threonine-protein kinase | 28 | 546 | 96.36 | ND | 93.68 | 0.56 | ND | 0.8 | Mammalian | Expressed in all cell types so far analyzed. | Kinase | Note=Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, plays also a pivotal role in the biology of glioblastoma. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15166380, ECO:0000269|PubMed:19164855}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH) [MIM:240900]: A disorder characterized by hypoglycemia, low insulin levels, low serum levels of ketone bodies and branched-chain amino acids, left-sided hemihypertrophy, neonatal macrosomia, reduced consciousness and hypoglycemic seizures. {ECO:0000269|PubMed:21979934}. Note=The disease is caused by mutations affecting the gene represented in this entry. | AKT2 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)- response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'. | RAC-alpha serine/threonine-protein kinase inducer: Arsenic trioxide RAC-alpha serine/threonine-protein kinase unknown: Adenosine triphosphate | 15.1 | ||
| kccAKT3 | RAC-gamma serine/threonine-protein kinase | 16 | 368 | 95.86 | ND | 90.14 | 0.56 | ND | 1.1 | Mammalian | In adult tissues, it is highly expressed in brain, lung and kidney, but weakly in heart, testis and liver. In fetal tissues, it is highly expressed in heart, liver and brain and not at all in kidney. | Kinase | Note=AKT3 is a key modulator of several tumors like melanoma, glioma and ovarian cancer. Active AKT3 increases progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Promotes melanoma tumorigenesis by decreasing apoptosis. Plays a key role in the genesis of ovarian cancers through modulation of G2/M phase transition. With AKT2, plays a pivotal role in the biology of glioblastoma. Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MPPH2) [MIM:615937]: A syndrome characterized by megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome. {ECO:0000269|PubMed:22500628, ECO:0000269|PubMed:22729223, ECO:0000269|PubMed:22729224}. Note=The disease is caused by mutations affecting the gene represented in this entry. | AKT3 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase- dependent apoptosis. {ECO:0000269|PubMed:18524868, ECO:0000269|PubMed:21191416}. | 15.1 | |||
| kccAL5AP | Arachidonate 5-lipoxygenase-activating protein | 4 | 225 | 99.13 | ND | 99.02 | 0.64 | ND | 0.7 | Mammalian | Other cytosolic protein | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Genetic variations in ALOX5AP may be associated with susceptibility to myocardial infarction. Involvement in myocardial infarction is however unclear: according to some authors (PubMed:14770184), a 4-SNP haplotype in ALOX5AP confers risk of myocardial infarction, while according to other (PubMed:17304054) ALOX5AP is not implicated in this condition. {ECO:0000269|PubMed:14770184, ECO:0000269|PubMed:17304054}. | Required for leukotriene biosynthesis by ALOX5 (5- lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, and could play an essential role in the transfer of arachidonic acid to ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of leukotrienes. {ECO:0000269|PubMed:2300173, ECO:0000269|PubMed:8440384}. | 15.1 | ||||
| kccALDH2 | Aldehyde dehydrogenase, mitochondrial | 2 | 60 | 99.56 | ND | 99.89 | 0.05 | ND | 1.1 | Mammalian | Oxidoreductase | Alcoholism | Aldehyde dehydrogenase, mitochondrial inhibitor: Disulfiram, Nitric Oxide Aldehyde dehydrogenase, mitochondrial substrate: Amyl Nitrite, Benzyl alcohol, Nitroglycerin Aldehyde dehydrogenase, mitochondrial unknown: Guanidine | 15.1 | ||||
| kccALDR | Aldose reductase | 57 | 1393 | 97.53 | ND | 97.80 | 0.62 | ND | 0.7 | Mammalian | Highly expressed in embryonic epithelial cells (EUE) in response to osmotic stress. {ECO:0000269|PubMed:8435445}. | Gastrointestinal disorder | Enzyme | Analgesics
Diabetic complications Diabetic neuropathy Diabetic retinopathy Neuropathic pain Noninsulin-dependent diabetes mellitus | Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies. | Aldose reductase inhibitor: Sulindac | 15.1 | |
| kccALK | ALK tyrosine kinase receptor | 34 | 751 | 94.50 | ND | 90.75 | 0.61 | ND | 1.1 | Mammalian | Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells. {ECO:0000269|PubMed:9174053}. | Kinase | Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. {ECO:0000269|PubMed:18724359, ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth. | Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK. {ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:11387242, ECO:0000269|PubMed:11809760, ECO:0000269|PubMed:12107166, ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:15908427, ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988}. | ALK tyrosine kinase receptor antagonist: Ceritinib ALK tyrosine kinase receptor inhibitor: Crizotinib ALK tyrosine kinase receptor unknown: Adenosine triphosphate | 15.1 | ||
| kccALKB3 | Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 | 1 | 41 | 99.95 | ND | 99.96 | 0.00 | ND | 0.8 | Mammalian | Ubiquitous. Detected in heart, pancreas, skeletal muscle, thymus, testis, ovary, spleen, prostate, small intestine, peripheral blood leukocytes, urinary bladder and colon. {ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:16174769, ECO:0000269|PubMed:17979886}. | Enzyme | Dioxygenase that repairs alkylated DNA containing 1- methyladenine (1meA) and 3-methylcytosine (3meC) by oxidative demethylation. Has a strong preference for single-stranded DNA. Able to process alkylated 3mC within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKHB3. May also act on RNA. Requires molecular oxygen, alpha-ketoglutarate and iron. {ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:12594517, ECO:0000269|PubMed:16174769, ECO:0000269|PubMed:22055184}. | Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 unknown: Vitamin C | 15.1 | |||
| kccALR | FAD-linked sulfhydryl oxidase ALR | 53 | 1167 | 88.48 | ND | 86.83 | 0.01 | ND | 1.1 | Mammalian | Ubiquitously expressed. Highest expression in the testis and liver and low expression in the muscle. {ECO:0000269|PubMed:19409522}. | Enzyme | Myopathy, mitochondrial progressive, with congenital cataract, hearing loss and developmental delay (MPMCHD) [MIM:613076]: A disease characterized by progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay. {ECO:0000269|PubMed:19409522}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Isoform 1: FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with GFER/ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4/MIA40, while GFER/ERV1 becomes re- oxidized by donating electrons to cytochrome c or molecular oxygen. Isoform 2: May act as an autocrine hepatotrophic growth factor promoting liver regeneration. | FAD-linked sulfhydryl oxidase ALR unknown: Flavin adenine dinucleotide | 15.1 | ||
| kccAMPB | Aminopeptidase B | 3 | 44 | 98.80 | ND | 92.44 | 0.41 | ND | 0.5 | Mammalian | Protease | Exopeptidase which selectively removes arginine and/or lysine residues from the N-terminus of several peptide substrates including Arg(0)-Leu-enkephalin, Arg(0)-Met-enkephalin and Arg(- 1)-Lys(0)-somatostatin-14. Can hydrolyze leukotriene A4 (LTA-4) into leukotriene B4 (LTB-4) (By similarity). {ECO:0000250}. | 15.1 | |||||
| kccAMPE | Glutamyl aminopeptidase | 3 | 48 | 97.92 | ND | 94.97 | 0.28 | ND | 1.1 | Mammalian | Expressed by epithelial cells of the proximal tubule cells and the glomerulus of the nephron. Also found in a variety of other tissues. | Protease | Hypertension | Appears to have a role in the catabolic pathway of the renin-angiotensin system. Probably plays a role in regulating growth and differentiation of early B-lineage cells. | FAD-linked sulfhydryl oxidase ALR unknown: Flavin adenine dinucleotide | 15.1 | ||
| kccAMPL | Cytosol aminopeptidase | 5 | 66 | 95.04 | ND | 91.31 | 0.43 | ND | 0.9 | Mammalian | Protease | Presumably involved in the processing and regular turnover of intracellular proteins. Catalyzes the removal of unsubstituted N-terminal amino acids from various peptides. | FAD-linked sulfhydryl oxidase ALR unknown: Flavin adenine dinucleotide | 15.1 | ||||
| kccAMPN | Aminopeptidase N | 27 | 692 | 98.32 | ND | 98.05 | 0.70 | ND | 0.6 | Mammalian | Expressed in epithelial cells of the kidney, intestine, and respiratory tract; granulocytes, monocytes, fibroblasts, endothelial cells, cerebral pericytes at the blood- brain barrier, synaptic membranes of cells in the CNS. Also expressed in endometrial stromal cells, but not in the endometrial glandular cells. Found in the vasculature of tissues that undergo angiogenesis and in malignant gliomas and lymph node metastases from multiple tumor types but not in blood vessels of normal tissues. A soluble form has been found in plasma. It is found to be elevated in plasma and effusions of cancer patients. | Protease | Coronaviruses infections
Severe acute respiratory syndrome Tumors | Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. May play a critical role in the pathogenesis of cholesterol gallstone disease. May be involved in the metabolism of regulatory peptides of diverse cell types, responsible for the processing of peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines. Found to cleave antigen peptides bound to major histocompatibility complex class II molecules of presenting cells and to degrade neurotransmitters at synaptic junctions. Is also implicated as a regulator of IL-8 bioavailability in the endometrium, and therefore may contribute to the regulation of angiogenesis. Is used as a marker for acute myeloid leukemia and plays a role in tumor invasion. In case of human coronavirus 229E (HCoV-229E) infection, serves as receptor for HCoV-229E spike glycoprotein. Mediates as well human cytomegalovirus (HCMV) infection. {ECO:0000269|PubMed:10605003, ECO:0000269|PubMed:10676659, ECO:0000269|PubMed:11384645, ECO:0000269|PubMed:12473585, ECO:0000269|PubMed:9056417}. (Microbial infection) Acts as a receptor for human coronavirus 229E/HCoV-229E. {ECO:0000269|PubMed:12551991, ECO:0000269|PubMed:1350662}. | Aminopeptidase N inhibitor: Icatibant Aminopeptidase N other: Ezetimibe | 15.1 | ||
| kccAMYP | Pancreatic alpha-amylase | 4 | 51 | 99.97 | ND | 100.00 | 0.98 | ND | 0.3 | Mammalian | Hydrolase | Hypoglycemia
Pancreatic disease | Pancreatic alpha-amylase inhibitor: Acarbose Pancreatic alpha-amylase unknown: Miglitol | 15.1 | ||||
| kccANDR | Androgen receptor | 84 | 1824 | 94.71 | ND | 95.58 | 0.67 | ND | 0.7 | Nature11159 VirtualToxLab | Mammalian | Isoform 2 is mainly expressed in heart and skeletal muscle. {ECO:0000269|PubMed:15634333}. | Acne Amenorrhoea Azoospermia Bone disorder Breast pain Cushingoid Depression Electrolyte imbalance Endocrine disorder Epiphyses premature fusion Gynaecomastia Hepatic function abnormal Hirsutism Hypercalcaemia Infertility Jaundice cholestatic Libido decreased Menstrual disorder Metrorrhagia Oedema Osteoporosis Priapism Virilism Weight increased | Nuclear receptor | Androgen insensitivity syndrome (AIS) [MIM:300068]: An X- linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10221770, ECO:0000269|PubMed:10404311, ECO:0000269|PubMed:10458483, ECO:0000269|PubMed:10571951, ECO:0000269|PubMed:10590024, ECO:0000269|PubMed:10690872, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:11744994, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1426313, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:1464650, ECO:0000269|PubMed:1480178, ECO:0000269|PubMed:1487249, ECO:0000269|PubMed:1569163, ECO:0000269|PubMed:1609793, ECO:0000269|PubMed:1775137, ECO:0000269|PubMed:1999491, ECO:0000269|PubMed:2082179, ECO:0000269|PubMed:2594783, ECO:0000269|PubMed:7537149, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7633398, ECO:0000269|PubMed:7641413, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7962294, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:7981689, ECO:0000269|PubMed:7993455, ECO:0000269|PubMed:8040309, ECO:0000269|PubMed:8096390, ECO:0000269|PubMed:8103398, ECO:0000269|PubMed:8162033, ECO:0000269|PubMed:8224266, ECO:0000269|PubMed:8281140, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8413310, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8626869, ECO:0000269|PubMed:8647313, ECO:0000269|PubMed:8683794, ECO:0000269|PubMed:8723113, ECO:0000269|PubMed:8768864, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8830623, ECO:0000269|PubMed:8918984, ECO:0000269|PubMed:8990010, ECO:0000269|PubMed:9001799, ECO:0000269|PubMed:9007482, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9106550, ECO:0000269|PubMed:9160185, ECO:0000269|PubMed:9252933, ECO:0000269|PubMed:9255042, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9328206, ECO:0000269|PubMed:9544375, ECO:0000269|PubMed:9554754, ECO:0000269|PubMed:9610419, ECO:0000269|PubMed:9627582, ECO:0000269|PubMed:9698822, ECO:0000269|PubMed:9788719, ECO:0000269|PubMed:9851768, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.109, ECO:0000269|Ref.175}. Note=The disease is caused by mutations affecting the gene represented in this entry. Spinal and bulbar muscular atrophy X-linked 1 (SMAX1) [MIM:313200]: An X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. {ECO:0000269|PubMed:15851746}. Note=The disease is caused by mutations affecting the gene represented in this entry. Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease. Note=Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. Androgen insensitivity, partial (PAIS) [MIM:312300]: A disorder that is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10470409, ECO:0000269|PubMed:10502786, ECO:0000269|PubMed:10543676, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:1303262, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1424203, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:2010552, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7649358, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7909256, ECO:0000269|PubMed:7910529, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:8033918, ECO:0000269|PubMed:8097257, ECO:0000269|PubMed:8126121, ECO:0000269|PubMed:8205256, ECO:0000269|PubMed:8281139, ECO:0000269|PubMed:8325932, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8550758, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8823308, ECO:0000269|PubMed:8824883, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9196614, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9329414, ECO:0000269|PubMed:9543136, ECO:0000269|PubMed:9607727, ECO:0000269|PubMed:9768671, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.117}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. {ECO:0000269|PubMed:14664718, ECO:0000269|PubMed:15563469, ECO:0000269|PubMed:17591767, ECO:0000269|PubMed:17911242, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:19345326, ECO:0000269|PubMed:20980437}. | Androgen receptor agonist: Danazol, Drostanolone, Fludrocortisone, Fluoxymesterone, Levonorgestrel, Methyltestosterone, Nandrolone decanoate, Nandrolone phenpropionate, Oxandrolone, Testosterone, Testosterone Propionate Androgen receptor antagonist: Bicalutamide, Cyproterone acetate, Drospirenone, Flutamide, Nilutamide, Spironolactone Androgen receptor binder: Ketoconazole Androgen receptor inhibitor: Enzalutamide | 15.1 |
| kccANM3 | Protein arginine N-methyltransferase 3 | 1 | 48 | 99.94 | ND | 99.73 | 0.46 | ND | 0.5 | Mammalian | Writer | Methylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in some proteins. | Androgen receptor agonist: Danazol, Drostanolone, Fludrocortisone, Fluoxymesterone, Levonorgestrel, Methyltestosterone, Nandrolone decanoate, Nandrolone phenpropionate, Oxandrolone, Testosterone, Testosterone Propionate Androgen receptor antagonist: Bicalutamide, Cyproterone acetate, Drospirenone, Flutamide, Nilutamide, Spironolactone Androgen receptor binder: Ketoconazole Androgen receptor inhibitor: Enzalutamide | 15.1 | ||||
| kccAOC1 | Amiloride-sensitive amine oxidase [copper-containing] | 2 | 40 | 99.75 | ND | 99.91 | 0.16 | ND | 0.8 | Mammalian | Placenta and kidney. | Enzyme | Catalyzes the degradation of compounds such as putrescine, histamine, spermine, and spermidine, substances involved in allergic and immune responses, cell proliferation, tissue differentiation, tumor formation, and possibly apoptosis. Placental DAO is thought to play a role in the regulation of the female reproductive function. | Amiloride-sensitive amine oxidase [copper-containing] inhibitor: Amiloride | 15.1 | |||
| kccAOC3 | Membrane primary amine oxidase | 9 | 146 | 94.68 | ND | 97.93 | 0.49 | ND | 0.9 | Mammalian | Strongly expressed on the high endothelial venules of peripheral lymph nodes and on hepatic endothelia. Also highly expressed in appendix, lung and small intestine. Expressed also in adipose tissue, in bone marrow, colon, heart, kidney, ovary, pancreas, placenta, prostate, skeletal muscle, spleen and testis. Isoform 2 seems to be the predominant transcript in fetal kidneys, fetal cartilage and fetal tonsils. The highest relative expression of isoform 2 occurs in skeletal muscle, heart, pancreas, kidney, and lung. {ECO:0000269|PubMed:17400359, ECO:0000269|PubMed:23349812, ECO:0000269|PubMed:9653080}. | Enzyme | Inflammation | Cell adhesion protein that participates in lymphocyte extravasation and recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin-independent fashion. Has semicarbazide-sensitive (SSAO) monoamine oxidase activity. May play a role in adipogenesis. {ECO:0000269|PubMed:17400359, ECO:0000269|PubMed:19588076, ECO:0000269|PubMed:23349812, ECO:0000269|PubMed:9653080}. | Membrane primary amine oxidase inhibitor: Hydralazine, Phenelzine | 15.1 | ||
| kccAOFA | Amine oxidase [flavin-containing] A | 59 | 1829 | 89.37 | ND | 96.88 | 0.58 | ND | 0.8 | Nature11159 | Mammalian | Heart, liver, duodenum, blood vessels and kidney. | Dry mouth Hyperhidrosis Irritability Mania Psychotic disorder | Oxidoreductase | Brunner syndrome (BRUNS) [MIM:300615]: A form of X-linked non-dysmorphic mild mental retardation. Male patients are affected by borderline mental retardation and exhibit abnormal behavior, including disturbed regulation of impulsive aggression. Obligate female carriers have normal intelligence and behavior. {ECO:0000269|PubMed:8211186}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOA preferentially oxidizes biogenic amines such as 5-hydroxytryptamine (5-HT), norepinephrine and epinephrine. | Amine oxidase [flavin-containing] A antagonist: Phenelzine, Phentermine Amine oxidase [flavin-containing] A cofactor: Riboflavin Amine oxidase [flavin-containing] A inducer: Testosterone Amine oxidase [flavin-containing] A inhibitor: Furazolidone, Isocarboxazid, Linezolid, Methamphetamine, Minaprine, Moclobemide, Nandrolone decanoate, Nicotine, Pargyline, Phentermine, Phenylpropanolamine, Pseudoephedrine, Selegiline, Tranylcypromine, Zonisamide Amine oxidase [flavin-containing] A substrate: Almotriptan, Dopamine, Naratriptan, Phenelzine, Phenylephrine, Rizatriptan, Sertraline, Sumatriptan, Zolmitriptan Amine oxidase [flavin-containing] A unknown: Flavin adenine dinucleotide, Procaine | 15.1 |
| kccAOFB | Amine oxidase [flavin-containing] B | 58 | 1951 | 94.99 | ND | 97.66 | 0.47 | ND | 0.9 | Mammalian | Mania Psychotic disorder | Oxidoreductase | Major depressive disorder
Neurological diseases Parkinson's disease | Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine. | Amine oxidase [flavin-containing] B antagonist: Phenelzine, Phentermine Amine oxidase [flavin-containing] B inhibitor: Amantadine, Furazolidone, Isocarboxazid, Linezolid, Methamphetamine, Nandrolone decanoate, Nicotine, Pargyline, Phentermine, Rasagiline, Selegiline, Tranylcypromine, Zonisamide Amine oxidase [flavin-containing] B substrate: Dopamine, Phenelzine, Sertraline Amine oxidase [flavin-containing] B unknown: Amphetamine, Flavin adenine dinucleotide, Moclobemide, Procaine | 15.1 | ||
| kccAPAF | Apoptotic protease-activating factor 1 | 7 | 395 | 84.96 | ND | 80.17 | 0.00 | ND | 0.8 | Mammalian | Ubiquitous. Highest levels of expression in adult spleen and peripheral blood leukocytes, and in fetal brain, kidney and lung. Isoform 1 is expressed in heart, kidney and liver. | Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis. {ECO:0000269|PubMed:10393175, ECO:0000269|PubMed:12804598}. | Apoptotic protease-activating factor 1 unknown: Adenosine triphosphate | 15.1 | ||||
| kccAPEX1 | DNA-(apurinic or apyrimidinic site) lyase | 8 | 461 | 85.73 | ND | 85.71 | 0.22 | ND | 0.9 | Mammalian | Enzyme | Ovarian cancer
Tumors | Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 in DNA repair and redox regulation of transcriptional factors. Functions as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Does also incise at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Has a 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses a DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate) blocking the 3' side of DNA strand breaks. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Acts as a loading factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'- phosphate (dRp) excision activity of POLB. Plays a role in the protection from granzymes-mediated cellular repair leading to cell death. Also involved in the DNA cleavage step of class switch recombination (CSR). On the other hand, APEX1 also exerts reversible nuclear redox activity to regulate DNA binding affinity and transcriptional activity of transcriptional factors by controlling the redox status of their DNA-binding domain, such as the FOS/JUN AP-1 complex after exposure to IR. Involved in calcium-dependent down-regulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of transcriptional repression. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Acts also as an endoribonuclease involved in the control of single-stranded RNA metabolism. Plays a role in regulating MYC mRNA turnover by preferentially cleaving in between UA and CA dinucleotides of the MYC coding region determinant (CRD). In association with NMD1, plays a role in the rRNA quality control process during cell cycle progression. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA. Binds DNA and RNA. {ECO:0000269|PubMed:10023679, ECO:0000269|PubMed:11118054, ECO:0000269|PubMed:11452037, ECO:0000269|PubMed:11809897, ECO:0000269|PubMed:11832948, ECO:0000269|PubMed:12524539, ECO:0000269|PubMed:16617147, ECO:0000269|PubMed:1719477, ECO:0000269|PubMed:18179823, ECO:0000269|PubMed:18439621, ECO:0000269|PubMed:18579163, ECO:0000269|PubMed:18809583, ECO:0000269|PubMed:19188445, ECO:0000269|PubMed:19401441, ECO:0000269|PubMed:19934257, ECO:0000269|PubMed:20699270, ECO:0000269|PubMed:21496894, ECO:0000269|PubMed:21762700, ECO:0000269|PubMed:8355688, ECO:0000269|PubMed:8621488, ECO:0000269|PubMed:8932375, ECO:0000269|PubMed:9108029, ECO:0000269|PubMed:9207062, ECO:0000269|PubMed:9560228, ECO:0000269|PubMed:9804799}. | DNA-(apurinic or apyrimidinic site) lyase inhibitor: Lucanthone | 15.1 | |||
| kccARGI1 | Arginase-1 | 1 | 54 | 99.40 | ND | 100.00 | 0.56 | ND | 0.6 | Mammalian | Enzyme | Argininemia (ARGIN) [MIM:207800]: A rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia and progressive spastic quadriplegia. {ECO:0000269|PubMed:1463019, ECO:0000269|PubMed:22959135, ECO:0000269|PubMed:23859858, ECO:0000269|PubMed:7649538}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Arginase-1 unknown: L-Ornithine | 15.1 | ||||
| kccARGI2 | Arginase-2, mitochondrial | 1 | 41 | 99.88 | ND | 100.00 | 0.38 | ND | 0.4 | Mammalian | Expressed most strongly in kidney and prostate, much less strongly in the brain, skeletal muscle, placenta, lung, mammary gland, macrophage, uterus, testis and gut, but apparently not in the liver, heart and pancreas. | Enzyme | Erectile dysfunction
Sexual arousal disorders | May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis. Extrahepatic arginase functions to regulate L-arginine bioavailability to NO synthase. Since NO synthase is found in the penile corpus cavernosum smooth muscle, the clitoral corpus cavernosum and the vagina, arginase II plays a role in both male and female sexual arousal. It is therefore a potential target for the treatment of male and female sexual arousal disorders. {ECO:0000269|PubMed:12859189}. | Arginase-2, mitochondrial unknown: L-Arginine, L-Ornithine | 15.1 | ||
| kccARY2 | Arylamine N-acetyltransferase 2 | 4 | 59 | 99.83 | ND | 99.83 | 0.34 | ND | 0.3 | Mammalian | Enzyme | Participates in the detoxification of a plethora of hydrazine and arylamine drugs. Catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivate several known carcinogens. | Arylamine N-acetyltransferase 2 inhibitor: Acetaminophen Arylamine N-acetyltransferase 2 substrate: Clonazepam, Dapsone, Ezogabine, Isoniazid, Sulfamethoxazole | 15.1 | ||||
| kccASIC3 | Acid-sensing ion channel 3 | 2 | 45 | 99.13 | ND | 99.77 | 0.26 | ND | 1.1 | Mammalian | Expressed by sensory neurons. Strongly expressed in brain, spinal chord, lung, lymph nodes, kidney, pituitary, heart and testis. {ECO:0000269|PubMed:9571199, ECO:0000269|PubMed:9886053}. | Ligand-gated ion channel | Analgesics
Pain, unspecific | Cation channel with high affinity for sodium, which is gated by extracellular protons and inhibited by the diuretic amiloride. Generates a biphasic current with a fast inactivating and a slow sustained phase. In sensory neurons is proposed to mediate the pain induced by acidosis that occurs in ischemic, damaged or inflamed tissue. May be involved in hyperalgesia. May play a role in mechanoreception. Heteromeric channel assembly seems to modulate channel properties. {ECO:0000269|PubMed:9744806, ECO:0000269|PubMed:9886053}. | Arylamine N-acetyltransferase 2 inhibitor: Acetaminophen Arylamine N-acetyltransferase 2 substrate: Clonazepam, Dapsone, Ezogabine, Isoniazid, Sulfamethoxazole | 15.1 | ||
| kccAT1A1 | Sodium/potassium-transporting ATPase subunit alpha-1 | 3 | 44 | 97.16 | ND | 99.86 | 0.59 | ND | 0.3 | Mammalian | Purine metabolism disorder | Primary active transporter | Atrial fibrillation and flutter
Heart failure | This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients. | Sodium/potassium-transporting ATPase subunit alpha-1 binder: Almitrine, Aluminium, Ciclopirox Sodium/potassium-transporting ATPase subunit alpha-1 inhibitor: Acetyldigitoxin, Bepridil, Bretylium, Deslanoside, Digitoxin, Ethacrynic acid, Ouabain, Trichlormethiazide Sodium/potassium-transporting ATPase subunit alpha-1 other: Diazoxide Sodium/potassium-transporting ATPase subunit alpha-1 other/unknown: Hydroflumethiazide Sodium/potassium-transporting ATPase subunit alpha-1 unknown: Digoxin | 15.1 | ||
| kccATR | Serine/threonine-protein kinase ATR | 2 | 88 | 94.36 | ND | 97.19 | 0.60 | ND | 0.7 | Mammalian | Ubiquitous, with highest expression in testis. Isoform 2 is found in pancreas, placenta and liver but not in heart, testis and ovary. {ECO:0000269|PubMed:11470508, ECO:0000269|PubMed:8610130, ECO:0000269|PubMed:8843195}. | Kinase | Seckel syndrome 1 (SCKL1) [MIM:210600]: A rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation. {ECO:0000269|PubMed:12640452}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cutaneous telangiectasia and cancer syndrome, familial (FCTCS) [MIM:614564]: A disease characterized by cutaneous telangiectases in infancy with patchy alopecia over areas of affected skin, thinning of the lateral eyebrows, and mild dental and nail anomalies. Affected individuals are at increased risk of developing oropharyngeal cancer, and other malignancies have been reported as well. {ECO:0000269|PubMed:22341969}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. {ECO:0000269|PubMed:10597277, ECO:0000269|PubMed:10608806, ECO:0000269|PubMed:10859164, ECO:0000269|PubMed:11114888, ECO:0000269|PubMed:11418864, ECO:0000269|PubMed:11673449, ECO:0000269|PubMed:11721054, ECO:0000269|PubMed:11865061, ECO:0000269|PubMed:12526805, ECO:0000269|PubMed:12791985, ECO:0000269|PubMed:12814551, ECO:0000269|PubMed:14657349, ECO:0000269|PubMed:14729973, ECO:0000269|PubMed:14742437, ECO:0000269|PubMed:15210935, ECO:0000269|PubMed:15314022, ECO:0000269|PubMed:15496423, ECO:0000269|PubMed:16260606, ECO:0000269|PubMed:21144835, ECO:0000269|PubMed:9427750, ECO:0000269|PubMed:9636169, ECO:0000269|PubMed:9925639}. | 15.1 | |||
| kccATS4 | A disintegrin and metalloproteinase with thrombospondin motifs 4 | 9 | 196 | 96.41 | ND | 98.47 | 0.80 | ND | 0.6 | Mammalian | Expressed in brain, lung and heart. Expressed at very low level in placenta and skeletal muscles. Isoform 2 is detected in osteoarthritic synovium. {ECO:0000269|PubMed:23897278}. | Protease | Osteoarthritis | Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. Could also be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease. Cleaves aggrecan at the '392-Glu-|-Ala-393' site. | 15.1 | |||
| kccATS5 | A disintegrin and metalloproteinase with thrombospondin motifs 5 | 18 | 378 | 99.76 | ND | 99.27 | 0.69 | ND | 0.5 | Mammalian | Expressed at low level in placenta primarily but also detected in heart and brain, cervix, uterus, bladder, esophagus, rib cartilage, chondroblastoma, fibrous tissue and a joint capsule from an arthritic patient. | Protease | Osteoarthritis | Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. May play a role in proteolytic processing mostly during the peri-implantation period. | Sodium/potassium-transporting ATPase subunit alpha-1 binder: Almitrine, Aluminium, Ciclopirox Sodium/potassium-transporting ATPase subunit alpha-1 inhibitor: Acetyldigitoxin, Bepridil, Bretylium, Deslanoside, Digitoxin, Ethacrynic acid, Ouabain, Trichlormethiazide Sodium/potassium-transporting ATPase subunit alpha-1 other: Diazoxide Sodium/potassium-transporting ATPase subunit alpha-1 other/unknown: Hydroflumethiazide Sodium/potassium-transporting ATPase subunit alpha-1 unknown: Digoxin | 15.1 | ||
| kccAURKA | Aurora kinase A | 93 | 1914 | 97.62 | ND | 94.93 | 0.63 | ND | 0.8 | Mammalian | Highly expressed in testis and weakly in skeletal muscle, thymus and spleen. Also highly expressed in colon, ovarian, prostate, neuroblastoma, breast and cervical cancer cell lines. | Kinase | Colorectal Cancer
Lymphoma, Unspecified Solid tumors | Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis. {ECO:0000269|PubMed:11039908, ECO:0000269|PubMed:11551964, ECO:0000269|PubMed:12390251, ECO:0000269|PubMed:13678582, ECO:0000269|PubMed:14523000, ECO:0000269|PubMed:14702041, ECO:0000269|PubMed:14990569, ECO:0000269|PubMed:15128871, ECO:0000269|PubMed:15147269, ECO:0000269|PubMed:15987997, ECO:0000269|PubMed:17125279, ECO:0000269|PubMed:17360485, ECO:0000269|PubMed:17604723, ECO:0000269|PubMed:18056443, ECO:0000269|PubMed:18615013, ECO:0000269|PubMed:19351716, ECO:0000269|PubMed:19357306, ECO:0000269|PubMed:19668197, ECO:0000269|PubMed:19812038, ECO:0000269|PubMed:20643351, ECO:0000269|PubMed:9606188}. | Sodium/potassium-transporting ATPase subunit alpha-1 binder: Almitrine, Aluminium, Ciclopirox Sodium/potassium-transporting ATPase subunit alpha-1 inhibitor: Acetyldigitoxin, Bepridil, Bretylium, Deslanoside, Digitoxin, Ethacrynic acid, Ouabain, Trichlormethiazide Sodium/potassium-transporting ATPase subunit alpha-1 other: Diazoxide Sodium/potassium-transporting ATPase subunit alpha-1 other/unknown: Hydroflumethiazide Sodium/potassium-transporting ATPase subunit alpha-1 unknown: Digoxin | 15.1 | ||
| kccAURKB | Aurora kinase B | 77 | 1488 | 96.14 | ND | 94.12 | 0.48 | ND | 1.1 | Mammalian | High level expression seen in the thymus. It is also expressed in the spleen, lung, testis, colon, placenta and fetal liver. Expressed during S and G2/M phase and expression is up-regulated in cancer cells during M phase. {ECO:0000269|PubMed:9809983, ECO:0000269|PubMed:9858806}. | Kinase | Note=Disruptive regulation of expression is a possible mechanism of the perturbation of chromosomal integrity in cancer cells through its dominant-negative effect on cytokinesis. | Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis. Required for central/midzone spindle assembly and cleavage furrow formation. Key component of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage: phosphorylates CHMP4C, leading to retain abscission- competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis (PubMed:22422861, PubMed:24814515). AURKB phosphorylates the CPC complex subunits BIRC5/survivin, CDCA8/borealin and INCENP. Phosphorylation of INCENP leads to increased AURKB activity. Other known AURKB substrates involved in centromeric functions and mitosis are CENPA, DES/desmin, GPAF, KIF2C, NSUN2, RACGAP1, SEPT1, VIM/vimentin, GSG2/Haspin, and histone H3. A positive feedback loop involving GSG2 and AURKB contributes to localization of CPC to centromeres. Phosphorylation of VIM controls vimentin filament segregation in cytokinetic process, whereas histone H3 is phosphorylated at 'Ser-10' and 'Ser-28' during mitosis (H3S10ph and H3S28ph, respectively). A positive feedback between GSG2 and AURKB contributes to CPC localization. AURKB is also required for kinetochore localization of BUB1 and SGOL1. Phosphorylation of p53/TP53 negatively regulates its transcriptional activity. Key regulator of active promoters in resting B- and T-lymphocytes: acts by mediating phosphorylation of H3S28ph at active promoters in resting B-cells, inhibiting RNF2/RING1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes. {ECO:0000269|PubMed:11516652, ECO:0000269|PubMed:11756469, ECO:0000269|PubMed:11784863, ECO:0000269|PubMed:11856369, ECO:0000269|PubMed:12458200, ECO:0000269|PubMed:12686604, ECO:0000269|PubMed:12689593, ECO:0000269|PubMed:12925766, ECO:0000269|PubMed:14602875, ECO:0000269|PubMed:14610074, ECO:0000269|PubMed:14722118, ECO:0000269|PubMed:15020684, ECO:0000269|PubMed:15249581, ECO:0000269|PubMed:16103226, ECO:0000269|PubMed:17617734, ECO:0000269|PubMed:20959462, ECO:0000269|PubMed:21658950, ECO:0000269|PubMed:22422861, ECO:0000269|PubMed:24814515}. | Sodium/potassium-transporting ATPase subunit alpha-1 binder: Almitrine, Aluminium, Ciclopirox Sodium/potassium-transporting ATPase subunit alpha-1 inhibitor: Acetyldigitoxin, Bepridil, Bretylium, Deslanoside, Digitoxin, Ethacrynic acid, Ouabain, Trichlormethiazide Sodium/potassium-transporting ATPase subunit alpha-1 other: Diazoxide Sodium/potassium-transporting ATPase subunit alpha-1 other/unknown: Hydroflumethiazide Sodium/potassium-transporting ATPase subunit alpha-1 unknown: Digoxin | 15.1 | ||
| kccAURKC | Aurora kinase C | 3 | 104 | 87.04 | ND | 84.47 | 0.55 | ND | 1.3 | Mammalian | Isoform 1 and isoform 2 are expressed in testis. Elevated expression levels were seen only in a subset of cancer cell lines such as Hep-G2, Huh-7 and HeLa. Expression is maximum at M phase. {ECO:0000269|PubMed:15670791}. | Kinase | Spermatogenic failure 5 (SPGF5) [MIM:243060]: An infertility disorder caused by spermatogenesis defects. Semen from affected men show close to 100% morphologically abnormal multiflagellar spermatozoa with low motility, oversized irregular heads, and abnormal midpiece and acrosome. {ECO:0000269|PubMed:17435757, ECO:0000269|PubMed:21733974}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Plays also a role in meiosis and more particularly in spermatogenesis. Has redundant cellular functions with AURKB and can rescue an AURKB knockdown. Like AURKB, AURKC phosphorylates histone H3 at 'Ser-10' and 'Ser-28'. Phosphorylates TACC1, another protein involved in cell division, at 'Ser-228'. {ECO:0000269|PubMed:15316025, ECO:0000269|PubMed:15499654, ECO:0000269|PubMed:15670791, ECO:0000269|PubMed:15938719, ECO:0000269|PubMed:21493633, ECO:0000269|PubMed:21531210}. | 15.1 | |||
| kccB2CL1 | Bcl-2-like protein 1 | 16 | 492 | 96.51 | ND | 99.37 | 0.77 | ND | 0.7 | Mammalian | Bcl-X(S) is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, Bcl-X(L) is found in tissues containing long-lived postmitotic cells, such as adult brain. | Other ion channel | Anaplastic Large Cell Lymphomas
Colorectal cancer Mesothelioma | Potent inhibitor of cell death. Inhibits activation of caspases. Appears to regulate cell death by blocking the voltage- dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis. Isoform Bcl-X(L) also regulates presynaptic plasticity, including neurotransmitter release and recovery, number of axonal mitochondria as well as size and number of synaptic vesicle clusters. During synaptic stimulation, increases ATP availability from mitochondria through regulation of mitochondrial membrane ATP synthase F(1)F(0) activity and regulates endocytic vesicle retrieval in hippocampal neurons through association with DMN1L and stimulation of its GTPase activity in synaptic vesicles. Isoform Bcl-X(S) promotes apoptosis. | Sodium/potassium-transporting ATPase subunit alpha-1 binder: Almitrine, Aluminium, Ciclopirox Sodium/potassium-transporting ATPase subunit alpha-1 inhibitor: Acetyldigitoxin, Bepridil, Bretylium, Deslanoside, Digitoxin, Ethacrynic acid, Ouabain, Trichlormethiazide Sodium/potassium-transporting ATPase subunit alpha-1 other: Diazoxide Sodium/potassium-transporting ATPase subunit alpha-1 other/unknown: Hydroflumethiazide Sodium/potassium-transporting ATPase subunit alpha-1 unknown: Digoxin | 15.1 | ||
| kccB2CL2 | Bcl-2-like protein 2 | 3 | 52 | 96.56 | ND | 99.97 | 0.59 | ND | 0.7 | Mammalian | Expressed (at protein level) in a wide range of tissues with highest levels in brain, spinal cord, testis, pancreas, heart, spleen and mammary glands. Moderate levels found in thymus, ovary and small intestine. Not detected in salivary gland, muscle or liver. Also expressed in cell lines of myeloid, fibroblast and epithelial origin. Not detected in most lymphoid cell lines. {ECO:0000269|PubMed:11423909}. | Other cytosolic protein | Chronic lymphocytic leukemia
Hematologic malignancies Lymphoid malignancies Small cell lung cancer | Promotes cell survival. Blocks dexamethasone-induced apoptosis. Mediates survival of postmitotic Sertoli cells by suppressing death-promoting activity of BAX. {ECO:0000269|PubMed:8761287}. | 15.1 | |||
| kccB2LA1 | Bcl-2-related protein A1 | 3 | 143 | 83.29 | ND | 88.50 | 0.03 | ND | 0.6 | Mammalian | Seems to be restricted to the hematopoietic compartment. Expressed in peripheral blood, spleen, and bone marrow, at moderate levels in lung, small intestine and testis, at a minimal levels in other tissues. Also found in vascular smooth muscle cells and hematopoietic malignancies. | Bcl-2 | Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity). Can inhibit apoptosis induced by serum starvation in the mammary epithelial cell line HC11 (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q07440}. | 15.1 | ||||
| kccBACE1 | Beta-secretase 1 | 99 | 2669 | 98.19 | ND | 99.31 | 0.72 | ND | 0.7 | Mammalian | Expressed at high levels in the brain and pancreas. In the brain, expression is highest in the substantia nigra, locus coruleus and medulla oblongata. {ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:11083922}. | Protease | Alzheimer's disease | Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. {ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:20354142}. | Sodium/potassium-transporting ATPase subunit alpha-1 binder: Almitrine, Aluminium, Ciclopirox Sodium/potassium-transporting ATPase subunit alpha-1 inhibitor: Acetyldigitoxin, Bepridil, Bretylium, Deslanoside, Digitoxin, Ethacrynic acid, Ouabain, Trichlormethiazide Sodium/potassium-transporting ATPase subunit alpha-1 other: Diazoxide Sodium/potassium-transporting ATPase subunit alpha-1 other/unknown: Hydroflumethiazide Sodium/potassium-transporting ATPase subunit alpha-1 unknown: Digoxin | 15.1 | ||
| kccBACE2 | Beta-secretase 2 | 18 | 417 | 99.62 | ND | 99.34 | 0.46 | ND | 0.6 | Mammalian | Brain. Present in neurons within the hippocampus, frontal cortex and temporal cortex (at protein level). Expressed at low levels in most peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at low levels in the brain. Found in spinal cord, medulla oblongata, substantia nigra and locus coruleus. Expressed in the ductal epithelium of both normal and malignant prostate. {ECO:0000269|PubMed:10591213, ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:10683441, ECO:0000269|PubMed:10749877, ECO:0000269|PubMed:10838186, ECO:0000269|PubMed:10965118, ECO:0000269|PubMed:11083922}. | Protease | Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C- terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672. {ECO:0000269|PubMed:10591213, ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:11423558, ECO:0000269|PubMed:15857888, ECO:0000269|PubMed:16816112}. | 15.1 | ||||
| kccBAD | Bcl2-associated agonist of cell death | 5 | 79 | 97.92 | ND | 96.38 | 0.93 | ND | 0.4 | Mammalian | Expressed in a wide variety of tissues. | Other cytosolic protein | Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathways. {ECO:0000250}. | 15.1 | ||||
| kccBCL2 | Apoptosis regulator Bcl-2 | 26 | 438 | 98.10 | ND | 98.27 | 0.78 | ND | 0.6 | Mammalian | Expressed in a variety of tissues. | Other ion channel | Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. | Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1). {ECO:0000269|PubMed:18570871}. | Apoptosis regulator Bcl-2 activator: Rasagiline Apoptosis regulator Bcl-2 inhibitor: Paclitaxel Apoptosis regulator Bcl-2 modulator: Ibuprofen Apoptosis regulator Bcl-2 unknown: Docetaxel | 15.1 | ||
| kccBGAL | Beta-galactosidase | 2 | 65 | 98.82 | ND | 99.45 | 0.33 | ND | 0.9 | Mammalian | Enzyme | GM1-gangliosidosis 1 (GM1G1) [MIM:230500]: An autosomal recessive lysosomal storage disease marked by the accumulation of GM1 gangliosides, glycoproteins and keratan sulfate primarily in neurons of the central nervous system. GM1-gangliosidosis type 1 is characterized by onset within the first three months of life, central nervous system degeneration, coarse facial features, hepatosplenomegaly, skeletal dysmorphology reminiscent of Hurler syndrome, and rapidly progressive psychomotor deterioration. Urinary oligosaccharide levels are high. It leads to death usually between the first and second year of life. {ECO:0000269|PubMed:10338095, ECO:0000269|PubMed:10737981, ECO:0000269|PubMed:10839995, ECO:0000269|PubMed:1487238, ECO:0000269|PubMed:15365997, ECO:0000269|PubMed:15714521, ECO:0000269|PubMed:15791924, ECO:0000269|PubMed:16538002, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:1928092, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:8213816, ECO:0000269|Ref.24, ECO:0000269|Ref.27}. Note=The disease is caused by mutations affecting the gene represented in this entry. GM1-gangliosidosis 2 (GM1G2) [MIM:230600]: A gangliosidosis characterized by onset between ages 1 and 5. The main symptom is locomotor ataxia, ultimately leading to a state of decerebration with epileptic seizures. Patients do not display the skeletal changes associated with the infantile form, but they nonetheless excrete elevated amounts of beta-linked galactose- terminal oligosaccharides. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10737981, ECO:0000269|PubMed:12644936, ECO:0000269|PubMed:15714521, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:8213816}. Note=The disease is caused by mutations affecting the gene represented in this entry. GM1-gangliosidosis 3 (GM1G3) [MIM:230650]: A gangliosidosis with a variable phenotype. Patients show mild skeletal abnormalities, dysarthria, gait disturbance, dystonia and visual impairment. Visceromegaly is absent. Intellectual deficit can initially be mild or absent but progresses over time. Inheritance is autosomal recessive. {ECO:0000269|PubMed:11511921, ECO:0000269|PubMed:15986423, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:17309651, ECO:0000269|PubMed:1907800, ECO:0000269|PubMed:1909089, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:8198123, ECO:0000269|Ref.24, ECO:0000269|Ref.26}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mucopolysaccharidosis 4B (MPS4B) [MIM:253010]: A form of mucopolysaccharidosis type 4, an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate. Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal and there is no direct central nervous system involvement, although the skeletal changes may result in neurologic complications. There is variable severity, but patients with the severe phenotype usually do not survive past the second or third decade of life. {ECO:0000269|PubMed:11511921, ECO:0000269|PubMed:12393180, ECO:0000269|PubMed:16538002, ECO:0000269|PubMed:16941474, ECO:0000269|PubMed:1928092, ECO:0000269|PubMed:19472408, ECO:0000269|PubMed:7586649}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans. Isoform 2 has no beta-galactosidase catalytic activity, but plays functional roles in the formation of extracellular elastic fibers (elastogenesis) and in the development of connective tissue. Seems to be identical to the elastin-binding protein (EBP), a major component of the non-integrin cell surface receptor expressed on fibroblasts, smooth muscle cells, chondroblasts, leukocytes, and certain cancer cell types. In elastin producing cells, associates with tropoelastin intracellularly and functions as a recycling molecular chaperone which facilitates the secretions of tropoelastin and its assembly into elastic fibers. | 15.1 | ||||
| kccBIRC2 | Baculoviral IAP repeat-containing protein 2 | 6 | 190 | 99.83 | ND | 99.92 | 0.53 | ND | 0.8 | Mammalian | Present in many fetal and adult tissues. Mainly expressed in adult skeletal muscle, thymus, testis, ovary, and pancreas, low or absent in brain and peripheral blood leukocytes. | Enzyme | Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin- protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin- protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO, IKBKE and MXD1/MAD1. Can also function as an E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase- dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle. {ECO:0000269|PubMed:15665297, ECO:0000269|PubMed:18082613, ECO:0000269|PubMed:21145488, ECO:0000269|PubMed:21653699, ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:23453969}. | 15.1 | ||||
| kccBIRC3 | Baculoviral IAP repeat-containing protein 3 | 1 | 62 | 99.41 | ND | 96.56 | 0.41 | ND | 0.8 | Mammalian | Highly expressed in fetal lung, and kidney. In the adult, expression is mainly seen in lymphoid tissues, including spleen, thymus and peripheral blood lymphocytes. | Enzyme | Note=A chromosomal aberration involving BIRC3 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with MALT1. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma. | Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin- protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin- protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, IKBKE, TRAF1, and BCL10. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase- independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. {ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:23453969}. | 15.1 | |||
| kccBKRB1 | B1 bradykinin receptor | 32 | 655 | 99.86 | ND | 99.93 | 0.63 | ND | 0.8 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Diabetic nephropathy
Inflammatory diseases Ischemic vascular disease Prostate cancer | This is a receptor for bradykinin. Could be a factor in chronic pain and inflammation. | 15.1 | |||
| kccBKRB2 | B2 bradykinin receptor | 9 | 540 | 97.70 | ND | 98.14 | 0.80 | ND | 0.7 | Nature11159 | Mammalian | Ubiquitous. Widespread in normal smooth muscle tissue and neurons. {ECO:0000269|PubMed:7835885}. | Family A G protein-coupled receptor | Alzheimer's disease
Analgesics Arthritis Asthma Brain Cancer Cardiac hypertrophy Cardiovascular disease, unspecified Cerebral edema Chronic rhinitis Colitis Diabetic disorders Diabetic nephropathy Hepatorenal syndrome Hereditary Angioedema (HAE) Hypertension Liver Disease Lung cancer Myocardial infarction Pancreatitis Pediatric Restenosis Sepsis Tissue injury Traumatic brain injuries Visceral pain | Receptor for bradykinin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. | B2 bradykinin receptor antagonist: Icatibant | 15.1 | |
| kccBLK | Tyrosine-protein kinase Blk | 7 | 260 | 95.20 | ND | 87.40 | 0.10 | ND | 1.7 | Mammalian | Expressed in lymphatic organs, pancreatic islets, Leydig cells, striate ducts of salivary glands and hair follicles. {ECO:0000269|PubMed:19667185}. | Kinase | Maturity-onset diabetes of the young 11 (MODY11) [MIM:613375]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:19667185}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling. B-cell receptor (BCR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated coreceptors. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. Signaling through BLK plays an important role in transmitting signals through surface immunoglobulins and supports the pro-B to pre-B transition, as well as the signaling for growth arrest and apoptosis downstream of B-cell receptor. Specifically binds and phosphorylates CD79A at 'Tyr-188'and 'Tyr-199', as well as CD79B at 'Tyr-196' and 'Tyr- 207'. Phosphorylates also the immunoglobulin G receptors FCGR2A, FCGR2B and FCGR2C. With FYN and LYN, plays an essential role in pre-B-cell receptor (pre-BCR)-mediated NF-kappa-B activation. Contributes also to BTK activation by indirectly stimulating BTK intramolecular autophosphorylation. In pancreatic islets, acts as a modulator of beta-cells function through the up-regulation of PDX1 and NKX6-1 and consequent stimulation of insulin secretion in response to glucose. {ECO:0000269|PubMed:19667185, ECO:0000269|PubMed:8756631}. | 15.1 | |||
| kccBMP1 | Bone morphogenetic protein 1 | 9 | 312 | 99.88 | ND | 99.98 | 0.73 | ND | 0.5 | Mammalian | Ubiquitous. | Protease | Osteogenesis imperfecta 13 (OI13) [MIM:614856]: An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI13 is characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, severe bone deformity, and recurrent fractures affecting both upper and lower limbs. {ECO:0000269|PubMed:22052668, ECO:0000269|PubMed:22482805, ECO:0000269|PubMed:25402547}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cleaves the C-terminal propeptides of procollagen I, II and III. Induces cartilage and bone formation. May participate in dorsoventral patterning during early development by cleaving chordin (CHRD). Responsible for the proteolytic activation of lysyl oxidase LOX. | 15.1 | |||
| kccBMPR2 | Bone morphogenetic protein receptor type-2 | 1 | 71 | 91.74 | ND | 99.85 | 0.12 | ND | 1.3 | Mammalian | Highly expressed in heart and liver. | Kinase | Pulmonary hypertension, primary, 1 (PPH1) [MIM:178600]: A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. {ECO:0000269|PubMed:10903931, ECO:0000269|PubMed:10973254, ECO:0000269|PubMed:11015450, ECO:0000269|PubMed:11115378, ECO:0000269|PubMed:12358323, ECO:0000269|PubMed:15965979, ECO:0000269|PubMed:25187962}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pulmonary venoocclusive disease 1, autosomal dominant (PVOD1) [MIM:265450]: A disease characterized by widespread fibrous obstruction and intimal thickening of septal veins and preseptal venules, a low diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and nodular ground-glass opacities, septal lines and lymph node enlargement showed by high-resolution computed tomography of the chest. It is frequently associated with pulmonary capillary dilatation and proliferation, and is a rare and devastating cause of pulmonary hypertension. {ECO:0000269|PubMed:12446270, ECO:0000269|PubMed:16429395}. Note=The disease is caused by mutations affecting the gene represented in this entry. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP-7, BMP-2 and, less efficiently, BMP-4. Binding is weak but enhanced by the presence of type I receptors for BMPs. | 15.1 | |||
| kccBMR1B | Bone morphogenetic protein receptor type-1B | 1 | 70 | 93.44 | ND | 90.87 | 0.40 | ND | 0.9 | Mammalian | Kinase | Acromesomelic chondrodysplasia, with genital anomalies (AMDGA) [MIM:609441]: A form of chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). {ECO:0000269|PubMed:15805157}. Note=The disease is caused by mutations affecting the gene represented in this entry. Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. {ECO:0000269|PubMed:14523231, ECO:0000269|PubMed:16957682}. Note=The disease is caused by mutations affecting the gene represented in this entry. | On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP7/OP-1 and GDF5. Positively regulates chondrocyte differentiation through GDF5 interaction (By similarity). {ECO:0000250|UniProtKB:P36898}. | 15.1 | ||||
| kccBMX | Cytoplasmic tyrosine-protein kinase BMX | 1 | 84 | 96.79 | ND | 99.51 | 0.03 | ND | 1.0 | Mammalian | Highly expressed in cells with great migratory potential, including endothelial cells and metastatic carcinoma cell lines. | Kinase | Non-receptor tyrosine kinase that plays central but diverse modulatory roles in various signaling processes involved in the regulation of actin reorganization, cell migration, cell proliferation and survival, cell adhesion, and apoptosis. Participates in signal transduction stimulated by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen receptors and integrins. Induces tyrosine phosphorylation of BCAR1 in response to integrin regulation. Activation of BMX by integrins is mediated by PTK2/FAK1, a key mediator of integrin signaling events leading to the regulation of actin cytoskeleton and cell motility. Plays a critical role in TNF-induced angiogenesis, and implicated in the signaling of TEK and FLT1 receptors, 2 important receptor families essential for angiogenesis. Required for the phosphorylation and activation of STAT3, a transcription factor involved in cell differentiation. Also involved in interleukin-6 (IL6) induced differentiation. Plays also a role in programming adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts. May be involved in regulation of endocytosis through its interaction with an endosomal protein RUFY1. May also play a role in the growth and differentiation of hematopoietic cells; as well as in signal transduction in endocardial and arterial endothelial cells. {ECO:0000269|PubMed:10688651, ECO:0000269|PubMed:11331870, ECO:0000269|PubMed:12370298, ECO:0000269|PubMed:12832404, ECO:0000269|PubMed:15788485, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:9520419}. | 15.1 | ||||
| kccBRAF | Serine/threonine-protein kinase B-raf | 31 | 610 | 99.00 | ND | 97.07 | 0.66 | ND | 1.0 | Mammalian | Brain and testis. | Kinase | Note=Defects in BRAF are found in a wide range of cancers. {ECO:0000269|PubMed:18974108}. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:12198537, ECO:0000269|PubMed:23263490, ECO:0000269|PubMed:24455489}. Note=The disease may be caused by mutations affecting the gene represented in this entry. Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:12460919}. Note=The gene represented in this entry is involved in disease pathogenesis. Familial non-Hodgkin lymphoma (NHL) [MIM:605027]: Cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss. {ECO:0000269|PubMed:14612909}. Note=The gene represented in this entry is involved in disease pathogenesis. Cardiofaciocutaneous syndrome 1 (CFC1) [MIM:115150]: A multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:16474404, ECO:0000269|PubMed:18042262, ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry. Noonan syndrome 7 (NS7) [MIM:613706]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry. LEOPARD syndrome 3 (LPRD3) [MIM:613707]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation. {ECO:0000269|PubMed:18974108}. | Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, and thereby contributes to the MAP kinase signal transduction pathway. {ECO:0000269|PubMed:21441910}. | Serine/threonine-protein kinase B-raf inhibitor: Dabrafenib, Regorafenib, Sorafenib, Vemurafenib | 15.1 | ||
| kccBRCA1 | Breast cancer type 1 susceptibility protein | 142 | 3236 | 87.80 | ND | 88.46 | 0.01 | ND | 0.8 | Mammalian | Isoform 1 and isoform 3 are widely expressed. Isoform 3 is reduced or absent in several breast and ovarian cancer cell lines. | Enzyme | Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:10323242, ECO:0000269|PubMed:12442275, ECO:0000269|PubMed:12938098, ECO:0000269|PubMed:14722926, ECO:0000269|PubMed:18285836, ECO:0000269|PubMed:7545954, ECO:0000269|PubMed:7894491, ECO:0000269|PubMed:7894493, ECO:0000269|PubMed:7939630, ECO:0000269|PubMed:8554067, ECO:0000269|PubMed:8723683, ECO:0000269|PubMed:8776600, ECO:0000269|PubMed:9482581, ECO:0000269|PubMed:9609997, ECO:0000269|PubMed:9760198}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Mutations in BRCA1 are thought to be responsible for 45% of inherited breast cancer. Moreover, BRCA1 carriers have a 4-fold increased risk of colon cancer, whereas male carriers face a 3- fold increased risk of prostate cancer. Cells lacking BRCA1 show defects in DNA repair by homologous recombination. Breast-ovarian cancer, familial, 1 (BROVCA1) [MIM:604370]: A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate. {ECO:0000269|PubMed:12938098, ECO:0000269|PubMed:14722926, ECO:0000269|PubMed:8968716}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Mutations in BRCA1 are thought to be responsible for more than 80% of inherited breast-ovarian cancer. Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. {ECO:0000269|PubMed:10196379, ECO:0000269|PubMed:10486320, ECO:0000269|PubMed:14746861}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Pancreatic cancer 4 (PNCA4) [MIM:614320]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. {ECO:0000269|PubMed:18762988}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage. It is unclear whether it also mediates the formation of other types of polyubiquitin chains. The E3 ubiquitin-protein ligase activity is required for its tumor suppressor function. The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Regulates centrosomal microtubule nucleation. Required for normal cell cycle progression from G2 to mitosis. Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. Involved in transcriptional regulation of P21 in response to DNA damage. Required for FANCD2 targeting to sites of DNA damage. May function as a transcriptional regulator. Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation. Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8. Acts as a transcriptional activator (PubMed:20160719). {ECO:0000269|PubMed:10500182, ECO:0000269|PubMed:10724175, ECO:0000269|PubMed:11836499, ECO:0000269|PubMed:12887909, ECO:0000269|PubMed:12890688, ECO:0000269|PubMed:14976165, ECO:0000269|PubMed:14990569, ECO:0000269|PubMed:16326698, ECO:0000269|PubMed:16818604, ECO:0000269|PubMed:17525340, ECO:0000269|PubMed:18056443, ECO:0000269|PubMed:19261748, ECO:0000269|PubMed:19369211, ECO:0000269|PubMed:20160719, ECO:0000269|PubMed:20351172, ECO:0000269|PubMed:20364141}. | 15.1 | |||
| kccBRD2 | Bromodomain-containing protein 2 | 4 | 75 | 99.78 | ND | 99.90 | 0.03 | ND | 0.6 | Mammalian | Reader | May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly. {ECO:0000250, ECO:0000269|PubMed:18406326}. | 15.1 | |||||
| kccBRD3 | Bromodomain-containing protein 3 | 5 | 70 | 97.92 | ND | 96.56 | 0.19 | ND | 0.3 | Mammalian | Ubiquitous. | Reader | Note=A chromosomal aberration involving BRD3 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with NUT which produces a BRD3-NUT fusion protein. | Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors. Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets (By similarity). Regulates transcription of the CCND1 gene. {ECO:0000250, ECO:0000269|PubMed:18406326}. | 15.1 | |||
| kccBRD4 | Bromodomain-containing protein 4 | 10 | 212 | 97.46 | ND | 96.38 | 0.50 | ND | 0.5 | Mammalian | Ubiquitously expressed. {ECO:0000269|PubMed:12543779}. | Reader | Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. {ECO:0000269|PubMed:11733348, ECO:0000269|PubMed:12543779}. | Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P- TEFb complex and recruiting it to promoters: BRD4 is required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P- TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo (PubMed:22509028). In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters. {ECO:0000269|PubMed:22509028}. Isoform B: Acts as a chromatin insulator in the DNA damage response pathway. Inhibits DNA damage response signaling by recruiting the condensin-2 complex to acetylated histones, leading to chromatin structure remodeling, insulating the region from DNA damage response by limiting spreading of histone H2AFX/H2A.x phosphorylation. | 15.1 | |||
| kccBRS3 | Bombesin receptor subtype-3 | 10 | 236 | 99.80 | ND | 99.95 | 0.59 | ND | 0.6 | Mammalian | In germ cells in testis. Lung carcinoma cells. | Family A G protein-coupled receptor | Cancer, unspecific
Obesity | Role in sperm cell division, maturation, or function. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. | 15.1 | |||
| kccBRSK1 | Serine/threonine-protein kinase BRSK1 | 9 | 232 | 92.72 | ND | 92.72 | 0.20 | ND | 1.2 | Mammalian | Widely expressed, with highest levels in brain and testis. Protein levels remain constant throughout the cell cycle. {ECO:0000269|PubMed:15150265}. | Kinase | Serine/threonine-protein kinase that plays a key role in polarization of neurons and centrosome duplication. Phosphorylates CDC25B, CDC25C, MAPT/TAU, RIMS1, TUBG1, TUBG2 and WEE1. Following phosphorylation and activation by STK11/LKB1, acts as a key regulator of polarization of cortical neurons, probably by mediating phosphorylation of microtubule-associated proteins such as MAPT/TAU at 'Thr-529' and 'Ser-579'. Also regulates neuron polarization by mediating phosphorylation of WEE1 at 'Ser-642' in post-mitotic neurons, leading to down-regulate WEE1 activity in polarized neurons. In neurons, localizes to synaptic vesicles and plays a role in neurotransmitter release, possibly by phosphorylating RIMS1. Also acts as a positive regulator of centrosome duplication by mediating phosphorylation of gamma- tubulin (TUBG1 and TUBG2) at 'Ser-131', leading to translocation of gamma-tubulin and its associated proteins to the centrosome. Involved in the UV-induced DNA damage checkpoint response, probably by inhibiting CDK1 activity through phosphorylation and activation of WEE1, and inhibition of CDC25B and CDC25C. {ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15150265, ECO:0000269|PubMed:20026642, ECO:0000269|PubMed:21985311}. | 15.1 | ||||
| kccBTK | Tyrosine-protein kinase BTK | 9 | 341 | 96.77 | ND | 90.43 | 0.39 | ND | 1.4 | Mammalian | Predominantly expressed in B-lymphocytes. | Kinase | X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin. {ECO:0000269|PubMed:10220140, ECO:0000269|PubMed:10612838, ECO:0000269|PubMed:10678660, ECO:0000269|PubMed:7627183, ECO:0000269|PubMed:7633420, ECO:0000269|PubMed:7633429, ECO:0000269|PubMed:7711734, ECO:0000269|PubMed:7809124, ECO:0000269|PubMed:7849006, ECO:0000269|PubMed:7849697, ECO:0000269|PubMed:7849721, ECO:0000269|PubMed:7880320, ECO:0000269|PubMed:7897635, ECO:0000269|PubMed:8013627, ECO:0000269|PubMed:8162018, ECO:0000269|PubMed:8162056, ECO:0000269|PubMed:8634718, ECO:0000269|PubMed:8695804, ECO:0000269|PubMed:8723128, ECO:0000269|PubMed:8834236, ECO:0000269|PubMed:9260159, ECO:0000269|PubMed:9280283, ECO:0000269|PubMed:9445504, ECO:0000269|PubMed:9545398}. Note=The disease is caused by mutations affecting the gene represented in this entry. X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). Note=The disease may be caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. {ECO:0000269|PubMed:11606584, ECO:0000269|PubMed:16415872, ECO:0000269|PubMed:16517732, ECO:0000269|PubMed:16738337, ECO:0000269|PubMed:17932028, ECO:0000269|PubMed:9012831}. | Tyrosine-protein kinase BTK inhibitor: Ibrutinib | 15.1 | ||
| kccC11B1 | Cytochrome P450 11B1, mitochondrial | 21 | 447 | 99.15 | ND | 98.60 | 0.36 | ND | 0.8 | Mammalian | Cytochrome P450 | Adrenal hyperplasia 4 (AH4) [MIM:202010]: A form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late- onset (NC or LOAH)and 'cryptic' (asymptomatic). {ECO:0000269|PubMed:16046588, ECO:0000269|PubMed:2022736, ECO:0000269|PubMed:20331679, ECO:0000269|PubMed:20947076, ECO:0000269|PubMed:9302260}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperaldosteronism 1 (FH1) [MIM:103900]: A disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol. There is significant phenotypic heterogeneity, and some individuals never develop hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2. | Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochrome P450 XIB. | Cytochrome P450 11B1, mitochondrial inducer: Mitotane Cytochrome P450 11B1, mitochondrial inhibitor: Cimetidine, Clotrimazole, Etomidate, Fluconazole, Ketoconazole, Metoclopramide, Metyrapone, Miconazole, Phenytoin Cytochrome P450 11B1, mitochondrial inhibitor;inducer: Spironolactone Cytochrome P450 11B1, mitochondrial substrate: Hydrocortisone | 15.1 | |||
| kccC11B2 | Cytochrome P450 11B2, mitochondrial | 31 | 456 | 99.32 | ND | 99.20 | 0.60 | ND | 0.6 | Mammalian | Cytochrome P450 | Corticosterone methyloxidase 1 deficiency (CMO-1 deficiency) [MIM:203400]: Autosomal recessive disorder of aldosterone biosynthesis. There are two biochemically different forms of selective aldosterone deficiency be termed corticosterone methyloxidase (CMO) deficiency type 1 and type 2. In CMO-1 deficiency, aldosterone is undetectable in plasma, while its immediate precursor, 18-hydroxycorticosterone, is low or normal. {ECO:0000269|PubMed:11238478, ECO:0000269|PubMed:9177280}. Note=The disease is caused by mutations affecting the gene represented in this entry. Corticosterone methyloxidase 2 deficiency (CMO-2 deficiency) [MIM:610600]: Autosomal recessive disorder of aldosterone biosynthesis. In CMO-2 deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18- hydroxycorticosterone. Consequently, patients have a greatly increased ratio of 18-hydroxycorticosterone to aldosterone and a low ratio of corticosterone to 18-hydroxycorticosterone in serum. {ECO:0000269|PubMed:12788848, ECO:0000269|PubMed:1346492, ECO:0000269|PubMed:1594605, ECO:0000269|PubMed:9625333, ECO:0000269|PubMed:9814506}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperaldosteronism 1 (FH1) [MIM:103900]: A disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol. There is significant phenotypic heterogeneity, and some individuals never develop hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2. | Preferentially catalyzes the conversion of 11- deoxycorticosterone to aldosterone via corticosterone and 18- hydroxycorticosterone. {ECO:0000269|PubMed:23322723}. | Cytochrome P450 11B2, mitochondrial antagonist: Spironolactone Cytochrome P450 11B2, mitochondrial inducer: Metoclopramide Cytochrome P450 11B2, mitochondrial inhibitor: Eplerenone, Etomidate, Metyrapone Cytochrome P450 11B2, mitochondrial substrate: Hydrocortisone | 15.1 | |||
| kccC1R | Complement C1r subcomponent | 3 | 79 | 99.79 | ND | 99.91 | 0.40 | ND | 0.6 | Mammalian | Protease | C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system. | 15.1 | |||||
| kccC1S | Complement C1s subcomponent | 5 | 116 | 99.94 | ND | 99.52 | 0.44 | ND | 0.4 | Mammalian | Protease | Complement component C1s deficiency (C1SD) [MIM:613783]: A rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis. {ECO:0000269|PubMed:11390518}. Note=The disease is caused by mutations affecting the gene represented in this entry. | C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activate C2 and C4. | Cytochrome P450 11B2, mitochondrial antagonist: Spironolactone Cytochrome P450 11B2, mitochondrial inducer: Metoclopramide Cytochrome P450 11B2, mitochondrial inhibitor: Eplerenone, Etomidate, Metyrapone Cytochrome P450 11B2, mitochondrial substrate: Hydrocortisone | 15.1 | |||
| kccC3AR | C3a anaphylatoxin chemotactic receptor | 4 | 100 | 99.87 | ND | 99.95 | 0.25 | ND | 0.8 | Mammalian | Widely expressed in several differentiated hematopoietic cell lines, in the lung, spleen, ovary, placenta, small intestine, throughout the brain, heart, and endothelial cells. Mostly expressed in lymphoid tissues. | Family A G protein-coupled receptor | Receptor for the chemotactic and inflammatory peptide anaphylatoxin C3a. This receptor stimulates chemotaxis, granule enzyme release and superoxide anion production. | 15.1 | ||||
| kccC5AR1 | C5a anaphylatoxin chemotactic receptor 1 | 7 | 278 | 96.72 | ND | 98.77 | 0.44 | ND | 0.6 | Mammalian | Family A G protein-coupled receptor | Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:1847994, PubMed:8182049, PubMed:7622471, PubMed:9553099, PubMed:10636859, PubMed:15153520). The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events (PubMed:8182049, PubMed:7622471, PubMed:9553099). Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:10636859, PubMed:15153520). {ECO:0000269|PubMed:10636859, ECO:0000269|PubMed:15153520, ECO:0000269|PubMed:1847994, ECO:0000269|PubMed:7622471, ECO:0000269|PubMed:8182049, ECO:0000269|PubMed:9553099}. | 15.1 | |||||
| kccCA2D1 | Voltage-dependent calcium channel subunit alpha-2/delta-1 | 7 | 179 | 99.14 | ND | 98.45 | 0.53 | ND | 0.5 | Mammalian | Isoform 1 is expressed in skeletal muscle. Isoform 2 is expressed in the central nervous system. Isoform 2, isoform 4 and isoform 5 are expressed in neuroblastoma cells. Isoform 3, isoform 4 and isoform 5 are expressed in the aorta. {ECO:0000269|PubMed:1309651, ECO:0000269|PubMed:8107964}. | Arrhythmia Flushing Headache Oedema peripheral | Calcium channel auxiliary subunit alpha2delta family | Analgesics
Chronic stable angina Heart transplant Hypertension Vasospastic angina | The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction coupling (By similarity). {ECO:0000250}. | Voltage-dependent calcium channel subunit alpha-2/delta-1 activator: Ibutilide Voltage-dependent calcium channel subunit alpha-2/delta-1 inhibitor: Amlodipine, Cyclandelate, Felodipine, Gabapentin, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Nisoldipine, Nitrendipine Voltage-dependent calcium channel subunit alpha-2/delta-1 unknown: Magnesium Sulfate, Spironolactone | 15.1 | |
| kccCAC1B | Voltage-dependent N-type calcium channel subunit alpha-1B | 15 | 323 | 98.36 | ND | 99.03 | 0.79 | ND | 0.3 | Nature11159 | Mammalian | Isoform Alpha-1b-1 and isoform Alpha-1b-2 are expressed in the central nervous system, but not in skeletal muscle or aorta. | Flushing Oedema peripheral | Voltage-gated ion channel | Dystonia 23 (DYT23) [MIM:614860]: A form of dystonia, a disorder defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT23 is an autosomal dominant dystonia affecting the face, neck, limbs. Some DYT23 patients manifest generalized myoclonus in addition to progressive action-induced multifocal dystonia. {ECO:0000269|PubMed:25296916}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1B gives rise to N-type calcium currents. N-type calcium channels belong to the 'high-voltage activated' (HVA) group and are blocked by omega-conotoxin-GVIA (omega-CTx-GVIA) and by omega-agatoxin- IIIA (omega-Aga-IIIA). They are however insensitive to dihydropyridines (DHP), and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing alpha-1B subunit may play a role in directed migration of immature neurons. | Voltage-dependent N-type calcium channel subunit alpha-1B inhibitor: Amlodipine, Gabapentin, Levetiracetam, Verapamil Voltage-dependent N-type calcium channel subunit alpha-1B unknown: Spironolactone | 15.1 |
| kccCAC1C | Voltage-dependent L-type calcium channel subunit alpha-1C | 14 | 460 | 96.63 | ND | 98.29 | 0.76 | ND | 0.7 | Nature11159 | Mammalian | Expressed in brain, heart, jejunum, ovary, pancreatic beta-cells and vascular smooth muscle. Overall expression is reduced in atherosclerotic vascular smooth muscle. {ECO:0000269|PubMed:12176756, ECO:0000269|PubMed:17071743, ECO:0000269|PubMed:8392192}. | Arrhythmia Flushing Gingival hyperplasia Oedema peripheral | Voltage-gated ion channel | Timothy syndrome (TS) [MIM:601005]: Disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism. {ECO:0000269|PubMed:15454078, ECO:0000269|PubMed:15863612, ECO:0000269|PubMed:25260352}. Note=The disease is caused by mutations affecting the gene represented in this entry. Brugada syndrome 3 (BRGDA3) [MIM:611875]: A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:17224476}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds. Binding of calmodulin or CABP1 at the same regulatory sites results in an opposit effects on the channel function. {ECO:0000269|PubMed:12176756, ECO:0000269|PubMed:17071743, ECO:0000269|PubMed:7737988, ECO:0000269|PubMed:8392192, ECO:0000269|PubMed:9013606, ECO:0000269|PubMed:9607315}. | Voltage-dependent L-type calcium channel subunit alpha-1C activator: Ibutilide Voltage-dependent L-type calcium channel subunit alpha-1C inhibitor: Amlodipine, Cinnarizine, Drotaverine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil Voltage-dependent L-type calcium channel subunit alpha-1C unknown: Clevidipine, Dronedarone, Ethanol, Magnesium Sulfate, Spironolactone | 15.1 |
| kccCAC1D | Voltage-dependent L-type calcium channel subunit alpha-1D | 6 | 242 | 99.60 | ND | 99.82 | 0.48 | ND | 0.7 | Mammalian | Expressed in pancreatic islets and in brain, where it has been seen in cerebral cortex, hippocampus, basal ganglia, habenula and thalamus. Expressed in the small cell lung carcinoma cell line SCC-9. No expression in skeletal muscle. {ECO:0000269|PubMed:1335101}. | Arrhythmia Diplopia Flushing Oedema peripheral | Voltage-gated ion channel | Sinoatrial node dysfunction and deafness (SANDD) [MIM:614896]: A disease characterized by congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia. {ECO:0000269|PubMed:21131953}. Note=The disease is caused by mutations affecting the gene represented in this entry. Primary aldosteronism, seizures, and neurologic abnormalities (PASNA) [MIM:615474]: A disorder characterized by hypertension, hypokalemia, and high aldosterone levels with low plasma renin activity and an elevated aldosterone/renin ratio. Other features include generalized seizures, cerebral palsy, spasticity, intellectual disability, and developmental delay. {ECO:0000269|PubMed:23913001}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1D gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). {ECO:0000269|PubMed:18482979}. | Voltage-dependent L-type calcium channel subunit alpha-1D inhibitor: Amlodipine, Cinnarizine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil Voltage-dependent L-type calcium channel subunit alpha-1D unknown: Clevidipine, Dronedarone, Ethanol, Spironolactone | 15.1 | |
| kccCAC1G | Voltage-dependent T-type calcium channel subunit alpha-1G | 12 | 227 | 99.62 | ND | 98.77 | 0.23 | ND | 0.4 | Mammalian | Highly expressed in brain, in particular in the amygdala, subthalamic nuclei, cerebellum and thalamus. Moderate expression in heart; low expression in placenta, kidney and lung. Also expressed in colon and bone marrow and in tumoral cells to a lesser extent. Highly expressed in fetal brain, but also in peripheral fetal tissues as heart, kidney and lung, suggesting a developmentally regulated expression. | Voltage-gated ion channel | Analgesics
Angina pectoris Cardiac dysrhythmias Cardiovascular disease, unspecified Epilepsy Heart failure Hypertension Hypoinsulinemia Neuropathic pain | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. | Voltage-dependent T-type calcium channel subunit alpha-1G inhibitor: Cinnarizine, Ethosuximide, Flunarizine, Methsuximide, Trimethadione, Verapamil, Zonisamide Voltage-dependent T-type calcium channel subunit alpha-1G unknown: Spironolactone | 15.1 | ||
| kccCAC1H | Voltage-dependent T-type calcium channel subunit alpha-1H | 42 | 696 | 93.06 | ND | 89.92 | 0.32 | ND | 0.9 | Mammalian | Expressed in kidney, liver, heart, brain. Isoform 2 seems to be testis-specific. | Extrapyramidal disorder | Voltage-gated ion channel | Epilepsy, idiopathic generalized 6 (EIG6) [MIM:611942]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Epilepsy, childhood absence 6 (ECA6) [MIM:611942]: A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood. {ECO:0000269|PubMed:12891677}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1H gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. | Voltage-dependent T-type calcium channel subunit alpha-1H inhibitor: Amiodarone, Bepridil, Cinnarizine, Felodipine, Flunarizine, Isradipine, Nifedipine, Nitrendipine, Zonisamide Voltage-dependent T-type calcium channel subunit alpha-1H unknown: Spironolactone | 15.1 | |
| kccCAC1S | Voltage-dependent L-type calcium channel subunit alpha-1S | 4 | 80 | 99.90 | ND | 99.96 | 0.10 | ND | 0.5 | Mammalian | Skeletal muscle specific. | Voltage-gated ion channel | Periodic paralysis hypokalemic 1 (HOKPP1) [MIM:170400]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:17418573, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:7987325, ECO:0000269|PubMed:8004673}. Note=The disease is caused by mutations affecting the gene represented in this entry. Malignant hyperthermia 5 (MHS5) [MIM:601887]: Autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. {ECO:0000269|PubMed:9199552}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Thyrotoxic periodic paralysis 1 (TTPP1) [MIM:188580]: A sporadic muscular disorder characterized by episodic weakness and hypokalemia during a thyrotoxic state. It is clinically similar to hereditary hypokalemic periodic paralysis, except for the fact that hyperthyroidism is an absolute requirement for disease manifestation. The disease presents with recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Thyrotoxic periodic paralysis can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves disease. {ECO:0000269|PubMed:15001631}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle. | Voltage-dependent L-type calcium channel subunit alpha-1S inhibitor: Amlodipine, Cinnarizine, Felodipine, Isradipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Verapamil Voltage-dependent L-type calcium channel subunit alpha-1S unknown: Clevidipine, Dronedarone, Ethanol, Magnesium Sulfate, Spironolactone | 15.1 | ||
| kccCAH1 | Carbonic anhydrase 1 | 117 | 2851 | 95.15 | ND | 97.54 | 0.64 | ND | 0.7 | Mammalian | Aplastic anaemia Decreased appetite Electrolyte imbalance Glycosuria Gout Haemolysis Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Hyponatraemia Pancreatic disorder Pancreatitis Purine metabolism disorder Thrombocytopenia Xanthopsia | Lyase | Glaucoma
Hypertension Pancreatic cancer | Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea. {ECO:0000269|PubMed:10550681}. | Carbonic anhydrase 1 inhibitor: Acetazolamide, Amlodipine, Bendroflumethiazide, Benzthiazide, Brinzolamide, Chlorothiazide, Cyclothiazide, Diazoxide, Diclofenamide, Dorzolamide, Ethinamate, Hydrochlorothiazide, Hydroflumethiazide, Methazolamide, Methocarbamol, Methyclothiazide, Quinethazone, Trichlormethiazide, Zonisamide | 15.1 | ||
| kccCAH12 | Carbonic anhydrase 12 | 73 | 1156 | 93.40 | ND | 95.40 | 0.55 | ND | 0.9 | Mammalian | Highly expressed in colon, kidney, prostate, intestine and activated lymphocytes. Expressed at much higher levels in the renal cell cancers than in surrounding normal kidney tissue. Moderately expressed in pancreas, ovary and testis. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Photosensitivity reaction Purine metabolism disorder Thrombocytopenia | Lyase | Hyperchlorhidrosis, isolated (HCHLH) [MIM:143860]: A disorder characterized by excessive sweating and increased sweat chloride levels. Affected individuals suffer from episodes of hyponatremic dehydration and report increased amounts of visible salt precipitates in sweat. {ECO:0000269|PubMed:21035102}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Reversible hydration of carbon dioxide. | Carbonic anhydrase 12 inhibitor: Benzthiazide, Hydrochlorothiazide, Hydroflumethiazide, Zonisamide | 15.1 | |
| kccCAH13 | Carbonic anhydrase 13 | 11 | 222 | 90.93 | ND | 88.28 | 0.44 | ND | 1.2 | Mammalian | Expressed in thymus, small intestine, spleen, prostate, ovary, colon and testis. {ECO:0000269|PubMed:14600151}. | Electrolyte imbalance Haemorrhagic diathesis Hypokalaemia Paraesthesia | Lyase | Reversible hydration of carbon dioxide. | Carbonic anhydrase 13 inhibitor: Zonisamide | 15.1 | ||
| kccCAH14 | Carbonic anhydrase 14 | 20 | 384 | 89.45 | ND | 90.46 | 0.56 | ND | 0.9 | Mammalian | High expression in all parts of the central nervous system and lower expression in adult liver, heart, small intestine, colon, kidney, urinary bladder and skeletal muscle. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Photosensitivity reaction Purine metabolism disorder | Lyase | Renal failure | Reversible hydration of carbon dioxide. | Carbonic anhydrase 14 inhibitor: Acetazolamide, Zonisamide | 15.1 | |
| kccCAH15 | Carbonic anhydrase 15 | 2 | 77 | 83.85 | ND | 90.59 | 0.00 | ND | 1.4 | Mammalian | Enzyme | Reversible hydration of carbon dioxide. {ECO:0000250}. | 15.1 | |||||
| kccCAH2 | Carbonic anhydrase 2 | 117 | 3431 | 95.88 | ND | 97.93 | 0.69 | ND | 0.7 | Mammalian | Aplastic anaemia Decreased appetite Electrolyte imbalance Glycosuria Gout Haemolysis Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatic disorder Pancreatitis Photosensitivity reaction Pulmonary oedema Purine metabolism disorder Purpura Thrombocytopenia Xanthopsia | Lyase | Osteopetrosis, autosomal recessive 3 (OPTB3) [MIM:259730]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation. {ECO:0000269|PubMed:15300855, ECO:0000269|PubMed:1542674, ECO:0000269|PubMed:1928091, ECO:0000269|PubMed:8834238, ECO:0000269|PubMed:9143915}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate exchange activity of SLC26A6. {ECO:0000250, ECO:0000269|PubMed:10550681, ECO:0000269|PubMed:11831900, ECO:0000269|PubMed:15990874}. | Carbonic anhydrase 2 inhibitor: Acetazolamide, Bendroflumethiazide, Benzthiazide, Brinzolamide, Chlorothiazide, Cyclothiazide, Diazoxide, Diclofenamide, Dorzolamide, Ethinamate, Hydrochlorothiazide, Hydroflumethiazide, Methazolamide, Methyclothiazide, Quinethazone, Topiramate, Trichlormethiazide, Zonisamide Carbonic anhydrase 2 unknown: Furosemide | 15.1 | ||
| kccCAH3 | Carbonic anhydrase 3 | 4 | 112 | 84.82 | ND | 86.78 | 0.10 | ND | 0.8 | Mammalian | Muscle specific. | Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Paraesthesia | Lyase | Reversible hydration of carbon dioxide. | Carbonic anhydrase 3 inhibitor: Acetazolamide, Zonisamide | 15.1 | ||
| kccCAH4 | Carbonic anhydrase 4 | 31 | 1187 | 94.31 | ND | 97.55 | 0.67 | ND | 0.6 | Mammalian | Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels. {ECO:0000269|PubMed:15563508}. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatic disorder Pancreatitis Photosensitivity reaction Purine metabolism disorder Thirst Thrombocytopenia Xanthopsia | Lyase | Retinitis pigmentosa 17 (RP17) [MIM:600852]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:15563508, ECO:0000269|PubMed:17652713, ECO:0000269|PubMed:20450258}. Note=The disease is caused by mutations affecting the gene represented in this entry. Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype. | Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid. {ECO:0000269|PubMed:15563508}. | Carbonic anhydrase 4 inhibitor: Acetazolamide, Bendroflumethiazide, Benzthiazide, Brinzolamide, Chlorothiazide, Cyclothiazide, Diclofenamide, Dorzolamide, Hydrochlorothiazide, Hydroflumethiazide, Methazolamide, Methyclothiazide, Topiramate, Trichlormethiazide, Zonisamide | 15.1 | |
| kccCAH5A | Carbonic anhydrase 5A, mitochondrial | 14 | 198 | 88.07 | ND | 94.72 | 0.39 | ND | 1.3 | Mammalian | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Purine metabolism disorder | Lyase | Hyperammonemia due to carbonic anhydrase VA deficiency (CA5AD) [MIM:615751]: An autosomal recessive inborn error of metabolism, clinically characterized by infantile hyperammonemic encephalopathy. Metabolic abnormalities include hypoglycemia, hyperlactatemia, metabolic acidosis and respiratory alkalosis. {ECO:0000269|PubMed:24530203}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Reversible hydration of carbon dioxide. Low activity. | Carbonic anhydrase 5A, mitochondrial inhibitor: Brinzolamide, Zonisamide | 15.1 | ||
| kccCAH5B | Carbonic anhydrase 5B, mitochondrial | 6 | 153 | 86.18 | ND | 83.32 | 0.77 | ND | 0.8 | Mammalian | Strongest expression in heart, pancreas, kidney, placenta, lung, and skeletal muscle. Not expressed in liver. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Purine metabolism disorder | Lyase | Reversible hydration of carbon dioxide. | Carbonic anhydrase 5B, mitochondrial inhibitor: Zonisamide | 15.1 | ||
| kccCAH7 | Carbonic anhydrase 7 | 25 | 364 | 93.70 | ND | 94.45 | 0.53 | ND | 0.9 | Mammalian | Lyase | Reversible hydration of carbon dioxide. | Carbonic anhydrase 7 inhibitor: Acetazolamide, Diclofenamide, Methazolamide, Zonisamide | 15.1 | ||||
| kccCAH9 | Carbonic anhydrase 9 | 91 | 1585 | 96.02 | ND | 97.17 | 0.57 | ND | 0.8 | Mammalian | Expressed primarily in carcinoma cells lines. Expression is restricted to very few normal tissues and the most abundant expression is found in the epithelial cells of gastric mucosa. | Aplastic anaemia Electrolyte imbalance Glycosuria Gout Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatitis Purine metabolism disorder Thrombocytopenia | Lyase | Bladder cancer
Head and neck squamous cell carcinomas Pancreatic cancer Renal cell carcinoma | Reversible hydration of carbon dioxide. Participates in pH regulation. May be involved in the control of cell proliferation and transformation. Appears to be a novel specific biomarker for a cervical neoplasia. {ECO:0000269|PubMed:18703501}. | Carbonic anhydrase 9 inhibitor: Benzthiazide, Hydrochlorothiazide, Hydroflumethiazide, Zonisamide | 15.1 | |
| kccCALRL | Calcitonin gene-related peptide type 1 receptor | 14 | 541 | 99.97 | ND | 99.93 | 0.70 | ND | 0.9 | Mammalian | Predominantly expressed in the lung and heart. | Family B G protein-coupled receptor | Cluster Headaches
Diabetes mellitus Migraine Opioid dependence | Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. {ECO:0000250, ECO:0000269|PubMed:22102369}. | 15.1 | |||
| kccCAN1 | Calpain-1 catalytic subunit | 18 | 539 | 97.42 | ND | 99.73 | 0.72 | ND | 0.7 | Mammalian | Ubiquitous. | Protease | Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. | Calmodulin binder: Bepridil Calmodulin inhibitor: Aprindine, Cinchocaine, Fluphenazine, Loperamide, Nifedipine, Perphenazine, Phenoxybenzamine, Pimozide, Promethazine, Trifluoperazine Calmodulin other: Felodipine Calmodulin other/unknown: Isoflurane, Nicardipine Calmodulin unknown: Chlorpromazine, Flunarizine, Melatonin | 15.1 | |||
| kccCAN2 | Calpain-2 catalytic subunit | 10 | 202 | 86.05 | ND | 93.43 | 0.66 | ND | 0.9 | Mammalian | Ubiquitous. | Protease | Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Proteolytically cleaves MYOC at 'Arg-226' (PubMed:17650508). {ECO:0000269|PubMed:17650508}. | 15.1 | ||||
| kccCARM1 | Histone-arginine methyltransferase CARM1 | 3 | 96 | 97.86 | ND | 99.84 | 0.76 | ND | 0.6 | Mammalian | Overexpressed in prostate adenocarcinomas and high-grade prostatic intraepithelial neoplasia. {ECO:0000269|PubMed:15221992}. | Writer | Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg- 2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA- stabilizing properties and the half-life of their target mRNAs. {ECO:0000269|PubMed:16497732, ECO:0000269|PubMed:19405910}. | 15.1 | ||||
| kccCASP1 | Caspase-1 | 30 | 649 | 98.32 | ND | 98.49 | 0.66 | ND | 0.9 | Mammalian | Expressed in larger amounts in spleen and lung. Detected in liver, heart, small intestine, colon, thymus, prostate, skeletal muscle, peripheral blood leukocytes, kidney and testis. No expression in the brain. {ECO:0000269|PubMed:15498465}. | Protease | Brain inflammation
Cerebral ischemia Diabetic retinopathy Inflammation | Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis. {ECO:0000269|PubMed:15498465, ECO:0000269|PubMed:7876192}. | Caspase-1 negative modulator: Minocycline | 15.1 | ||
| kccCASP2 | Caspase-2 | 2 | 51 | 100.00 | ND | 99.98 | 0.78 | ND | 0.7 | Mammalian | Expressed at higher levels in the embryonic lung, liver and kidney than in the heart and brain. In adults, higher level expression is seen in the placenta, lung, kidney, and pancreas than in the heart, brain, liver and skeletal muscle. | Protease | Involved in the activation cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival. | 15.1 | ||||
| kccCASP3 | Caspase-3 | 36 | 1457 | 94.37 | ND | 94.93 | 0.80 | ND | 0.6 | Mammalian | Highly expressed in lung, spleen, heart, liver and kidney. Moderate levels in brain and skeletal muscle, and low in testis. Also found in many cell lines, highest expression in cells of the immune system. | Protease | Chronic experimental allergic encephalomyelitis
Dysregulation of apoptosis Multiple sclerosis Neurodegenerative diseases | Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop- helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage. {ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:7596430}. | Caspase-3 negative modulator: Minocycline | 15.1 | ||
| kccCASP6 | Caspase-6 | 4 | 170 | 96.20 | ND | 97.42 | 0.43 | ND | 0.5 | Mammalian | Protease | Not Available | Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. | 15.1 | ||||
| kccCASP7 | Caspase-7 | 8 | 348 | 99.25 | ND | 97.17 | 0.78 | ND | 0.7 | Mammalian | Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain. | Protease | Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly- 217' bond. Overexpression promotes programmed cell death. | Caspase-3 negative modulator: Minocycline | 15.1 | |||
| kccCASP8 | Caspase-8 | 9 | 328 | 99.22 | ND | 98.51 | 0.70 | ND | 0.8 | Mammalian | Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle. | Protease | Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. {ECO:0000269|PubMed:12353035}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:9006941}. | 15.1 | |||
| kccCASR | Extracellular calcium-sensing receptor | 16 | 426 | 99.13 | ND | 98.26 | 0.55 | ND | 0.7 | Mammalian | Expressed in the temporal lobe, frontal lobe, parietal lobe, hippocampus, and cerebellum. Also found in kidney, lung, liver, heart, skeletal muscle, placenta. {ECO:0000269|PubMed:18756473}. | Family C G protein-coupled receptor | Hypocalciuric hypercalcemia, familial 1 (HHC1) [MIM:145980]: A form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. It is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level. Hypermagnesemia is typically present. Affected individuals are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults. {ECO:0000269|PubMed:11762699, ECO:0000269|PubMed:15572418, ECO:0000269|PubMed:15579740, ECO:0000269|PubMed:15879434, ECO:0000269|PubMed:16598859, ECO:0000269|PubMed:17473068, ECO:0000269|PubMed:17698911, ECO:0000269|PubMed:21643651, ECO:0000269|PubMed:7673400, ECO:0000269|PubMed:7726161, ECO:0000269|PubMed:7916660, ECO:0000269|PubMed:9298824}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hyperparathyroidism, neonatal severe (NSHPT) [MIM:239200]: A disorder characterized by severe hypercalcemia, bone demineralization, and failure to thrive usually manifesting in the first 6 months of life. If untreated, NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. {ECO:0000269|PubMed:8675635, ECO:0000269|PubMed:9253359}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypocalcemia, autosomal dominant 1 (HYPOC1) [MIM:601198]: A disorder of mineral homeostasis characterized by blood calcium levels below normal, and low or normal serum parathyroid hormone concentrations. Disease manifestations include mild or asymptomatic hypocalcemia, paresthesias, carpopedal spasm, seizures, hypercalciuria with nephrocalcinosis or kidney stones, and ectopic and basal ganglia calcifications. Few patients manifest hypocalcemia and features of Bartter syndrome, including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. {ECO:0000269|PubMed:10487661, ECO:0000269|PubMed:12050233, ECO:0000269|PubMed:12107202, ECO:0000269|PubMed:12241879, ECO:0000269|PubMed:12574188, ECO:0000269|PubMed:12915654, ECO:0000269|PubMed:15551332, ECO:0000269|PubMed:16608894, ECO:0000269|PubMed:7874174, ECO:0000269|PubMed:8733126, ECO:0000269|PubMed:8813042, ECO:0000269|PubMed:9253358, ECO:0000269|PubMed:9661634, ECO:0000269|PubMed:9920108}. Note=The disease is caused by mutations affecting the gene represented in this entry. Epilepsy, idiopathic generalized 8 (EIG8) [MIM:612899]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Seizure types are variable, but include myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:18756473}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Homozygous defects in CASR can be a cause of primary hyperparathyroidism in adulthood. Patients suffer from osteoporosis and renal calculi, have marked hypercalcemia and increased serum PTH concentrations. | Senses changes in the extracellular concentration of calcium ions. The activity of this receptor is mediated by a G- protein that activates a phosphatidylinositol-calcium second messenger system. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | ||
| kccCATB | Cathepsin B | 53 | 1262 | 94.51 | ND | 97.09 | 0.71 | ND | 0.7 | Mammalian | Protease | Acute otitis media
Arthritis Ischemia Tumor angiogenesis | Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | |||
| kccCATC | Dipeptidyl peptidase 1 | 6 | 85 | 89.09 | ND | 93.49 | 0.51 | ND | 1.0 | Mammalian | Ubiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas. {ECO:0000269|PubMed:9092576}. | Protease | Papillon-Lefevre syndrome (PLS) [MIM:245000]: An autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees. {ECO:0000269|PubMed:10581027, ECO:0000269|PubMed:10662808, ECO:0000269|PubMed:11106356, ECO:0000269|PubMed:11158173, ECO:0000269|PubMed:11180012, ECO:0000269|PubMed:11180601, ECO:0000269|PubMed:11886537, ECO:0000269|PubMed:12112662, ECO:0000269|PubMed:12809647, ECO:0000269|PubMed:14974080, ECO:0000269|PubMed:15108292, ECO:0000269|PubMed:15991336}. Note=The disease is caused by mutations affecting the gene represented in this entry. Haim-Munk syndrome (HMS) [MIM:245010]: An autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis. {ECO:0000269|PubMed:10662807}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodontititis, aggressive, 1 (AP1) [MIM:170650]: A disease characterized by severe and protracted gingival infections, generalized or localized, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting. {ECO:0000269|PubMed:10662808, ECO:0000269|PubMed:14974080}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B. Can also activate neuraminidase and factor XIII. {ECO:0000269|PubMed:1586157}. | 15.1 | |||
| kccCATD | Cathepsin D | 28 | 1274 | 98.26 | ND | 98.47 | 0.52 | ND | 0.7 | Mammalian | Expressed in the aorta extrcellular space (at protein level). {ECO:0000269|PubMed:20551380}. | Protease | Ceroid lipofuscinosis, neuronal, 10 (CLN10) [MIM:610127]: A form of neuronal ceroid lipofuscinosis with onset at birth or early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. {ECO:0000269|PubMed:16670177, ECO:0000269|PubMed:16685649, ECO:0000269|PubMed:21990111}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Acid protease active in intracellular protein breakdown. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | ||
| kccCATE | Cathepsin E | 4 | 60 | 99.75 | ND | 100.00 | 0.10 | ND | 1.1 | Mammalian | Expressed abundantly in the stomach, the Clara cells of the lung and activated B-lymphocytes, and at lower levels in lymph nodes, skin and spleen. Not expressed in resting B- lymphocytes. {ECO:0000269|PubMed:11322887, ECO:0000269|PubMed:1370478, ECO:0000269|PubMed:8765029}. | Protease | May have a role in immune function. Probably involved in the processing of antigenic peptides during MHC class II-mediated antigen presentation. May play a role in activation-induced lymphocyte depletion in the thymus, and in neuronal degeneration and glial cell activation in the brain. {ECO:0000269|PubMed:8765029}. | 15.1 | ||||
| kccCATF | Cathepsin F | 3 | 49 | 94.25 | ND | 92.57 | 0.41 | ND | 0.7 | Mammalian | High expression levels in heart, skeletal muscle, brain, testis and ovary; moderate levels in prostate, placenta, liver and colon; and no detectable expression in peripheral leukocytes and thymus. | Protease | Ceroid lipofuscinosis, neuronal, 13 (CLN13) [MIM:615362]: A form of neuronal ceroid lipofuscinosis characterized by adult onset of progressive cognitive decline and motor dysfunction leading to dementia and often early death. Some patients develop seizures. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material. {ECO:0000269|PubMed:23297359}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | ||
| kccCATG | Cathepsin G | 9 | 208 | 92.49 | ND | 99.42 | 0.66 | ND | 0.9 | Mammalian | Protease | Alpha 1 Antitrypsin Deficiency
Atopic Dermatitis Chronic Obstructive Pulmonary Disease (COPD) | Serine protease with trypsin- and chymotrypsin-like specificity. Cleaves complement C3. Has antibacterial activity against the Gram-negative bacterium P.aeruginosa, antibacterial activity is inhibited by LPS from P.aeruginosa, Z-Gly-Leu-Phe- CH2Cl and phenylmethylsulfonyl fluoride. {ECO:0000269|PubMed:1861080, ECO:0000269|PubMed:1937776, ECO:0000269|PubMed:8194606}. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | |||
| kccCATK | Cathepsin K | 70 | 1569 | 97.66 | ND | 99.31 | 0.69 | ND | 0.8 | Mammalian | Predominantly expressed in osteoclasts (bones). | Protease | Pycnodysostosis (PKND) [MIM:265800]: A rare autosomal recessive bone disorder characterized by deformity of the skull, maxilla and phalanges, osteosclerosis, and fragility of bone. {ECO:0000269|PubMed:10491211, ECO:0000269|PubMed:10878663, ECO:0000269|PubMed:8703060, ECO:0000269|PubMed:9529353}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | ||
| kccCATL1 | Cathepsin L1 | 58 | 1350 | 96.15 | ND | 97.54 | 0.58 | ND | 0.8 | Mammalian | Protease | Autoimmune diseases
Melanoma | Important for the overall degradation of proteins in lysosomes. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | |||
| kccCATL2 | Cathepsin L2 | 9 | 129 | 96.50 | ND | 99.89 | 0.46 | ND | 0.8 | Mammalian | Predominantly expressed in the thymus and testis. Also expressed in corneal epithelium, and to a lesser extent in conjunctival epithelium and skin. {ECO:0000269|PubMed:10029531, ECO:0000269|PubMed:9563472, ECO:0000269|PubMed:9727401}. | Protease | Cysteine protease. May have an important role in corneal physiology. {ECO:0000269|PubMed:10029531, ECO:0000269|PubMed:9727401}. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | |||
| kccCATS | Cathepsin S | 57 | 1412 | 98.43 | ND | 99.05 | 0.63 | ND | 0.7 | Mammalian | Protease | Autoimmune diseases
Psoriasis and Psoriatic Disorders | Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules. The bond- specificity of this proteinase is in part similar to the specificities of cathepsin L and cathepsin N. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | |||
| kccCBP | CREB-binding protein | 5 | 141 | 94.35 | ND | 92.89 | 0.03 | ND | 1.2 | Mammalian | Writer | Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Rubinstein-Taybi syndrome 1 (RSTS1) [MIM:180849]: A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. {ECO:0000269|PubMed:11331617, ECO:0000269|PubMed:12114483, ECO:0000269|PubMed:12566391, ECO:0000269|PubMed:15706485, ECO:0000269|PubMed:20684013, ECO:0000269|PubMed:25388907}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK- ARNTL/BMAL1 heterodimers. Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). {ECO:0000269|PubMed:11154691, ECO:0000269|PubMed:12738767, ECO:0000269|PubMed:12929931, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:24939902, ECO:0000269|PubMed:9707565}. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | |||
| kccCBPA1 | Carboxypeptidase A1 | 8 | 136 | 98.08 | ND | 97.18 | 0.62 | ND | 0.6 | Mammalian | Protease | Carboxypeptidase that catalyzes the release of a C- terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro. {ECO:0000269|PubMed:8806703}. | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | ||||
| kccCBPB1 | Carboxypeptidase B | 8 | 77 | 95.11 | ND | 95.70 | 0.41 | ND | 1.2 | Mammalian | Pancreas. | Protease | Extracellular calcium-sensing receptor agonist: Cinacalcet | 15.1 | ||||
| kccCBPB2 | Carboxypeptidase B2 | 5 | 87 | 99.66 | ND | 99.95 | 0.45 | ND | 0.9 | Mammalian | Plasma; synthesized in the liver. | Protease | Thrombosis | Cleaves C-terminal arginine or lysine residues from biologically active peptides such as kinins or anaphylatoxins in the circulation thereby regulating their activities. Down- regulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin. {ECO:0000269|PubMed:10574983}. | 15.1 | |||
| kccCCKAR | Cholecystokinin receptor type A | 19 | 1675 | 98.86 | ND | 99.12 | 0.61 | ND | 0.8 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Acid-related diseases
Alcoholism Gastroesophageal Reflux Disease (GERD) Gastrointestinal Diseases and Disorders, miscellaneous Gastrointestinal motility disorders Irritable Bowel Syndrome (IBS) Obesity Pancreatic Cancer | Receptor for cholecystokinin. Mediates pancreatic growth and enzyme secretion, smooth muscle contraction of the gall bladder and stomach. Has a 1000-fold higher affinity for CCK rather than for gastrin. It modulates feeding and dopamine-induced behavior in the central and peripheral nervous system. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. | Cholecystokinin receptor type A inducer: Ceruletide | 15.1 | ||
| kccCCR1 | C-C chemokine receptor type 1 | 17 | 576 | 97.82 | ND | 99.02 | 0.54 | ND | 0.8 | Mammalian | Widely expressed in different hematopoietic cells. | Family A G protein-coupled receptor | Autoimmune diseases
Chronic inflammatory diseases Ovarian cancer Renal fibrosis | Receptor for a C-C type chemokine. Binds to MIP-1-alpha, MIP-1-delta, RANTES, and MCP-3 and, less efficiently, to MIP-1- beta or MCP-1 and subsequently transduces a signal by increasing the intracellular calcium ions level. Responsible for affecting stem cell proliferation. | 15.1 | |||
| kccCCR2 | C-C chemokine receptor type 2 | 28 | 1250 | 99.31 | ND | 99.24 | 0.65 | ND | 0.6 | Mammalian | Family A G protein-coupled receptor | Inflammatory demyelination
Multiple Sclerosis (MS) Obese Insulin-resistant Subjects Rheumatoid arthritis | Receptor for the CCL2, CCL7 and CCL13 chemokines. Transduces a signal by increasing intracellular calcium ion levels. Alternative coreceptor with CD4 for HIV-1 infection. {ECO:0000269|PubMed:23408426}. | 15.1 | ||||
| kccCCR3 | C-C chemokine receptor type 3 | 33 | 871 | 99.63 | ND | 99.58 | 0.75 | ND | 0.6 | Mammalian | In eosinophils as well as trace amounts in neutrophils and monocytes. | Family A G protein-coupled receptor | Allergic diseases | Receptor for a C-C type chemokine. Binds to eotaxin, eotaxin-3, MCP-3, MCP-4, RANTES and MIP-1 delta. Subsequently transduces a signal by increasing the intracellular calcium ions level. Alternative coreceptor with CD4 for HIV-1 infection. | 15.1 | |||
| kccCCR4 | C-C chemokine receptor type 4 | 15 | 314 | 97.97 | ND | 98.86 | 0.64 | ND | 0.5 | Mammalian | Predominantly expressed in the thymus, in peripheral blood leukocytes, including T-cells, mostly CD4+ cells, and basophils, and in platelets; at lower levels, in the spleen and in monocytes. Detected also in macrophages, IL-2-activated natural killer cells and skin-homing memory T-cells, mostly the ones expressing the cutaneous lymphocyte antigen (CLA). Expressed in brain microvascular and coronary artery endothelial cells. {ECO:0000269|PubMed:10754297}. | Family A G protein-coupled receptor | Asthma | High affinity receptor for the C-C type chemokines CCL17/TARC, CCL22/MDC and CKLF isoform 1/CKLF1. The activity of this receptor is mediated by G(i) proteins which activate a phosphatidylinositol-calcium second messenger system. Can function as a chemoattractant homing receptor on circulating memory lymphocytes and as a coreceptor for some primary HIV-2 isolates. In the CNS, could mediate hippocampal-neuron survival. {ECO:0000269|PubMed:10466728, ECO:0000269|PubMed:10754297, ECO:0000269|PubMed:16137713, ECO:0000269|PubMed:9169480, ECO:0000269|PubMed:9430724}. | 15.1 | |||
| kccCCR5 | C-C chemokine receptor type 5 | 39 | 1648 | 98.28 | ND | 98.80 | 0.75 | ND | 0.6 | Mammalian | Highly expressed in spleen, thymus, in the myeloid cell line THP-1, in the promyeloblastic cell line KG-1a and on CD4+ and CD8+ T-cells. Medium levels in peripheral blood leukocytes and in small intestine. Low levels in ovary and lung. {ECO:0000269|PubMed:8639485, ECO:0000269|PubMed:8663314}. | Family A G protein-coupled receptor | Diabetes mellitus, insulin-dependent, 22 (IDDM22) [MIM:612522]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:19073967}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for a number of inflammatory CC-chemokines including MIP-1-alpha, MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a role in the control of granulocytic lineage proliferation or differentiation. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 R5 isolates. {ECO:0000269|PubMed:11323418, ECO:0000269|PubMed:8639485, ECO:0000269|PubMed:8649511, ECO:0000269|PubMed:8649512, ECO:0000269|PubMed:8663314, ECO:0000269|PubMed:8699119}. (Microbial infection) Acts as a receptor for human immunodeficiency virus-1/HIV-1. {ECO:0000269|PubMed:21763489, ECO:0000269|PubMed:9632396}. | C-C chemokine receptor type 5 antagonist: Maraviroc | 15.1 | ||
| kccCCR8 | C-C chemokine receptor type 8 | 7 | 163 | 99.77 | ND | 99.97 | 0.58 | ND | 0.8 | Mammalian | Family A G protein-coupled receptor | Allergic diseases | Receptor for the chemokine CCL1/SCYA1/I-309. May regulate monocyte chemotaxis and thymic cell line apoptosis. Alternative coreceptor with CD4 for HIV-1 infection. {ECO:0000269|PubMed:10540332, ECO:0000269|PubMed:9207005, ECO:0000269|PubMed:9469461, ECO:0000269|PubMed:9521068}. | 15.1 | ||||
| kccCD36 | Platelet glycoprotein 4 | 2 | 48 | 99.82 | ND | 99.90 | 0.47 | ND | 0.2 | Mammalian | Platelet glycoprotein IV deficiency (PG4D) [MIM:608404]: A disorder characterized by macrothrombocytopenia without notable hemostatic problems and bleeding tendency. Platelet glycoprotein IV deficiency can be divided into 2 subgroups. The type I phenotype is characterized by platelets and monocytes/macrophages exhibiting complete CD36 deficiency. The type II phenotype lacks the surface expression of CD36 in platelets, but expression in monocytes/macrophages is near normal. {ECO:0000269|PubMed:11950861, ECO:0000269|PubMed:7533783}. Note=The disease is caused by mutations affecting the gene represented in this entry. Coronary heart disease 7 (CHDS7) [MIM:610938]: A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. {ECO:0000269|PubMed:15282206}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Binds to collagen, thrombospondin, anionic phospholipids and oxidized low-density lipoprotein (oxLDL). May function as a cell adhesion molecule. Directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. Binds long chain fatty acids and may function in the transport and/or as a regulator of fatty acid transport. Receptor for thombospondins, THBS1 AND THBS2, mediating their antiangiogenic effects. As a coreceptor for TLR4-TLR6 heterodimer, promotes inflammation in monocytes/macrophages. Upon ligand binding, such as oxLDL or amyloid-beta 42, rapidly induces the formation of a heterodimer of TLR4 and TLR6, which is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. {ECO:0000269|PubMed:10890433, ECO:0000269|PubMed:12506336, ECO:0000269|PubMed:20037584}. | 15.1 | |||||
| kccCDC7 | Cell division cycle 7-related protein kinase | 20 | 458 | 98.17 | ND | 96.57 | 0.52 | ND | 0.8 | Mammalian | Kinase | Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3. {ECO:0000269|PubMed:12065429}. | 15.1 | |||||
| kccCDK1 | Cyclin-dependent kinase 1 | 57 | 1152 | 97.22 | ND | 96.62 | 0.39 | ND | 1.0 | Mammalian | Isoform 2 is found in breast cancer tissues. | Kinase | Cancer, unspecific
Malaria | Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins. Required in higher cells for entry into S-phase and mitosis. Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl- xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SIRT2 and RUNX2. CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs. Essential for early stages of embryonic development. During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation. Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis. Inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation upon DNA damage to stop cell cycle and genome replication at the G2 checkpoint thus facilitating DNA repair. Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C- mediated dephosphorylation and restoring cell cycle progression. In proliferating cells, CDK1-mediated FOXO1 phosphorylation at the G2-M phase represses FOXO1 interaction with 14-3-3 proteins and thereby promotes FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons. The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis. NEDD1 phosphorylation promotes PLK1-mediated NEDD1 phosphorylation and subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis. The phosphorylation of Bcl- xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis. In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration. {ECO:0000269|PubMed:16371510, ECO:0000269|PubMed:16407259, ECO:0000269|PubMed:16933150, ECO:0000269|PubMed:17459720, ECO:0000269|PubMed:18356527, ECO:0000269|PubMed:18480403, ECO:0000269|PubMed:19509060, ECO:0000269|PubMed:19917720, ECO:0000269|PubMed:20171170, ECO:0000269|PubMed:20360007, ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20935635, ECO:0000269|PubMed:20937773, ECO:0000269|PubMed:21063390}. | C-C chemokine receptor type 5 antagonist: Maraviroc | 15.1 | ||
| kccCDK19 | Cyclin-dependent kinase 19 | 2 | 97 | 97.80 | ND | 98.93 | 0.07 | ND | 1.0 | Mammalian | Kinase | 15.1 | ||||||
| kccCDK2 | Cyclin-dependent kinase 2 | 97 | 1916 | 96.97 | ND | 95.07 | 0.59 | ND | 0.9 | Mammalian | Kinase | Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML) Advanced Solid tumors B-cell malignancies Cancer, unspecific Cardiovascular disease, unspecified Chronic lymphocytic leukemia (CLL) Hepatocellular Carcinoma (HCC) Nasopharyngeal Cancer (NPC) Non-Hodgkin's Lymphoma Non-small Cell Lung Cancer Solid tumors Viral infection, unspecified | Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Interacts with cyclins A, B1, B3, D, or E. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT- mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). {ECO:0000250|UniProtKB:P97377, ECO:0000269|PubMed:10499802, ECO:0000269|PubMed:10884347, ECO:0000269|PubMed:10995386, ECO:0000269|PubMed:10995387, ECO:0000269|PubMed:11051553, ECO:0000269|PubMed:11113184, ECO:0000269|PubMed:15800615, ECO:0000269|PubMed:17495531, ECO:0000269|PubMed:18372919, ECO:0000269|PubMed:19966300, ECO:0000269|PubMed:20079829, ECO:0000269|PubMed:20147522, ECO:0000269|PubMed:20195506, ECO:0000269|PubMed:20935635, ECO:0000269|PubMed:21262353, ECO:0000269|PubMed:21319273, ECO:0000269|PubMed:21596315}. | Cyclin-dependent kinase 2 inhibitor: Bosutinib | 15.1 | |||
| kccCDK4 | Cyclin-dependent kinase 4 | 20 | 528 | 98.46 | ND | 95.52 | 0.51 | ND | 0.8 | Mammalian | Kinase | Melanoma, cutaneous malignant 3 (CMM3) [MIM:609048]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:7652577, ECO:0000269|PubMed:8528263, ECO:0000269|PubMed:9311594, ECO:0000269|PubMed:9425228}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. {ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:18827403, ECO:0000269|PubMed:9003781}. | Cyclin-dependent kinase 4 Inhibitor: Palbociclib | 15.1 | |||
| kccCDK5 | Cyclin-dependent-like kinase 5 | 32 | 625 | 96.00 | ND | 93.41 | 0.23 | ND | 1.4 | Mammalian | Isoform 1 is ubiquitously expressed. Accumulates in cortical neurons (at protein level). Isoform 2 has only been detected in testis, skeletal muscle, colon, bone marrow and ovary. {ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:19693690}. | Kinase | Lissencephaly 7, with cerebellar hypoplasia (LIS7) [MIM:616342]: A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six- layered cortex. LIS7 patients manifest lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy. {ECO:0000269|PubMed:25560765}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3- type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma- dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin- dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1- EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution. {ECO:0000269|PubMed:12393264, ECO:0000269|PubMed:12691662, ECO:0000269|PubMed:15992363, ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:17121855, ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17611284, ECO:0000269|PubMed:17671990, ECO:0000269|PubMed:18042622, ECO:0000269|PubMed:19081376, ECO:0000269|PubMed:19693690, ECO:0000269|PubMed:20061803, ECO:0000269|PubMed:20213743, ECO:0000269|PubMed:20826806, ECO:0000269|PubMed:21209322, ECO:0000269|PubMed:21220307, ECO:0000269|PubMed:21442427, ECO:0000269|PubMed:21465480, ECO:0000269|PubMed:21499257, ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:9822744}. | Cyclin-dependent kinase 4 Inhibitor: Palbociclib | 15.1 | ||
| kccCDK7 | Cyclin-dependent kinase 7 | 14 | 293 | 94.71 | ND | 91.17 | 0.17 | ND | 1.6 | Mammalian | Ubiquitous. | Kinase | B-cell malignancies
Cancer, unspecific Solid tumors | Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. Cyclin- dependent kinases (CDKs) are activated by the binding to a cyclin and mediate the progression through the cell cycle. Each different complex controls a specific transition between 2 subsequent phases in the cell cycle. Required for both activation and complex formation of CDK1/cyclin-B during G2-M transition, and for activation of CDK2/cyclins during G1-S transition (but not complex formation). CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Phosphorylates SPT5/SUPT5H, SF1/NR5A1, POLR2A, p53/TP53, CDK1, CDK2, CDK4, CDK6 and CDK11B/CDK11. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation, thus regulating cell cycle progression. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Phosphorylation of POLR2A in complex with DNA promotes transcription initiation by triggering dissociation from DNA. Its expression and activity are constant throughout the cell cycle. Upon DNA damage, triggers p53/TP53 activation by phosphorylation, but is inactivated in turn by p53/TP53; this feedback loop may lead to an arrest of the cell cycle and of the transcription, helping in cell recovery, or to apoptosis. Required for DNA-bound peptides-mediated transcription and cellular growth inhibition. {ECO:0000269|PubMed:10024882, ECO:0000269|PubMed:11113184, ECO:0000269|PubMed:16327805, ECO:0000269|PubMed:17373709, ECO:0000269|PubMed:17386261, ECO:0000269|PubMed:17901130, ECO:0000269|PubMed:19015234, ECO:0000269|PubMed:19071173, ECO:0000269|PubMed:19136461, ECO:0000269|PubMed:19450536, ECO:0000269|PubMed:19667075, ECO:0000269|PubMed:20360007, ECO:0000269|PubMed:9372954, ECO:0000269|PubMed:9840937}. | Cyclin-dependent kinase 4 Inhibitor: Palbociclib | 15.1 | ||
| kccCDK8 | Cyclin-dependent kinase 8 | 11 | 264 | 92.94 | ND | 88.64 | 0.47 | ND | 1.4 | Mammalian | Kinase | Cancer, unspecific | Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. {ECO:0000269|PubMed:10993082, ECO:0000269|PubMed:15546612}. | Cyclin-dependent kinase 4 Inhibitor: Palbociclib | 15.1 | |||
| kccCDK9 | Cyclin-dependent kinase 9 | 11 | 264 | 92.05 | ND | 87.72 | 0.20 | ND | 1.6 | Mammalian | Ubiquitous. | Kinase | Note=Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy, and confers predisposition to heart failure. | Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single- stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation. {ECO:0000269|PubMed:10393184, ECO:0000269|PubMed:10574912, ECO:0000269|PubMed:10757782, ECO:0000269|PubMed:10912001, ECO:0000269|PubMed:11112772, ECO:0000269|PubMed:11145967, ECO:0000269|PubMed:11575923, ECO:0000269|PubMed:11809800, ECO:0000269|PubMed:11884399, ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:14701750, ECO:0000269|PubMed:15564463, ECO:0000269|PubMed:16109376, ECO:0000269|PubMed:16109377, ECO:0000269|PubMed:17956865, ECO:0000269|PubMed:18362169, ECO:0000269|PubMed:19575011, ECO:0000269|PubMed:19844166, ECO:0000269|PubMed:20081228, ECO:0000269|PubMed:20493174, ECO:0000269|PubMed:20930849, ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:21127351, ECO:0000269|PubMed:9857195}. | Cyclin-dependent kinase 4 Inhibitor: Palbociclib | 15.1 | ||
| kccCEGT | Ceramide glucosyltransferase | 3 | 112 | 99.29 | ND | 99.89 | 0.65 | ND | 0.9 | Mammalian | Found in all tissues examined. {ECO:0000269|PubMed:8643456}. | Transferase | Sphingolipid storage disorders | Catalyzes the first glycosylation step in glycosphingolipid biosynthesis, the transfer of glucose to ceramide. May also serve as a "flippase". {ECO:0000269|PubMed:8643456}. | Ceramide glucosyltransferase antagonist: Eliglustat Ceramide glucosyltransferase inhibitor: Miglustat | 15.1 | ||
| kccCEL2A | Chymotrypsin-like elastase family member 2A | 5 | 84 | 97.65 | ND | 91.17 | 0.37 | ND | 1.1 | Mammalian | Pancreas. Not detected in keratinocytes. {ECO:0000269|PubMed:10620133}. | peptidase S1 | Acts upon elastin. | Ceramide glucosyltransferase antagonist: Eliglustat Ceramide glucosyltransferase inhibitor: Miglustat | 15.1 | |||
| kccCETP | Cholesteryl ester transfer protein {ECO:0000303|PubMed:3600759} | 12 | 676 | 96.95 | ND | 99.41 | 0.61 | ND | 0.6 | Mammalian | Expressed by the liver and secreted in plasma. | Other ion channel | Hyperalphalipoproteinemia 1 (HALP1) [MIM:143470]: A condition characterized by high levels of high density lipoprotein (HDL) and increased HDL cholesterol levels. {ECO:0000269|PubMed:12091484, ECO:0000269|PubMed:2215607, ECO:0000269|PubMed:8408659}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles. Allows the net movement of cholesteryl ester from high density lipoproteins/HDL to triglyceride-rich very low density lipoproteins/VLDL, and the equimolar transport of triglyceride from VLDL to HDL (PubMed:3600759, PubMed:24293641). Regulates the reverse cholesterol transport, by which excess cholesterol is removed from peripheral tissues and returned to the liver for elimination (PubMed:17237796). {ECO:0000269|PubMed:24293641, ECO:0000303|PubMed:17237796, ECO:0000305|PubMed:3600759}. | 15.1 | |||
| kccCFTR | Cystic fibrosis transmembrane conductance regulator | 4 | 130 | 99.86 | ND | 99.93 | 0.89 | ND | 0.4 | Mammalian | Expressed in the respiratory airway, including bronchial epithelium, and in the female reproductive tract, including oviduct (at protein level). {ECO:0000269|PubMed:22207244}. | Other ion channel | Cystic fibrosis (CF) [MIM:219700]: A common generalized disorder of the exocrine glands which impairs clearance of secretions in a variety of organs. It is characterized by the triad of chronic bronchopulmonary disease (with recurrent respiratory infections), pancreatic insufficiency (which leads to malabsorption and growth retardation) and elevated sweat electrolytes. It is the most common genetic disease in Caucasians, with a prevalence of about 1 in 2'000 live births. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10094564, ECO:0000269|PubMed:1284466, ECO:0000269|PubMed:1284468, ECO:0000269|PubMed:1284529, ECO:0000269|PubMed:1284530, ECO:0000269|PubMed:1695717, ECO:0000269|PubMed:1710600, ECO:0000269|PubMed:2236053, ECO:0000269|PubMed:7504969, ECO:0000269|PubMed:7505694, ECO:0000269|PubMed:7513296, ECO:0000269|PubMed:7517264, ECO:0000269|PubMed:7520022, ECO:0000269|PubMed:7522211, ECO:0000269|PubMed:7524909, ECO:0000269|PubMed:7524913, ECO:0000269|PubMed:7525450, ECO:0000269|PubMed:7537150, ECO:0000269|PubMed:7541273, ECO:0000269|PubMed:7541510, ECO:0000269|PubMed:7543567, ECO:0000269|PubMed:7544319, ECO:0000269|PubMed:7581407, ECO:0000269|PubMed:7680525, ECO:0000269|PubMed:7683628, ECO:0000269|PubMed:7683954, ECO:0000269|PubMed:8081395, ECO:0000269|PubMed:8522333, ECO:0000269|PubMed:8723693, ECO:0000269|PubMed:8723695, ECO:0000269|PubMed:8800923, ECO:0000269|PubMed:8829633, ECO:0000269|PubMed:8956039, ECO:0000269|PubMed:9101301, ECO:0000269|PubMed:9222768, ECO:0000269|PubMed:9375855, ECO:0000269|PubMed:9401006, ECO:0000269|PubMed:9443874, ECO:0000269|PubMed:9452048, ECO:0000269|PubMed:9452054, ECO:0000269|PubMed:9452073, ECO:0000269|PubMed:9482579, ECO:0000269|PubMed:9521595, ECO:0000269|PubMed:9554753, ECO:0000269|PubMed:9736778, ECO:0000269|PubMed:9921909}. Note=The disease is caused by mutations affecting the gene represented in this entry. Congenital bilateral absence of the vas deferens (CBAVD) [MIM:277180]: Important cause of sterility in men and could represent an incomplete form of cystic fibrosis, as the majority of men suffering from cystic fibrosis lack the vas deferens. {ECO:0000269|PubMed:10651488, ECO:0000269|PubMed:7529962, ECO:0000269|PubMed:7539342, ECO:0000269|PubMed:9067761, ECO:0000269|Ref.77}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO1. Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation. {ECO:0000269|PubMed:22178883}. | Cystic fibrosis transmembrane conductance regulator antagonist: Bumetanide, Glyburide Cystic fibrosis transmembrane conductance regulator inhibitor: Ibuprofen Cystic fibrosis transmembrane conductance regulator potentiator: Ivacaftor | 15.1 | ||
| kccCHK1 | Serine/threonine-protein kinase Chk1 | 60 | 1721 | 98.45 | ND | 96.77 | 0.62 | ND | 0.9 | Mammalian | Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon. {ECO:0000269|PubMed:9278511, ECO:0000269|PubMed:9382850}. | Kinase | Solid tumors | Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser- 124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell- cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest. Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition. | Cystic fibrosis transmembrane conductance regulator antagonist: Bumetanide, Glyburide Cystic fibrosis transmembrane conductance regulator inhibitor: Ibuprofen Cystic fibrosis transmembrane conductance regulator potentiator: Ivacaftor | 15.1 | ||
| kccCHK2 | Serine/threonine-protein kinase Chk2 | 25 | 528 | 95.09 | ND | 90.29 | 0.45 | ND | 1.1 | Mammalian | High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues. | Kinase | Li-Fraumeni syndrome 2 (LFS2) [MIM:609265]: A highly penetrant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers. {ECO:0000269|PubMed:11719428}. Note=The disease is caused by mutations affecting the gene represented in this entry. Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:12533788}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Osteogenic sarcoma (OSRC) [MIM:259500]: A sarcoma originating in bone-forming cells, affecting the ends of long bones. Note=The gene represented in this entry may be involved in disease pathogenesis. Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:12094328, ECO:0000269|PubMed:21618645, ECO:0000269|PubMed:25619829}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. {ECO:0000269|PubMed:12094328}. | Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X- R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition (PubMed:25361978). {ECO:0000250|UniProtKB:Q9Z265, ECO:0000269|PubMed:10097108, ECO:0000269|PubMed:10724175, ECO:0000269|PubMed:11298456, ECO:0000269|PubMed:12402044, ECO:0000269|PubMed:12607004, ECO:0000269|PubMed:12717439, ECO:0000269|PubMed:12810724, ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:17101782, ECO:0000269|PubMed:17380128, ECO:0000269|PubMed:17715138, ECO:0000269|PubMed:18317453, ECO:0000269|PubMed:18644861, ECO:0000269|PubMed:18728393, ECO:0000269|PubMed:20364141, ECO:0000269|PubMed:25361978, ECO:0000269|PubMed:25619829, ECO:0000269|PubMed:9836640, ECO:0000269|PubMed:9889122}. | 15.1 | |||
| kccCHLE | Cholinesterase | 101 | 2662 | 92.46 | ND | 96.93 | 0.73 | ND | 0.7 | Mammalian | Detected in blood plasma (at protein level). Present in most cells except erythrocytes. {ECO:0000269|PubMed:19368529, ECO:0000269|PubMed:19542320}. | Bradycardia Salivary hypersecretion | Hydrolase | Butyrylcholinesterase deficiency (BChE deficiency) [MIM:177400]: A metabolic disorder characterized by prolonged apnea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnea varies significantly depending on the extent of the enzyme deficiency. {ECO:0000269|PubMed:10404729, ECO:0000269|PubMed:11928765, ECO:0000269|PubMed:12881446, ECO:0000269|PubMed:1306123, ECO:0000269|PubMed:1349196, ECO:0000269|PubMed:1415224, ECO:0000269|PubMed:15563885, ECO:0000269|PubMed:15781196, ECO:0000269|PubMed:1611188, ECO:0000269|PubMed:16788378, ECO:0000269|PubMed:17700357, ECO:0000269|PubMed:18075469, ECO:0000269|PubMed:18300943, ECO:0000269|PubMed:25054547, ECO:0000269|PubMed:25264279, ECO:0000269|PubMed:2915989, ECO:0000269|PubMed:7634491, ECO:0000269|PubMed:8554068, ECO:0000269|PubMed:8680411, ECO:0000269|PubMed:9110359, ECO:0000269|PubMed:9191541, ECO:0000269|PubMed:9388484, ECO:0000269|PubMed:9543549, ECO:0000269|PubMed:9694584}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters. {ECO:0000269|PubMed:19452557, ECO:0000269|PubMed:19542320}. | Cholinesterase activator: Pralidoxime Cholinesterase antagonist: Pyridostigmine Cholinesterase inducer: Chlorphenesin, Pentagastrin, Triamcinolone Cholinesterase inhibitor: Chlorpromazine, Cinchocaine, Cisplatin, Decamethonium, Demecarium, Diethylcarbamazine, Echothiophate, Edrophonium, Ethopropazine, Galantamine, Hexafluronium, Isoflurophate, Malathion, Mefloquine, Nizatidine, Pancuronium, Perindopril, Pipecuronium, Procainamide, Procaine, Ramipril, Rivastigmine, Sulpiride, Terbutaline, Triflupromazine Cholinesterase potentiator: Dipivefrin Cholinesterase product of: Choline Cholinesterase substrate: Aclidinium, Chloroprocaine, Clevidipine, Cyclopentolate, Doxacurium chloride, Drospirenone, Ephedrine, Irinotecan, Mirabegron, Oxybuprocaine, Succinylcholine Cholinesterase substrate;inhibitor: Bambuterol Cholinesterase unknown: Ambenonium, Mivacurium, Neostigmine, Trimethaphan | 15.1 | |
| kccCLAT | Choline O-acetyltransferase | 1 | 49 | 88.85 | ND | 99.60 | 0.08 | ND | 0.9 | Mammalian | Enzyme | Myasthenic syndrome, congenital, 6, presynaptic (CMS6) [MIM:254210]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS6 affected individuals have myasthenic symptoms since birth or early infancy, negative tests for anti-AChR antibodies, and abrupt episodic crises with increased weakness, bulbar paralysis, and apnea precipitated by undue exertion, fever, or excitement. CMS6 inheritance is autosomal recessive. {ECO:0000269|PubMed:11172068, ECO:0000269|PubMed:12756141}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. | Choline O-acetyltransferase substrate: Choline Choline O-acetyltransferase unknown: Nicotine | 15.1 | |||
| kccCLK1 | Dual specificity protein kinase CLK1 | 19 | 402 | 94.43 | ND | 91.65 | 0.26 | ND | 1.2 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA. {ECO:0000269|PubMed:10480872, ECO:0000269|PubMed:19168442}. | Choline O-acetyltransferase substrate: Choline Choline O-acetyltransferase unknown: Nicotine | 15.1 | |||
| kccCLK2 | Dual specificity protein kinase CLK2 | 32 | 483 | 95.84 | ND | 92.10 | 0.21 | ND | 1.2 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. {ECO:0000269|PubMed:10480872, ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:8910305, ECO:0000269|PubMed:9637771}. | 15.1 | ||||
| kccCLK3 | Dual specificity protein kinase CLK3 | 3 | 138 | 88.65 | ND | 83.19 | 0.23 | ND | 0.7 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Phosphorylates SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. {ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:9637771}. | Choline O-acetyltransferase substrate: Choline Choline O-acetyltransferase unknown: Nicotine | 15.1 | |||
| kccCLK4 | Dual specificity protein kinase CLK4 | 54 | 1195 | 96.28 | ND | 93.20 | 0.24 | ND | 1.2 | Mammalian | Expressed in liver, kidney, heart, muscle, brain and endothelial cells. {ECO:0000269|PubMed:11170754, ECO:0000269|PubMed:19168442}. | Kinase | Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates SRSF1 and SRSF3. Required for the regulation of alternative splicing of MAPT/TAU. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. {ECO:0000269|PubMed:11170754, ECO:0000269|PubMed:19168442}. | 15.1 | ||||
| kccCLTR1 | Cysteinyl leukotriene receptor 1 | 16 | 397 | 99.72 | ND | 99.36 | 0.53 | ND | 0.9 | Mammalian | Widely expressed, with highest levels in spleen and peripheral blood leukocytes. Lower expression in several tissues, such as lung (mostly in smooth muscle bundles and alveolar macrophages), placenta, small intestine, pancreas, colon and heart. | Family A G protein-coupled receptor | Asthma | Receptor for cysteinyl leukotrienes mediating bronchoconstriction of individuals with and without asthma. Stimulation by LTD4 results in the contraction and proliferation of smooth muscle, edema, eosinophil migration and damage to the mucus layer in the lung. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The rank order of affinities for the leukotrienes is LTD4 >> LTE4 = LTC4 >> LTB4. | Cysteinyl leukotriene receptor 1 antagonist: Cinalukast, Montelukast, Pranlukast, Zafirlukast Cysteinyl leukotriene receptor 1 suppressor: Nedocromil | 15.1 | ||
| kccCMA1 | Chymase | 14 | 345 | 99.02 | ND | 98.26 | 0.66 | ND | 0.6 | Mammalian | Mast cells in lung, heart, skin and placenta. Expressed in both normal skin and in urticaria pigmentosa lesions. {ECO:0000269|PubMed:8144971}. | Protease | Asthma
Atopic dermatitis Cardiovascular disease, unspecified Inflammation Myocardial infarction | Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion. | Cysteinyl leukotriene receptor 1 antagonist: Cinalukast, Montelukast, Pranlukast, Zafirlukast Cysteinyl leukotriene receptor 1 suppressor: Nedocromil | 15.1 | ||
| kccCNR1 | Cannabinoid receptor 1 | 126 | 4676 | 95.36 | ND | 97.23 | 0.72 | ND | 0.7 | Nature11159 | Mammalian | Widely expressed. {ECO:0000269|PubMed:15620723}. | Family A G protein-coupled receptor | Analgesics
Inflammatory bowel disease Migraine Pain, unspecified | Involved in cannabinoid-induced CNS effects. Acts by inhibiting adenylate cyclase. Could be a receptor for anandamide. Inhibits L-type Ca(2+) channel current. Isoform 2 and isoform 3 have altered ligand binding. {ECO:0000269|PubMed:15620723}. | Cannabinoid receptor 1 agonist: Dronabinol Cannabinoid receptor 1 antagonist: Rimonabant Cannabinoid receptor 1 partial agonist: Nabilone | 15.1 | |
| kccCNR2 | Cannabinoid receptor 2 | 147 | 3856 | 95.79 | ND | 96.94 | 0.59 | ND | 0.7 | Mammalian | Preferentially expressed in cells of the immune system with higher expression in B-cells and NK cells (at protein level). Expressed in skin in suprabasal layers and hair follicles (at protein level). Highly expressed in tonsil and to a lower extent in spleen, peripheral blood mononuclear cells, and thymus. PubMed:14657172 could not detect expression in normal brain. Expressed in brain by perivascular microglial cells and dorsal root ganglion sensory neurons (at protein level). Two isoforms are produced by alternative promoter usage and differ only in the 5' UTR: isoform CB2A is observed predominantly in testis with some expression in brain, while isoform CB2B is predominant in spleen and leukocytes. {ECO:0000269|PubMed:12153574, ECO:0000269|PubMed:12511587, ECO:0000269|PubMed:14657172, ECO:0000269|PubMed:15266552, ECO:0000269|PubMed:18692962, ECO:0000269|PubMed:19496827, ECO:0000269|PubMed:7556170}. | Family A G protein-coupled receptor | Analgesics
Pain, unspecified | Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis. {ECO:0000269|PubMed:10051546, ECO:0000269|PubMed:12663043, ECO:0000269|PubMed:12711605, ECO:0000269|PubMed:18692962}. | Cannabinoid receptor 2 agonist: Dronabinol Cannabinoid receptor 2 partial agonist: Nabilone | 15.1 | ||
| kccCOMT | Catechol O-methyltransferase | 7 | 82 | 95.03 | ND | 95.30 | 0.84 | ND | 0.6 | Mammalian | Brain, liver, placenta, lymphocytes and erythrocytes. | Transferase | Parkinson's disease | Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol. | Catechol O-methyltransferase cofactor: S-Adenosylmethionine Catechol O-methyltransferase inhibitor: Entacapone, Testosterone Propionate, Tolcapone Catechol O-methyltransferase substrate: Conjugated Estrogens, Diethylstilbestrol, Dobutamine, Dopamine, Methyldopa, Micafungin | 15.1 | ||
| kccCOX1 | Cytochrome c oxidase subunit 1 | 2 | 63 | 91.57 | ND | 90.86 | 0.77 | ND | 0.4 | Mammalian | Primary active transporter | Leber hereditary optic neuropathy (LHON) [MIM:535000]: A maternally inherited disease resulting in acute or subacute loss of central vision, due to optic nerve dysfunction. Cardiac conduction defects and neurological defects have also been described in some patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. {ECO:0000269|PubMed:1322638}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=MT-CO1 may play a role in the pathogenesis of acquired idiopathic sideroblastic anemia, a disease characterized by inadequate formation of heme and excessive accumulation of iron in mitochondria. Mitochondrial iron overload may be attributable to mutations of mitochondrial DNA because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron to ferrous iron. The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. Mitochondrial complex IV deficiency (MT-C4D) [MIM:220110]: A disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. {ECO:0000269|PubMed:12140182, ECO:0000269|PubMed:16284789}. Note=The disease is caused by mutations affecting the gene represented in this entry. Recurrent myoglobinuria mitochondrial (RM-MT) [MIM:550500]: Recurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis (necrosis or disintegration of skeletal muscle) associated with muscle pain and weakness, and followed by excretion of myoglobin in the urine. {ECO:0000269|PubMed:10980727}. Note=The gene represented in this entry may be involved in disease pathogenesis. Deafness, sensorineural, mitochondrial (DFNM) [MIM:500008]: A form of non-syndromic deafness with maternal inheritance. Affected individuals manifest progressive, postlingual, sensorineural hearing loss involving high frequencies. {ECO:0000269|PubMed:10577941}. Note=The disease is caused by mutations affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:16407113}. Note=The gene represented in this entry may be involved in disease pathogenesis. | Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Subunits 1- 3 form the functional core of the enzyme complex. CO I is the catalytic subunit of the enzyme. Electrons originating in cytochrome c are transferred via the copper A center of subunit 2 and heme A of subunit 1 to the bimetallic center formed by heme A3 and copper B. | Catechol O-methyltransferase cofactor: S-Adenosylmethionine Catechol O-methyltransferase inhibitor: Entacapone, Testosterone Propionate, Tolcapone Catechol O-methyltransferase substrate: Conjugated Estrogens, Diethylstilbestrol, Dobutamine, Dopamine, Methyldopa, Micafungin | 15.1 | |||
| kccCP17A | Steroid 17-alpha-hydroxylase/17,20 lyase | 26 | 418 | 97.98 | ND | 99.06 | 0.57 | ND | 0.6 | Mammalian | Cytochrome P450 | Adrenal hyperplasia 5 (AH5) [MIM:202110]: A form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late- onset (NC or LOAH)and 'cryptic' (asymptomatic). {ECO:0000269|PubMed:10720067, ECO:0000269|PubMed:11549685, ECO:0000269|PubMed:11836339, ECO:0000269|PubMed:12466376, ECO:0000269|PubMed:14671162, ECO:0000269|PubMed:1515452, ECO:0000269|PubMed:1714904, ECO:0000269|PubMed:1740503, ECO:0000269|PubMed:19793597, ECO:0000269|PubMed:24140098, ECO:0000269|PubMed:24498484, ECO:0000269|PubMed:25650406, ECO:0000269|PubMed:2808364, ECO:0000269|PubMed:8027220, ECO:0000269|PubMed:8245018, ECO:0000269|PubMed:8345056, ECO:0000269|PubMed:8396144, ECO:0000269|PubMed:8550762, ECO:0000269|Ref.20}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Conversion of pregnenolone and progesterone to their 17- alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty. {ECO:0000269|PubMed:22266943}. | Steroid 17-alpha-hydroxylase/17,20 lyase inhibitor: Abiraterone, Dexamethasone, Metoclopramide, Progesterone Steroid 17-alpha-hydroxylase/17,20 lyase substrate: Aminophenazone | 15.1 | |||
| kccCP19A | Aromatase | 46 | 1401 | 91.55 | ND | 97.48 | 0.63 | ND | 0.8 | Mammalian | Brain, placenta and gonads. {ECO:0000269|PubMed:2040633, ECO:0000269|PubMed:3018730, ECO:0000269|PubMed:7690033, ECO:0000269|PubMed:8117272}. | Pain | Cytochrome P450 | Aromatase excess syndrome (AEXS) [MIM:139300]: An autosomal dominant disorder characterized by increased extraglandular aromatization of steroids that presents with heterosexual precocity in males and isosexual precocity in females. Note=The disease is caused by mutations affecting the gene represented in this entry. Aromatase deficiency (AROD) [MIM:613546]: A rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries. {ECO:0000269|PubMed:24705274, ECO:0000269|PubMed:8265607, ECO:0000269|PubMed:8530621, ECO:0000269|PubMed:9211678}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the formation of aromatic C18 estrogens from C19 androgens. | Aromatase antagonist: Letrozole Aromatase inducer: Chlorphenesin, Dexamethasone, Diethylstilbestrol, Dinoprostone, Methyltestosterone, Nandrolone decanoate, Sulfathiazole Aromatase inhibitor: Aminoglutethimide, Anastrozole, Bifonazole, Carbimazole, Clomifene, Clotrimazole, Cyproterone acetate, Danazol, Drostanolone, Econazole, Etomidate, Exemestane, Levonorgestrel, Mefloquine, Melatonin, Miconazole, Paclitaxel, Raloxifene, Tamoxifen, Terbinafine, Testolactone, Tioconazole Aromatase substrate: Edetic Acid, Levomethadyl Acetate, Methadone, Nandrolone phenpropionate, Testosterone Aromatase substrate;inducer: Betamethasone Aromatase substrate;inhibitor: Letrozole Aromatase unknown: Ketoconazole, Nicotine | 15.1 | |
| kccCP1A1 | Cytochrome P450 1A1 | 4 | 202 | 80.76 | ND | 95.05 | 0.73 | ND | 0.8 | Mammalian | Lung, lymphocytes and placenta. | Cytochrome P450 | Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. | Cytochrome P450 1A1 inducer: Albendazole, Bezafibrate, Clofibrate, Clomifene, Clozapine, Dicyclomine, Fluorescein, Itraconazole, Lansoprazole, Mebendazole, Omeprazole, Phenobarbital, Primaquine, Rabeprazole, Streptozocin, Thiabendazole Cytochrome P450 1A1 inhibitor: Amlodipine, Arsenic trioxide, Bortezomib, Caffeine, Cholecalciferol, Clobetasol propionate, Dexmedetomidine, Ethanol, Fluvoxamine, Isoprenaline, Methoxsalen, Nifedipine, Nitroprusside, Norfloxacin, Ouabain, Propofol, Propranolol, Pyridoxine, Quinidine, Sildenafil, Sulindac, Ticlopidine Cytochrome P450 1A1 inhibitor;inducer: Dexamethasone, Ketoconazole, Quinine, Vitamin A Cytochrome P450 1A1 substrate: Acetaminophen, Amiodarone, Amodiaquine, Azelastine, Carvedilol, Chloroquine, Chlorzoxazone, Cinnarizine, Clenbuterol, Clonidine, Dacarbazine, Dapagliflozin, Dasatinib, Daunorubicin, Debrisoquin, Diclofenac, Dronabinol, Erlotinib, Estradiol, Estrone, Flunarizine, Flutamide, Fluvastatin, Granisetron, Haloperidol, Oxaliplatin, Pentamidine, Prazosin, Progesterone, Riluzole, Tamoxifen, Testosterone, Thalidomide, Toremifene, Tretinoin, Warfarin Cytochrome P450 1A1 substrate;inducer: Menadione, Nicotine Cytochrome P450 1A1 substrate;inhibitor: Gefitinib, Melatonin, Theophylline Cytochrome P450 1A1 unknown: Benzyl alcohol | 15.1 | |||
| kccCP1B1 | Cytochrome P450 1B1 | 5 | 106 | 97.03 | ND | 93.40 | 0.46 | ND | 0.4 | Mammalian | Expressed in many tissues. {ECO:0000269|PubMed:8175734}. | Cytochrome P450 | Peters anomaly (PETAN) [MIM:604229]: Consists of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and a variable degree of iris and lenticular attachments to the central aspect of the posterior cornea. {ECO:0000269|PubMed:11403040}. Note=The disease is caused by mutations affecting the gene represented in this entry. Glaucoma 3, primary congenital, A (GLC3A) [MIM:231300]: An autosomal recessive form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. {ECO:0000269|PubMed:10227395, ECO:0000269|PubMed:10655546, ECO:0000269|PubMed:11184479, ECO:0000269|PubMed:11527932, ECO:0000269|PubMed:11980847, ECO:0000269|PubMed:12036985, ECO:0000269|PubMed:12525557, ECO:0000269|PubMed:14635112, ECO:0000269|PubMed:14640114, ECO:0000269|PubMed:15255109, ECO:0000269|PubMed:15342693, ECO:0000269|PubMed:15475877, ECO:0000269|PubMed:16490498, ECO:0000269|PubMed:16735994, ECO:0000269|PubMed:9463332, ECO:0000269|PubMed:9497261}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Glaucoma, primary open angle (POAG) [MIM:137760]: A complex and genetically heterogeneous ocular disorder characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. In some cases, POAG shows digenic inheritance involving mutations in CYP1B1 and MYOC genes. {ECO:0000269|PubMed:11774072, ECO:0000269|PubMed:15342693, ECO:0000269|PubMed:16688110, ECO:0000269|PubMed:16862072}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. CYP1B1 mutations have been reported to pose a significant risk for early-onset POAG and also modify glaucoma phenotype in patients who do not carry a MYOC mutation (PubMed:15342693). {ECO:0000269|PubMed:15342693}. Glaucoma 1, open angle, A (GLC1A) [MIM:137750]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. {ECO:0000269|PubMed:11774072}. Note=The gene represented in this entry acts as a disease modifier. Digenic mutations in CYP1B1 and MYOC have been found in a family segregating both primary adult- onset and juvenile forms of open angle glaucoma (PubMed:11774072). All affected family members with mutations in both MYOC and CYP1B1 had juvenile glaucoma, whereas those with only the MYOC mutation had the adult-onset form (PubMed:11774072). {ECO:0000269|PubMed:11774072}. | Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, retinoid and xenobiotics. Preferentially oxidizes 17beta- estradiol to the carcinogenic 4-hydroxy derivative, and a variety of procarcinogenic compounds to their activated forms, including polycyclic aromatic hydrocarbons. Promotes angiogenesis by removing cellular oxygenation products, thereby decreasing oxidative stress, release of antiangiogenic factor THBS2, then allowing endothelial cells migration, cell adhesion and capillary morphogenesis. These changes are concommitant with the endothelial nitric oxide synthase activity and nitric oxide synthesis. Plays an important role in the regulation of perivascular cell proliferation, migration, and survival through modulation of the intracellular oxidative state and NF-kappa-B expression and/or activity, during angiogenesis. Contributes to oxidative homeostasis and ultrastructural organization and function of trabecular meshwork tissue through modulation of POSTN expression. {ECO:0000269|PubMed:10426814, ECO:0000269|PubMed:15258110, ECO:0000269|PubMed:22888116, ECO:0000269|PubMed:23821647}. | Cytochrome P450 1B1 inducer: Biotin, Clozapine, Dexamethasone, Lansoprazole, Omeprazole, Phenobarbital, Primaquine Cytochrome P450 1B1 inhibitor: Arsenic trioxide, Daunorubicin, Doxorubicin, Ketoconazole, Mitoxantrone, Paclitaxel, Propofol Cytochrome P450 1B1 substrate: Amodiaquine, Caffeine, Dasatinib, Erlotinib, Estradiol, Estrone, Oxaliplatin, Procarbazine, Progesterone, Testosterone, Theophylline Cytochrome P450 1B1 substrate;inhibitor: Flutamide, Melatonin, Tamoxifen Cytochrome P450 1B1 substrate;inhibitor;inducer: Docetaxel | 15.1 | ||
| kccCP26A | Cytochrome P450 26A1 | 5 | 97 | 99.97 | ND | 99.97 | 0.46 | ND | 0.4 | Mammalian | Highest levels in adult liver, heart, pituitary gland, adrenal gland, placenta and regions of the brain. {ECO:0000269|PubMed:9826557}. | Cytochrome P450 | Cardiovascular disease, unspecified
Eye diseases Hyperproliferative disorders Inflammatory diseases Neurodegenerative diseases Noninsulin-dependent diabetes mellitus Skin diseases | Plays a key role in retinoic acid metabolism. Acts on retinoids, including all-trans-retinoic acid (RA) and its stereoisomer 9-cis-RA. Capable of both 4-hydroxylation and 18- hydroxylation. Responsible for generation of several hydroxylated forms of RA, including 4-OH-RA, 4-oxo-RA and 18-OH-RA. | Cytochrome P450 26A1 inducer: Vitamin A Cytochrome P450 26A1 inhibitor: Ketoconazole Cytochrome P450 26A1 substrate: Acitretin | 15.1 | ||
| kccCP2A6 | Cytochrome P450 2A6 | 5 | 203 | 98.48 | ND | 94.19 | 0.52 | ND | 0.7 | Mammalian | Liver. {ECO:0000269|PubMed:1889415, ECO:0000269|PubMed:1944238}. | Cytochrome P450 | Hypothalamic-pituitary ACTH function | Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4- cineole 2-exo-monooxygenase. Possesses low phenacetin O- deethylation activity. {ECO:0000269|PubMed:11695850, ECO:0000269|PubMed:16086027, ECO:0000269|PubMed:17125252, ECO:0000269|PubMed:18779312, ECO:0000269|PubMed:1889415, ECO:0000269|PubMed:1944238}. | Cytochrome P450 2A6 inducer: Amobarbital, Dexamethasone, Eletriptan, Pentobarbital Cytochrome P450 2A6 inhibitor: Amiodarone, Amlodipine, Amphetamine, Azelastine, Azithromycin, Buprenorphine, Clofibrate, Clomifene, Clotrimazole, Desipramine, Dexfenfluramine, Diethylstilbestrol, Ezogabine, Fomepizole, Isoniazid, Ketoconazole, Memantine, Menadione, Methimazole, Metyrapone, Miconazole, Nilvadipine, Norfloxacin, Prednisolone, Rosiglitazone, Sulfaphenazole, Tranylcypromine, Troleandomycin Cytochrome P450 2A6 inhibitor;inducer: Phenobarbital Cytochrome P450 2A6 substrate: Acetaminophen, Antipyrine, Arformoterol, Bupropion, Chlorzoxazone, Cinnarizine, Cisapride, Clozapine, Cyclophosphamide, Dapagliflozin, Dronabinol, Flunarizine, Flunitrazepam, Fluorouracil, Flurazepam, Formoterol, Halothane, Ifosfamide, Lidocaine, Methoxyflurane, Montelukast, Nevirapine, Nifedipine, Progesterone, Propofol, Selegiline, Sevoflurane, Tamoxifen, Tretinoin, Zidovudine Cytochrome P450 2A6 substrate;inducer: Valproic Acid Cytochrome P450 2A6 substrate;inhibitor: Letrozole, Methoxsalen, Nicotine, Pilocarpine Cytochrome P450 2A6 substrate;inhibitor;inducer: Rifampicin | 15.1 | ||
| kccCPT1A | Carnitine O-palmitoyltransferase 1, liver isoform | 2 | 41 | 80.26 | ND | 81.10 | 0.12 | ND | 1.0 | Mammalian | Strong expression in kidney and heart, and lower in liver and skeletal muscle. | Enzyme | Carnitine palmitoyltransferase 1A deficiency (CPT1AD) [MIM:255120]: Rare autosomal recessive metabolic disorder of long- chain fatty acid oxidation characterized by severe episodes of hypoketotic hypoglycemia usually occurring after fasting or illness. Onset is in infancy or early childhood. {ECO:0000269|PubMed:11350182, ECO:0000269|PubMed:11441142, ECO:0000269|PubMed:12189492, ECO:0000269|PubMed:14517221, ECO:0000269|PubMed:15110323, ECO:0000269|PubMed:15669684, ECO:0000269|PubMed:9691089}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the transfer of the acyl group of long-chain fatty acid-CoA conjugates onto carnitine, an essential step for the mitochondrial uptake of long-chain fatty acids and their subsequent beta-oxidation in the mitochondrion. Plays an important role in triglyceride metabolism. | Carnitine O-palmitoyltransferase 1, liver isoform activator: L-Carnitine Carnitine O-palmitoyltransferase 1, liver isoform inhibitor: Perhexiline Carnitine O-palmitoyltransferase 1, liver isoform unknown: Glyburide | 15.1 | ||
| kccCRFR1 | Corticotropin-releasing factor receptor 1 | 65 | 1780 | 99.30 | ND | 99.37 | 0.58 | ND | 0.6 | Nature11159 | Mammalian | Predominantly expressed in the cerebellum, pituitary, cerebral cortex and olfactory lobe. {ECO:0000269|PubMed:8243652}. | Family B G protein-coupled receptor | Anxiety Disorders
Depression Innate anxiety Irritable Bowel Syndrome (IBS) Obesity Stress-related disorders | G-protein coupled receptor for CRH (corticotropin- releasing factor) and UCN (urocortin). Has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. Inhibits the activity of the calcium channel CACNA1H. Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli. {ECO:0000269|PubMed:18292205, ECO:0000269|PubMed:18801728, ECO:0000269|PubMed:23576434, ECO:0000269|PubMed:23863939}. | 15.1 | ||
| kccCRFR2 | Corticotropin-releasing factor receptor 2 | 3 | 46 | 99.97 | ND | 99.95 | 0.73 | ND | 0.8 | Nature11159 | Mammalian | Family B G protein-coupled receptor | Angiogenesis
Congestive Heart Failure Eating disorders Obesity Stress-related disorders | G-protein coupled receptor for CRH (corticotropin- releasing factor), UCN (urocortin), UCN2 and UCN3. Has high affinity for UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. | 15.1 | |||
| kccCSF1R | Macrophage colony-stimulating factor 1 receptor | 37 | 875 | 97.97 | ND | 95.23 | 0.52 | ND | 1.2 | Mammalian | Expressed in bone marrow and in differentiated blood mononuclear cells. | Kinase | Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers. Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection. Leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:221820]: An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes. {ECO:0000269|PubMed:22197934, ECO:0000269|PubMed:24532199}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5- trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP- 1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:12882960, ECO:0000269|PubMed:15117969, ECO:0000269|PubMed:16170366, ECO:0000269|PubMed:16337366, ECO:0000269|PubMed:16648572, ECO:0000269|PubMed:17121910, ECO:0000269|PubMed:18467591, ECO:0000269|PubMed:18814279, ECO:0000269|PubMed:19193011, ECO:0000269|PubMed:19934330, ECO:0000269|PubMed:20489731, ECO:0000269|PubMed:20504948, ECO:0000269|PubMed:20829061, ECO:0000269|PubMed:7683918}. | Macrophage colony-stimulating factor 1 receptor antagonist: Imatinib Macrophage colony-stimulating factor 1 receptor other/unknown: Sunitinib | 15.1 | ||
| kccCSK | Tyrosine-protein kinase CSK | 4 | 161 | 88.74 | ND | 98.68 | 0.00 | ND | 1.1 | Mammalian | Expressed in lung and macrophages. {ECO:0000269|PubMed:1371489}. | Kinase | Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T- cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK. {ECO:0000269|PubMed:1639064, ECO:0000269|PubMed:9281320}. | Macrophage colony-stimulating factor 1 receptor antagonist: Imatinib Macrophage colony-stimulating factor 1 receptor other/unknown: Sunitinib | 15.1 | |||
| kccCSK21 | Casein kinase II subunit alpha | 22 | 400 | 95.30 | ND | 88.22 | 0.54 | ND | 1.2 | Mammalian | Expressed in gastric carcinoma tissue and the expression gradually increases with the progression of the carcinoma (at protein level). {ECO:0000269|PubMed:24962073}. | Kinase | Breast cancer
Cancer, unspecific | Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV. Phosphorylates PML at 'Ser-565' and primes it for ubiquitin- mediated degradation. Plays an important role in the circadian clock function by phosphorylating ARNTL/BMAL1 at 'Ser-90' which is pivotal for its interaction with CLOCK and which controls CLOCK nuclear entry (PubMed:11239457, PubMed:11704824, PubMed:16193064, PubMed:19188443, PubMed:20625391, PubMed:22406621). Phosphorylates CCAR2 at 'Thr-454' in gastric carcinoma tissue (PubMed:24962073). {ECO:0000269|PubMed:11239457, ECO:0000269|PubMed:11704824, ECO:0000269|PubMed:16193064, ECO:0000269|PubMed:19188443, ECO:0000269|PubMed:20625391, ECO:0000269|PubMed:22406621, ECO:0000269|PubMed:24962073}. | Macrophage colony-stimulating factor 1 receptor antagonist: Imatinib Macrophage colony-stimulating factor 1 receptor other/unknown: Sunitinib | 15.1 | ||
| kccCSK22 | Casein kinase II subunit alpha' | 2 | 101 | 91.44 | ND | 84.33 | 0.67 | ND | 0.7 | Mammalian | Kinase | Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV. {ECO:0000269|PubMed:11239457, ECO:0000269|PubMed:11704824, ECO:0000269|PubMed:16193064}. | Macrophage colony-stimulating factor 1 receptor antagonist: Imatinib Macrophage colony-stimulating factor 1 receptor other/unknown: Sunitinib | 15.1 | ||||
| kccCTDS1 | Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1 | 42 | 800 | 85.46 | ND | 86.56 | 0.02 | ND | 0.9 | Mammalian | Expression is restricted to non-neuronal tissues. Highest expression in skeletal muscle, spleen, lung and placenta. {ECO:0000269|PubMed:15681389}. | Enzyme | Preferentially catalyzes the dephosphorylation of 'Ser- 5' within the tandem 7 residue repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A. Negatively regulates RNA polymerase II transcription, possibly by controlling the transition from initiation/capping to processive transcript elongation. Recruited by REST to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells. {ECO:0000269|PubMed:12721286, ECO:0000269|PubMed:15681389}. | Macrophage colony-stimulating factor 1 receptor antagonist: Imatinib Macrophage colony-stimulating factor 1 receptor other/unknown: Sunitinib | 15.1 | |||
| kccCTRA | Chymotrypsinogen A | 7 | 206 | 87.83 | ND | 94.04 | 0.62 | ND | 0.8 | Mammalian | Protease | 15.1 | ||||||
| kccCTRB1 | Chymotrypsinogen B | 7 | 110 | 92.07 | ND | 91.84 | 0.75 | ND | 0.7 | Mammalian | Protease | Macrophage colony-stimulating factor 1 receptor antagonist: Imatinib Macrophage colony-stimulating factor 1 receptor other/unknown: Sunitinib | 15.1 | |||||
| kccCTRC | Chymotrypsin-C | 2 | 121 | 99.24 | ND | 95.91 | 0.45 | ND | 0.6 | Mammalian | Pancreas. | Protease | Pancreatitis, hereditary (PCTT) [MIM:167800]: A disease characterized by pancreas inflammation, permanent destruction of the pancreatic parenchyma, maldigestion, and severe abdominal pain attacks. {ECO:0000269|PubMed:18059268, ECO:0000269|PubMed:18172691, ECO:0000269|PubMed:22580415, ECO:0000269|PubMed:22942235}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Loss-of-function CTRC variants predispose to pancreatitis by diminishing its protective trypsin-degrading activity (PubMed:18059268). They cause loss of function by one or more of three mechanisms: reduced secretion, catalytic defect and increased degradation by trypsin (PubMed:22942235). {ECO:0000269|PubMed:18059268, ECO:0000269|PubMed:22942235}. | Regulates activation and degradation of trypsinogens and procarboxypeptidases by targeting specific cleavage sites within their zymogen precursors. Has chymotrypsin-type protease activity and hypocalcemic activity. {ECO:0000269|PubMed:23430245}. | 15.1 | |||
| kccCTRO | Citron Rho-interacting kinase | 1 | 65 | 91.33 | ND | 89.95 | 0.55 | ND | 0.6 | Mammalian | Kinase | Plays a role in cytokinesis. Required for KIF14 localization to the central spindle and midbody. Putative RHO/RAC effector that binds to the GTP-bound forms of RHO and RAC1. It probably binds p21 with a tighter specificity in vivo. Displays serine/threonine protein kinase activity. Plays an important role in the regulation of cytokinesis and the development of the central nervous system. Phosphorylates MYL9/MLC2. {ECO:0000269|PubMed:16236794, ECO:0000269|PubMed:16431929, ECO:0000269|PubMed:21457715}. | 15.1 | |||||
| kccCX3C1 | CX3C chemokine receptor 1 | 1 | 41 | 100.00 | ND | 100.00 | 0.23 | ND | 0.4 | Mammalian | Expressed in lymphoid and neural tissues. | Family A G protein-coupled receptor | Macular degeneration, age-related, 12 (ARMD12) [MIM:613784]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for the CX3C chemokine fractalkine and mediates both its adhesive and migratory functions. Acts as coreceptor with CD4 for HIV-1 virus envelope protein (in vitro). Isoform 2 and isoform 3 seem to be more potent HIV-1 coreceptors than isoform 1. | 15.1 | |||
| kccCXCR1 | C-X-C chemokine receptor type 1 | 5 | 186 | 95.44 | ND | 97.27 | 0.80 | ND | 0.4 | Mammalian | Family A G protein-coupled receptor | Acute respiratory distress syndrome
Asthma Human cytomegalovirus infections Lung injury | Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activate a phosphatidylinositol-calcium second messenger system. This receptor binds to IL-8 with a high affinity and to MGSA (GRO) with a low affinity. | C-X-C chemokine receptor type 1 other: Ketoprofen | 15.1 | |||
| kccCXCR2 | C-X-C chemokine receptor type 2 | 16 | 457 | 99.76 | ND | 99.47 | 0.71 | ND | 0.6 | Mammalian | Family A G protein-coupled receptor | Acute respiratory distress syndrome
Asthma Chronic Obstructive Pulmonary Disease (COPD) Colorectal cancer Lung injury | Receptor for interleukin-8 which is a powerful neutrophil chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. Binds to IL-8 with high affinity. Also binds with high affinity to CXCL3, GRO/MGSA and NAP-2. | 15.1 | ||||
| kccCXCR3 | C-X-C chemokine receptor type 3 | 19 | 704 | 99.51 | ND | 99.23 | 0.59 | ND | 0.7 | Mammalian | Isoform 1 and isoform 2 are mainly expressed in heart, kidney, liver and skeletal muscle. Isoform 1 is also expressed in placenta. Isoform 2 is expressed in endothelial cells. Expressed in T-cells (at protein level). {ECO:0000269|PubMed:12782716, ECO:0000269|PubMed:23121557}. | Family A G protein-coupled receptor | Autoimmune diseases
Focal stroke Inflammatory Disorders, Unspecified Insulin-dependent diabetes mellitus Multiple sclerosis Psoriasis and Psoriatic Disorders | Isoform 1: Receptor for the C-X-C chemokine CXCL9, CXCL10 and CXCL11 and mediates the proliferation, survival and angiogenic activity of human mesangial cells (HMC) through a heterotrimeric G-protein signaling pathway (PubMed:12782716). Binds to CCL21. Probably promotes cell chemotaxis response. {ECO:0000269|PubMed:12782716}. Isoform 2: Receptor for the C-X-C chemokine CXCL4 and also mediates the inhibitory activities of CXCL9, CXCL10 and CXCL11 on the proliferation, survival and angiogenic activity of human microvascular endothelial cells (HMVEC) through a cAMP- mediated signaling pathway (PubMed:12782716). Does not promote cell chemotaxis respons. Interaction with CXCL4 or CXCL10 leads to activation of the p38MAPK pathway and contributes to inhibition of angiogenesis. Overexpression in renal cancer cells down-regulates expression of the anti-apoptotic protein HMOX1 and promotes apoptosis. {ECO:0000269|PubMed:12782716}. Isoform 3: Mediates the activity of CXCL11. | 15.1 | |||
| kccCXCR4 | C-X-C chemokine receptor type 4 | 10 | 304 | 98.96 | ND | 99.03 | 0.39 | ND | 0.8 | Mammalian | Expressed in numerous tissues, such as peripheral blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex and medulla (in microglia as well as in astrocytes), brain microvascular, coronary artery and umbilical cord endothelial cells. Isoform 1 is predominant in all tissues tested. {ECO:0000269|PubMed:11276205}. | Family A G protein-coupled receptor | WHIM syndrome (WHIMS) [MIM:193670]: Immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. {ECO:0000269|PubMed:12692554}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival. {ECO:0000269|PubMed:10074102, ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:10825158, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:17197449, ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:20228059, ECO:0000269|PubMed:20505072, ECO:0000269|PubMed:8752280, ECO:0000269|PubMed:8752281}. (Microbial infection) Acts as a coreceptor (CD4 being the primary receptor) for human immunodeficiency virus-1/HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus (PubMed:9427609, PubMed:10074122, PubMed:10756055). Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). {ECO:0000269|PubMed:10074122, ECO:0000269|PubMed:10756055, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:9427609}. | C-X-C chemokine receptor type 4 antagonist: Framycetin, Plerixafor | 15.1 | ||
| kccDAPK3 | Death-associated protein kinase 3 | 20 | 364 | 92.37 | ND | 91.70 | 0.31 | ND | 1.3 | Mammalian | Widely expressed. Isoform 1 and isoform 2 are expressed in the bladder smooth muscle. {ECO:0000269|PubMed:15292222, ECO:0000269|PubMed:17126281}. | Kinase | Serine/threonine kinase which is involved in the regulation of apoptosis, autophagy, transcription, translation and actin cytoskeleton reorganization. Involved in the regulation of smooth muscle contraction. Regulates both type I (caspase- dependent) apoptotic and type II (caspase-independent) autophagic cell deaths signal, depending on the cellular setting. Involved in regulation of starvation-induced autophagy. Regulates myosin phosphorylation in both smooth muscle and non-muscle cells. In smooth muscle, regulates myosin either directly by phosphorylating MYL12B and MYL9 or through inhibition of smooth muscle myosin phosphatase (SMPP1M) via phosphorylation of PPP1R12A; the inhibition of SMPP1M functions to enhance muscle responsiveness to Ca(2+) and promote a contractile state. Phosphorylates MYL12B in non-muscle cells leading to reorganization of actin cytoskeleton. Isoform 2 can phosphorylate myosin, PPP1R12A and MYL12B. Overexpression leads to condensation of actin stress fibers into thick bundles. Involved in actin filament focal adhesion dynamics. The function in both reorganization of actin cytoskeleton and focal adhesion dissolution is modulated by RhoD. Positively regulates canonical Wnt/beta-catenin signaling through interaction with NLK and TCF7L2. Phosphorylates RPL13A on 'Ser-77' upon interferon-gamma activation which is causing RPL13A release from the ribosome, RPL13A association with the GAIT complex and its subsequent involvement in transcript-selective translation inhibition. Enhances transcription from AR-responsive promoters in a hormone- and kinase-dependent manner. Involved in regulation of cell cycle progression and cell proliferation. May be a tumor suppressor. {ECO:0000269|PubMed:10356987, ECO:0000269|PubMed:11384979, ECO:0000269|PubMed:11781833, ECO:0000269|PubMed:12917339, ECO:0000269|PubMed:15096528, ECO:0000269|PubMed:15367680, ECO:0000269|PubMed:16219639, ECO:0000269|PubMed:17126281, ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:18995835, ECO:0000269|PubMed:21169990, ECO:0000269|PubMed:21408167, ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:21487036, ECO:0000269|PubMed:23454120}. | C-X-C chemokine receptor type 4 antagonist: Framycetin, Plerixafor | 15.1 | |||
| kccDCAM | S-adenosylmethionine decarboxylase proenzyme | 4 | 53 | 99.40 | ND | 93.58 | 0.17 | ND | 1.4 | Mammalian | Enzyme | Cancer, unspecific
Parasitic diseases Proliferative diseases | Essential for biosynthesis of the polyamines spermidine and spermine. Promotes maintenance and self-renewal of embryonic stem cells, by maintaining spermine levels (By similarity). {ECO:0000250}. | S-adenosylmethionine decarboxylase proenzyme cofactor: S-Adenosylmethionine | 15.1 | |||
| kccDCK | Deoxycytidine kinase | 6 | 94 | 99.92 | ND | 100.00 | 0.59 | ND | 0.7 | Mammalian | Enzyme | Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents. {ECO:0000269|PubMed:18377927, ECO:0000269|PubMed:20614893}. | Deoxycytidine kinase agonist: Fludarabine Deoxycytidine kinase inducer: Pemetrexed Deoxycytidine kinase substrate: Cladribine, Clofarabine, Cytarabine, Emtricitabine, Gemcitabine, Lamivudine, Nelarabine, Zalcitabine Deoxycytidine kinase unknown: Decitabine | 15.1 | ||||
| kccDCLK1 | Serine/threonine-protein kinase DCLK1 | 2 | 106 | 88.52 | ND | 82.82 | 0.22 | ND | 1.0 | Mammalian | In fetal tissues, highly expressed in brain, detectable in lung and liver, but not in kidney. In adult tissues, expressed ubiquitously in the brain, detectable in the heart, liver, spleen, thymus, prostate, testis, ovary, small intestine and colon. The type A isoforms seem to be expressed predominantly in fetal brain whereas type B isoforms are expressed abundantly in both fetal and adult brain. {ECO:0000269|PubMed:10051403}. | Kinase | Probable kinase that may be involved in a calcium- signaling pathway controlling neuronal migration in the developing brain. May also participate in functions of the mature nervous system. | 15.1 | ||||
| kccDCMC | Malonyl-CoA decarboxylase, mitochondrial | 15 | 209 | 99.94 | ND | 99.00 | 0.54 | ND | 0.7 | Mammalian | Expressed in fibroblasts and hepatoblastoma cells (at protein level). Expressed strongly in heart, liver, skeletal muscle, kidney and pancreas. Expressed in myotubes. Expressed weakly in brain, placenta, spleen, thymus, testis, ovary and small intestine. {ECO:0000269|PubMed:10455107, ECO:0000269|PubMed:18314420}. | Enzyme | Malonyl-CoA decarboxylase deficiency (MLYCD deficiency) [MIM:248360]: Autosomal recessive disease characterized by abdominal pain, chronic constipation, episodic vomiting, metabolic acidosis and malonic aciduria. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of malonyl-CoA to acetyl-CoA. In the fatty acid biosynthesis MCD selectively removes malonyl-CoA and thus assures that methyl-malonyl-CoA is the only chain elongating substrate for fatty acid synthase and that fatty acids with multiple methyl side chains are produced. In peroxisomes it may be involved in degrading intraperoxisomal malonyl-CoA, which is generated by the peroxisomal beta-oxidation of odd chain-length dicarboxylic fatty acids. Plays a role in the metabolic balance between glucose and lipid oxidation in muscle independent of alterations in insulin signaling. May play a role in controlling the extent of ischemic injury by promoting glucose oxidation. {ECO:0000269|PubMed:10455107, ECO:0000269|PubMed:15003260, ECO:0000269|PubMed:18314420, ECO:0000269|PubMed:23482565}. | 15.1 | |||
| kccDDIT3 | DNA damage-inducible transcript 3 protein | 5 | 266 | 83.77 | ND | 86.40 | 0.04 | ND | 0.9 | Mammalian | Myxoid liposarcoma (MXLIPO) [MIM:613488]: A soft tissue tumor that tends to occur in the limbs (especially the thigh) of patients ranging in age from 35 to 55 years. It is defined by the presence of a hypocellular spindle cell proliferation set in a myxoid background, often with mucin pooling. Lipoblasts tend to be small and often monovacuolated and to cluster around vessels or at the periphery of the lesion. {ECO:0000269|PubMed:7503811}. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving DDIT3 has been found in a patient with malignant myxoid liposarcoma. Translocation t(12;16)(q13;p11) with FUS (PubMed:7503811). {ECO:0000269|PubMed:7503811}. | Multifunctional transcription factor in ER stress response. Plays an essential role in the response to a wide variety of cell stresses and induces cell cycle arrest and apoptosis in response to ER stress. Plays a dual role both as an inhibitor of CCAAT/enhancer-binding protein (C/EBP) function and as an activator of other genes. Acts as a dominant-negative regulator of C/EBP-induced transcription: dimerizes with members of the C/EBP family, impairs their association with C/EBP binding sites in the promoter regions, and inhibits the expression of C/EBP regulated genes. Positively regulates the transcription of TRIB3, IL6, IL8, IL23, TNFRSF10B/DR5, PPP1R15A/GADD34, BBC3/PUMA, BCL2L11/BIM and ERO1L. Negatively regulates; expression of BCL2 and MYOD1, ATF4-dependent transcriptional activation of asparagine synthetase (ASNS), CEBPA-dependent transcriptional activation of hepcidin (HAMP) and CEBPB-mediated expression of peroxisome proliferator-activated receptor gamma (PPARG). Inhibits the canonical Wnt signaling pathway by binding to TCF7L2/TCF4, impairing its DNA-binding properties and repressing its transcriptional activity. Plays a regulatory role in the inflammatory response through the induction of caspase-11 (CASP4/CASP11) which induces the activation of caspase-1 (CASP1) and both these caspases increase the activation of pro-IL1B to mature IL1B which is involved in the inflammatory response. {ECO:0000269|PubMed:15322075, ECO:0000269|PubMed:15775988, ECO:0000269|PubMed:16434966, ECO:0000269|PubMed:17709599, ECO:0000269|PubMed:18940792, ECO:0000269|PubMed:19672300, ECO:0000269|PubMed:20829347, ECO:0000269|PubMed:20876114, ECO:0000269|PubMed:22761832}. | 15.1 | |||||
| kccDDR1 | Epithelial discoidin domain-containing receptor 1 | 2 | 101 | 98.10 | ND | 99.44 | 0.26 | ND | 1.6 | Mammalian | Detected in T-47D, MDA-MB-175 and HBL-100 breast carcinoma cells, A-431 epidermoid carcinoma cells, SW48 and SNU-C2B colon carcinoma cells and Hs 294T melanoma cells (at protein level). Expressed at low levels in most adult tissues and is highest in the brain, lung, placenta and kidney. Lower levels of expression are detected in melanocytes, heart, liver, skeletal muscle and pancreas. Abundant in breast carcinoma cell lines. In the colonic mucosa, expressed in epithelia but not in the connective tissue of the lamina propria. In the thyroid gland, expressed in the epithelium of the thyroid follicles. In pancreas, expressed in the islets of Langerhans cells, but not in the surrounding epithelial cells of the exocrine pancreas. In kidney, expressed in the epithelia of the distal tubules. Not expressed in connective tissue, endothelial cells, adipose tissue, muscle cells or cells of hematopoietic origin. {ECO:0000269|PubMed:7845687, ECO:0000269|PubMed:7848919, ECO:0000269|PubMed:8247543}. | Kinase | Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11. {ECO:0000250, ECO:0000269|PubMed:12065315, ECO:0000269|PubMed:16234985, ECO:0000269|PubMed:16337946, ECO:0000269|PubMed:19401332, ECO:0000269|PubMed:20093046, ECO:0000269|PubMed:20432435, ECO:0000269|PubMed:20884741, ECO:0000269|PubMed:21044884, ECO:0000269|PubMed:9659899}. | Epithelial discoidin domain-containing receptor 1 antagonist: Imatinib | 15.1 | |||
| kccDDR2 | Discoidin domain-containing receptor 2 | 3 | 121 | 98.09 | ND | 95.63 | 0.18 | ND | 1.5 | Mammalian | Detected in osteocytes, osteoblastic cells in subchondral bone, bone lining cells, tibia and cartilage (at protein level). Detected at high levels in heart and lung, and at low levels in brain, placenta, liver, skeletal muscle, pancreas, and kidney. {ECO:0000269|PubMed:17665456, ECO:0000269|PubMed:20564243, ECO:0000269|PubMed:8247548}. | Kinase | Spondyloepimetaphyseal dysplasia short limb-hand type (SEMD-SL) [MIM:271665]: A bone disease characterized by short- limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping. {ECO:0000269|PubMed:19110212, ECO:0000269|PubMed:20223752}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing. {ECO:0000269|PubMed:16186104, ECO:0000269|PubMed:16186108, ECO:0000269|PubMed:17665456, ECO:0000269|PubMed:18201965, ECO:0000269|PubMed:20004161, ECO:0000269|PubMed:20564243, ECO:0000269|PubMed:20734453, ECO:0000269|PubMed:9659899}. | Discoidin domain-containing receptor 2 inhibitor: Regorafenib | 15.1 | ||
| kccDEFM | Peptide deformylase, mitochondrial | 1 | 45 | 84.39 | ND | 99.96 | 0.72 | ND | 0.7 | Mammalian | Ubiquitous. | Enzyme | Removes the formyl group from the N-terminal Met of newly synthesized proteins. {ECO:0000250}. | Discoidin domain-containing receptor 2 inhibitor: Regorafenib | 15.1 | |||
| kccDGAT1 | Diacylglycerol O-acyltransferase 1 | 26 | 571 | 99.82 | ND | 99.51 | 0.49 | ND | 0.6 | Mammalian | Enzyme | Diarrhea 7 (DIAR7) [MIM:615863]: A life-threatening disease characterized by severe, intractable, watery diarrhea. {ECO:0000269|PubMed:23114594}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. In contrast to DGAT2 it is not essential for survival. May be involved in VLDL (very low density lipoprotein) assembly. In liver, plays a role in esterifying exogenous fatty acids to glycerol. Functions as the major acyl-CoA retinol acyltransferase (ARAT) in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity leading to skin and hair disorders. {ECO:0000269|PubMed:16214399, ECO:0000269|PubMed:9756920}. | 15.1 | ||||
| kccDHB1 | Estradiol 17-beta-dehydrogenase 1 | 11 | 299 | 97.66 | ND | 99.78 | 0.58 | ND | 0.6 | Mammalian | Enzyme | Breast cancer (hormone-sensitive) | Favors the reduction of estrogens and androgens. Also has 20-alpha-HSD activity. Uses preferentially NADH. | Estradiol 17-beta-dehydrogenase 1 unknown: Equilin | 15.1 | |||
| kccDHB2 | Estradiol 17-beta-dehydrogenase 2 | 16 | 273 | 97.42 | ND | 97.41 | 0.41 | ND | 0.4 | Mammalian | Enzyme | Capable of catalyzing the interconversion of testosterone and androstenedione, as well as estradiol and estrone. Also has 20-alpha-HSD activity. Uses NADH while EDH17B3 uses NADPH. | Estradiol 17-beta-dehydrogenase 1 unknown: Equilin | 15.1 | ||||
| kccDHB3 | Testosterone 17-beta-dehydrogenase 3 | 5 | 146 | 95.73 | ND | 96.75 | 0.45 | ND | 0.7 | Mammalian | Testis. | Enzyme | Male pseudohermaphrodism with gynecomastia (MPH) [MIM:264300]: These individuals have unambiguous female external genitalia at birth, but fail to menstruate at the time of expected puberty and instead virilize as evidenced by growth of the phallus. Breast development may or may not take place. {ECO:0000269|PubMed:11158067, ECO:0000269|PubMed:8075637, ECO:0000269|PubMed:8550739, ECO:0000269|PubMed:9709959, ECO:0000269|PubMed:9758445}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Favors the reduction of androstenedione to testosterone. Uses NADPH while the two other EDH17B enzymes use NADH. | Estradiol 17-beta-dehydrogenase 1 unknown: Equilin | 15.1 | ||
| kccDHI1 | Corticosteroid 11-beta-dehydrogenase isozyme 1 | 76 | 1757 | 94.50 | ND | 97.40 | 0.59 | ND | 0.7 | Mammalian | Widely expressed. Highest expression in liver. | Enzyme | Cortisone reductase deficiency (CRD) [MIM:604931]: In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS). Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7- ketocholesterol to 7-beta-hydroxycholesterol (By similarity). {ECO:0000250}. | Corticosteroid 11-beta-dehydrogenase isozyme 1 ligand: Prednisone | 15.1 | ||
| kccDHI2 | Corticosteroid 11-beta-dehydrogenase isozyme 2 | 8 | 349 | 95.77 | ND | 94.17 | 0.41 | ND | 0.6 | Mammalian | Expressed in kidney, pancreas, prostate, ovary, small intestine and colon. At midgestation, expressed at high levels in placenta and in fetal kidney and, at much lower levels, in fetal lung and testis (PubMed:8530071). {ECO:0000269|PubMed:8530071}. | Enzyme | Apparent mineralocorticoid excess (AME) [MIM:218030]: An autosomal recessive form of low-renin hypertension. It is usually diagnosed within the first years of life and is characterized by polyuria and polydipsia, failure to thrive, hypernatremia, severe hypertension with low renin and aldosterone levels, profound hypokalemia with metabolic alkalosis, and most often nephrocalcinosis. {ECO:0000269|PubMed:12788846, ECO:0000269|PubMed:17314322, ECO:0000269|PubMed:7593417, ECO:0000269|PubMed:7608290, ECO:0000269|PubMed:9661590}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of cortisol to the inactive metabolite cortisone. Modulates intracellular glucocorticoid levels, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids. | Corticosteroid 11-beta-dehydrogenase isozyme 1 ligand: Prednisone | 15.1 | ||
| kccDHSO | Sorbitol dehydrogenase | 2 | 66 | 100.00 | ND | 100.00 | 0.47 | ND | 0.6 | Mammalian | Expressed in kidney and epithelial cells of both benign and malignant prostate tissue. Expressed in epididymis (at protein level). {ECO:0000269|PubMed:16278369, ECO:0000269|PubMed:19423711, ECO:0000269|PubMed:20372835}. | Enzyme | Diabetic complications
Myocardial ischemia | Converts sorbitol to fructose. Part of the polyol pathway that plays an important role in sperm physiology. May play a role in the sperm motility by providing an energetic source for sperm. {ECO:0000250|UniProtKB:Q64442}. | Corticosteroid 11-beta-dehydrogenase isozyme 1 ligand: Prednisone | 15.1 | ||
| kccDLG4 | Disks large homolog 4 | 1 | 44 | 99.92 | ND | 99.99 | 0.81 | ND | 0.2 | Mammalian | Brain. | Analgesics
Chronic neuropathic pain Opioid dependence | Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B (By similarity). {ECO:0000250}. | Disks large homolog 4 unknown: Guanidine | 15.1 | |||
| kccDMPK | Myotonin-protein kinase | 1 | 73 | 85.47 | ND | 98.09 | 0.13 | ND | 1.2 | Mammalian | Most isoforms are expressed in many tissues including heart, skeletal muscle, liver and brain, except for isoform 2 which is only found in the heart and skeletal muscle, and isoform 14 which is only found in the brain, with high levels in the striatum, cerebellar cortex and pons. {ECO:0000269|PubMed:7488138}. | Kinase | Dystrophia myotonica 1 (DM1) [MIM:160900]: A muscular disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness and cardiac arrhythmias. {ECO:0000269|PubMed:1302022, ECO:0000269|PubMed:1310900, ECO:0000269|PubMed:1546326, ECO:0000269|PubMed:19514047}. Note=The disease is caused by mutations affecting the gene represented in this entry. The causative mutation is a CTG expansion in the 3'- UTR of the DMPK gene. A length exceeding 50 CTG repeats is pathogenic, while normal individuals have 5 to 37 repeats. Intermediate alleles with 35-49 triplets are not disease-causing but show instability in intergenerational transmissions. Disease severity varies with the number of repeats: mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with congenital onset can have more than 2,000 repeats. {ECO:0000269|PubMed:1310900, ECO:0000269|PubMed:19514047}. | Non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function. May play a role in myocyte differentiation and survival by regulating the integrity of the nuclear envelope and the expression of muscle-specific genes. May also phosphorylate PPP1R12A and inhibit the myosin phosphatase activity to regulate myosin phosphorylation. Also critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction activity probably through the regulation of cellular calcium homeostasis. Phosphorylates PLN, a regulator of calcium pumps and may regulate sarcoplasmic reticulum calcium uptake in myocytes. May also phosphorylate FXYD1/PLM which is able to induce chloride currents. May also play a role in synaptic plasticity. {ECO:0000269|PubMed:10811636, ECO:0000269|PubMed:10913253, ECO:0000269|PubMed:11287000, ECO:0000269|PubMed:15598648, ECO:0000269|PubMed:21457715, ECO:0000269|PubMed:21949239}. | Disks large homolog 4 unknown: Guanidine | 15.1 | ||
| kccDOPO | Dopamine beta-hydroxylase | 4 | 77 | 88.26 | ND | 93.50 | 0.29 | ND | 0.6 | Mammalian | Enzyme | Dopamine beta-hydroxylase deficiency (DBH deficiency) [MIM:223360]: Characterized by profound deficits in autonomic and cardiovascular function, but apparently only subtle signs, if any, of central nervous system dysfunction. {ECO:0000269|PubMed:11857564}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Conversion of dopamine to noradrenaline. | Dopamine beta-hydroxylase inhibitor: Disulfiram, Propylthiouracil Dopamine beta-hydroxylase ligand: Dopamine Dopamine beta-hydroxylase substrate: Dopamine Dopamine beta-hydroxylase unknown: Vitamin C | 15.1 | |||
| kccDOT1L | Histone-lysine N-methyltransferase, H3 lysine-79 specific | 1 | 61 | 99.97 | ND | 99.96 | 0.89 | ND | 0.5 | Mammalian | Writer | Histone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA. | 15.1 | |||||
| kccDPEP1 | Dipeptidase 1 | 2 | 132 | 99.94 | ND | 99.94 | 0.65 | ND | 0.6 | Mammalian | Protease | Bacterial infections | Hydrolyzes a wide range of dipeptides. Implicated in the renal metabolism of glutathione and its conjugates. Converts leukotriene D4 to leukotriene E4; it may play an important role in the regulation of leukotriene activity. | Dipeptidase 1 inhibitor: Cilastatin | 15.1 | |||
| kccDPP2 | Dipeptidyl peptidase 2 | 33 | 1200 | 96.97 | ND | 98.12 | 0.69 | ND | 0.6 | Mammalian | Detected in seminal plasma (at protein level). {ECO:0000269|PubMed:15487984}. | Protease | Plays an important role in the degradation of some oligopeptides. {ECO:0000269|PubMed:15487984}. | 15.1 | ||||
| kccDPP4 | Dipeptidyl peptidase 4 | 91 | 3053 | 98.33 | ND | 99.14 | 0.66 | ND | 0.7 | Mammalian | Expressed specifically in lymphatic vessels but not in blood vessels in the skin, small intestine, esophagus, ovary, breast and prostate glands. Not detected in lymphatic vessels in the lung, kidney, uterus, liver and stomach (at protein level). Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon. {ECO:0000269|PubMed:1677636, ECO:0000269|PubMed:18708048}. | Protease | Autoimmune diseases
Diabetes mellitus Malignancies Noninsulin-dependent diabetes mellitus Obesity | Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF- kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline. {ECO:0000269|PubMed:10570924, ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:10900005, ECO:0000269|PubMed:10951221, ECO:0000269|PubMed:11772392, ECO:0000269|PubMed:14691230, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17287217, ECO:0000269|PubMed:17549790, ECO:0000269|PubMed:18708048}. | Dipeptidyl peptidase 4 inhibitor: Alogliptin, Atorvastatin, Linagliptin, Saxagliptin, Sitagliptin, Vildagliptin | 15.1 | ||
| kccDPP8 | Dipeptidyl peptidase 8 | 30 | 1235 | 98.12 | ND | 99.42 | 0.79 | ND | 0.6 | Mammalian | Ubiquitously expressed, with highest levels in testis, placenta, prostate, muscle and brain. {ECO:0000269|PubMed:11012666, ECO:0000269|PubMed:12662155}. | Protease | Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. May play a role in T-cell activation and immune function. {ECO:0000269|PubMed:11012666}. | 15.1 | ||||
| kccDPP9 | Dipeptidyl peptidase 9 | 30 | 901 | 98.83 | ND | 98.95 | 0.83 | ND | 0.6 | Mammalian | Ubiquitously expressed, with highest levels in liver, heart and muscle, and lowest levels in brain. {ECO:0000269|PubMed:12459266, ECO:0000269|PubMed:12662155, ECO:0000269|PubMed:15245913}. | Protease | Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. | 15.1 | ||||
| kccDRB3 | HLA class II histocompatibility antigen, DR beta 3 chain | 6 | 73 | 99.78 | ND | 99.92 | 0.83 | ND | 0.4 | Mammalian | Surface antigen | Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading. | 15.1 | |||||
| kccDRD1 | D(1A) dopamine receptor | 83 | 2026 | 93.05 | ND | 94.10 | 0.66 | ND | 0.7 | Nature11159 | Mammalian | Detected in caudate, nucleus accumbens and in the olfactory tubercle. {ECO:0000269|PubMed:2144334}. | Agranulocytosis Akathisia Amenorrhoea Cataract Cholestasis Corneal opacity Corneal pigmentation Dermatitis allergic Dermatitis exfoliative Dry mouth Dyskinesia Dystonia Ejaculation disorder Electrocardiogram change Endocrine disorder Extrapyramidal disorder Eyelash discolouration Fibrocystic breast disease Galactorrhoea Gynaecomastia Hypercholesterolaemia Hyperprolactinaemia Hyperthermia Hypothermia Insomnia Lenticular opacities Lipid metabolism disorder Menstrual disorder Miosis Mydriasis Nasal congestion Neuroleptic malignant syndrome Neutropenia Orthostatic hypotension Parkinsonism Photosensitivity reaction Tachycardia Tardive dyskinesia Weight increased | Family A G protein-coupled receptor | Parkinson's disease | Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase. | D(1A) dopamine receptor agonist: Apomorphine, Bromocriptine, Cabergoline, Dopamine, Ergotamine, Fenoldopam, L-DOPA, Minaprine, Pergolide, Ropinirole, Rotigotine D(1A) dopamine receptor antagonist: Acepromazine, Acetophenazine, Amoxapine, Asenapine, Chlorpromazine, Chlorprothixene, Clozapine, Flupentixol, Fluphenazine, Haloperidol, Iloperidone, Lisuride, Loxapine, Methotrimeprazine, Methylergometrine, Olanzapine, Paliperidone, Perphenazine, Pipotiazine, Promazine, Propericiazine, Propiomazine, Quetiapine, Risperidone, Thioproperazine, Thioridazine, Thiothixene, Triflupromazine, Ziprasidone D(1A) dopamine receptor antagonist;agonist: Ergoloid mesylate D(1A) dopamine receptor antagonist;partial agonist: Aripiprazole D(1A) dopamine receptor binder: Cinnarizine, Imipramine, Mianserin, Mirtazapine, Trimipramine D(1A) dopamine receptor partial agonist: Phenylpropanolamine D(1A) dopamine receptor unknown: Pramipexole | 15.1 |
| kccDRD2 | D(2) dopamine receptor | 149 | 7784 | 92.69 | ND | 94.42 | 0.51 | ND | 0.7 | Nature11159 | Mammalian | Akathisia Amenorrhoea Cataract Cholestasis Constipation Convulsion Corneal opacity Corneal pigmentation Dermatitis allergic Dermatitis exfoliative Dry mouth Dyskinesia Dystonia Ejaculation disorder Electrocardiogram change Endocrine disorder Erectile dysfunction Extrapyramidal disorder Eyelash discolouration Fibrocystic breast disease Galactorrhoea Gynaecomastia Hypercholesterolaemia Hyperprolactinaemia Hyperthermia Hypothermia Insomnia Lenticular opacities Lipid metabolism disorder Menstrual disorder Miosis Mydriasis Nasal congestion Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Sexual dysfunction Tachycardia Tardive dyskinesia Urinary retention Vision blurred Weight increased | Family A G protein-coupled receptor | Dystonia 11 (DYT11) [MIM:159900]: A myoclonic dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT11 is characterized by involuntary lightning jerks and dystonic movements and postures alleviated by alcohol. Inheritance is autosomal dominant. The age of onset, pattern of body involvement, presence of myoclonus and response to alcohol are all variable. {ECO:0000269|PubMed:10220438}. Note=The gene represented in this entry may be involved in disease pathogenesis. DRD2 mutations in myoclonic dystonia patients are rare, and their contribution to disease phenotype is unclear (PubMed:10716258). {ECO:0000269|PubMed:10716258}. | Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. {ECO:0000269|PubMed:17264214, ECO:0000269|PubMed:21645528}. | D(2) dopamine receptor agonist: Amantadine, Apomorphine, Bromocriptine, Cabergoline, Dopamine, Ergotamine, L-DOPA, Lisuride, Memantine, Minaprine, Pergolide, Pramipexole, Ropinirole, Rotigotine D(2) dopamine receptor agonist;partial agonist: Ketamine D(2) dopamine receptor antagonist: Acepromazine, Acetophenazine, Alizapride, Amisulpride, Amoxapine, Asenapine, Bromopride, Buspirone, Chlorpromazine, Chlorprothixene, Clozapine, Domperidone, Doxepin, Droperidol, Flupentixol, Fluphenazine, Fluspirilene, Haloperidol, Iloperidone, Loxapine, Lurasidone, Mesoridazine, Methotrimeprazine, Metoclopramide, Mianserin, Molindone, Nortriptyline, Paliperidone, Perphenazine, Pimozide, Pipotiazine, Prochlorperazine, Promazine, Promethazine, Propiomazine, Quetiapine, Remoxipride, Risperidone, Sertindole, Sulpiride, Thioproperazine, Thioridazine, Thiothixene, Trifluoperazine, Triflupromazine, Yohimbine, Ziprasidone D(2) dopamine receptor antagonist;agonist: Ergoloid mesylate, Olanzapine D(2) dopamine receptor antagonist;partial agonist: Aripiprazole D(2) dopamine receptor binder: Amphetamine, Desipramine, Imipramine, Maprotiline, Mirtazapine D(2) dopamine receptor inhibitor: Tetrabenazine D(2) dopamine receptor other/unknown: Cinnarizine, Trimipramine | 15.1 | |
| kccDRD3 | D(3) dopamine receptor | 157 | 2788 | 95.87 | ND | 96.05 | 0.65 | ND | 0.8 | Nature11159 | Mammalian | Brain. | Akathisia Amenorrhoea Dyskinesia Dystonia Ejaculation disorder Electrocardiogram change Extrapyramidal disorder Galactorrhoea Gynaecomastia Hyperprolactinaemia Hyperthermia Hypothermia Menstrual disorder Nasal congestion Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tardive dyskinesia Weight increased | Family A G protein-coupled receptor | Tremor, hereditary essential 1 (ETM1) [MIM:190300]: A common movement disorder mainly characterized by postural tremor of the arms. Head, legs, trunk, voice, jaw, and facial muscles also may be involved. The condition can be aggravated by emotions, hunger, fatigue and temperature extremes, and may cause a functional disability or even incapacitation. Inheritance is autosomal dominant. {ECO:0000269|PubMed:16650084, ECO:0000269|PubMed:16809426}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation. {ECO:0000269|PubMed:19520868}. | D(3) dopamine receptor agonist: Apomorphine, Bromocriptine, Cabergoline, Captodiame, Dopamine, L-DOPA, Lisuride, Pergolide, Pramipexole, Ropinirole, Rotigotine D(3) dopamine receptor antagonist: Amisulpride, Amoxapine, Asenapine, Chlorprothixene, Clozapine, Domperidone, Iloperidone, Methotrimeprazine, Olanzapine, Paliperidone, Pimozide, Quetiapine, Remoxipride, Risperidone, Sulpiride, Yohimbine, Ziprasidone D(3) dopamine receptor antagonist;partial agonist: Aripiprazole D(3) dopamine receptor binder: Loxapine, Mianserin D(3) dopamine receptor inverse agonist: Haloperidol D(3) dopamine receptor unknown: Chlorpromazine, Mirtazapine | 15.1 |
| kccDRD4 | D(4) dopamine receptor | 103 | 1693 | 96.85 | ND | 97.82 | 0.52 | ND | 0.8 | Nature11159 | Mammalian | Akathisia Amenorrhoea Dyskinesia Dystonia Ejaculation disorder Electrocardiogram change Extrapyramidal disorder Galactorrhoea Hypercholesterolaemia Hyperprolactinaemia Hyperthermia Hypothermia Lipid metabolism disorder Menstrual disorder Mydriasis Nasal congestion Neuroleptic malignant syndrome Orthostatic hypotension Parkinsonism Tardive dyskinesia | Family A G protein-coupled receptor | Parkinson's disease
Psychiatric illness Respiratory diseases | Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins which inhibit adenylyl cyclase. Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells (By similarity). {ECO:0000250}. | D(4) dopamine receptor agonist: Apomorphine, Cabergoline, Dopamine, L-DOPA, Lisuride, Pergolide, Pramipexole, Ropinirole, Rotigotine D(4) dopamine receptor antagonist: Amoxapine, Asenapine, Bromocriptine, Clozapine, Iloperidone, Methotrimeprazine, Olanzapine, Paliperidone, Promazine, Propiomazine, Quetiapine, Remoxipride, Risperidone, Ziprasidone D(4) dopamine receptor antagonist;partial agonist: Aripiprazole D(4) dopamine receptor binder: Chlorpromazine, Loxapine | 15.1 | |
| kccDRD5 | D(1B) dopamine receptor | 18 | 317 | 95.76 | ND | 95.53 | 0.41 | ND | 1.1 | Mammalian | Neuron-specific, localized primarily within limbic regions of the brain. {ECO:0000269|PubMed:1834671}. | Akathisia Amenorrhoea Dyskinesia Dystonia Electrocardiogram change Extrapyramidal disorder Galactorrhoea Hypothermia Nasal congestion Neuroleptic malignant syndrome Parkinsonism Tardive dyskinesia | Family A G protein-coupled receptor | Benign essential blepharospasm (BEB) [MIM:606798]: A primary focal dystonia affecting the orbicularis oculi muscles. Dystonia is defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. BEB usually begins in middle age. Initial symptoms include eye irritation and frequent blinking, progressing to involuntary spasms of eyelid closure. Patients have normal eyes. The visual disturbance is due solely to the forced closure of the eyelids. In severe cases, this can lead to functional blindness. {ECO:0000269|PubMed:11781417}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. | Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase. {ECO:0000269|PubMed:1834671}. | D(1B) dopamine receptor agonist: Apomorphine, Bromocriptine, Cabergoline, Dopamine, Ergotamine, Fenoldopam, L-DOPA, Pergolide, Ropinirole, Rotigotine D(1B) dopamine receptor antagonist: Lisuride, Methotrimeprazine, Olanzapine, Quetiapine, Ziprasidone D(1B) dopamine receptor antagonist;partial agonist: Aripiprazole D(1B) dopamine receptor binder: Cinnarizine, Imipramine, Loxapine, Mianserin, Mirtazapine, Trimipramine D(1B) dopamine receptor unknown: Chlorpromazine, Pramipexole | 15.1 | |
| kccDUS3 | Dual specificity protein phosphatase 3 | 16 | 444 | 85.62 | ND | 87.39 | 0.01 | ND | 1.0 | Mammalian | Phosphatase | Shows activity both for tyrosine-protein phosphate and serine-protein phosphate, but displays a strong preference toward phosphotyrosines. Specifically dephosphorylates and inactivates ERK1 and ERK2. {ECO:0000269|PubMed:10224087, ECO:0000269|PubMed:11863439}. | 15.1 | |||||
| kccDUT | Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial | 6 | 117 | 99.87 | ND | 99.93 | 0.87 | ND | 0.4 | Mammalian | Found in a variety of tissues. Isoform 3 expression is constitutive, while isoform 2 expression correlates with the onset of DNA replication (at protein level). Isoform 2 degradation coincides with the cessation of nuclear DNA replication (at protein level). {ECO:0000269|PubMed:9228092}. | Enzyme | This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA. {ECO:0000269|PubMed:8805593}. | D(1B) dopamine receptor agonist: Apomorphine, Bromocriptine, Cabergoline, Dopamine, Ergotamine, Fenoldopam, L-DOPA, Pergolide, Ropinirole, Rotigotine D(1B) dopamine receptor antagonist: Lisuride, Methotrimeprazine, Olanzapine, Quetiapine, Ziprasidone D(1B) dopamine receptor antagonist;partial agonist: Aripiprazole D(1B) dopamine receptor binder: Cinnarizine, Imipramine, Loxapine, Mianserin, Mirtazapine, Trimipramine D(1B) dopamine receptor unknown: Chlorpromazine, Pramipexole | 15.1 | |||
| kccDYN1 | Dynamin-1 | 2 | 135 | 99.14 | ND | 91.18 | 0.55 | ND | 0.3 | Mammalian | Structural protein | Epileptic encephalopathy, early infantile, 31 (EIEE31) [MIM:616346]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:25262651, ECO:0000269|PubMed:25533962}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Most probably involved in vesicular trafficking processes. Involved in receptor-mediated endocytosis. | 15.1 | ||||
| kccDYR | Dihydrofolate reductase | 53 | 1500 | 97.98 | ND | 98.97 | 0.58 | ND | 0.8 | Mammalian | Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain. {ECO:0000269|PubMed:21310276}. | Oxidoreductase | Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]: An inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms. {ECO:0000269|PubMed:21310276, ECO:0000269|PubMed:21310277}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1. {ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:21876188}. | Dihydrofolate reductase inhibitor: Methotrexate, Pemetrexed, Pralatrexate, Proguanil, Pyrimethamine, Trimethoprim, Trimetrexate Dihydrofolate reductase substrate: Methotrexate Dihydrofolate reductase unknown: Gentamicin | 15.1 | ||
| kccDYR1A | Dual specificity tyrosine-phosphorylation-regulated kinase 1A | 87 | 1928 | 92.55 | ND | 90.62 | 0.29 | ND | 1.0 | Mammalian | Ubiquitous. Highest levels in skeletal muscle, testis, fetal lung and fetal kidney. {ECO:0000269|PubMed:10329007, ECO:0000269|PubMed:8769099, ECO:0000269|PubMed:8872470, ECO:0000269|PubMed:8975710}. | Kinase | Mental retardation, autosomal dominant 7 (MRD7) [MIM:614104]: A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21294719}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Modulates alternative splicing by phosphorylating the splice factor SRSF6 (By similarity). Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates such as CRY2, FOXO1, SRSF6 and SIRT1. Exhibits a sugstrate preference for proline at position P+1 and arginine at position P-3. {ECO:0000250, ECO:0000269|PubMed:20981014, ECO:0000269|PubMed:21127067, ECO:0000269|PubMed:23665168, ECO:0000269|PubMed:8769099}. | Dihydrofolate reductase inhibitor: Methotrexate, Pemetrexed, Pralatrexate, Proguanil, Pyrimethamine, Trimethoprim, Trimetrexate Dihydrofolate reductase substrate: Methotrexate Dihydrofolate reductase unknown: Gentamicin | 15.1 | ||
| kccDYR1B | Dual specificity tyrosine-phosphorylation-regulated kinase 1B | 11 | 324 | 90.43 | ND | 83.43 | 0.33 | ND | 1.4 | Mammalian | Highest expression in skeletal muscle, testis, heart and brain with little expression in colon or lung. Expressed in a variety of tumor cell lines. {ECO:0000269|PubMed:10910078}. | Kinase | Abdominal obesity-metabolic syndrome 3 (AOMS3) [MIM:615812]: A form of abdominal obesity-metabolic syndrome, a disorder characterized by abdominal obesity, high triglycerides, low levels of high density lipoprotein cholesterol, high blood pressure, and elevated fasting glucose levels. AOMS3 is characterized by early-onset coronary artery disease, central obesity, hypertension, and diabetes. {ECO:0000269|PubMed:24827035}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. Enhances the transcriptional activity of TCF1/HNF1A and FOXO1. Inhibits epithelial cell migration. Mediates colon carcinoma cell survival in mitogen-poor environments. Inhibits the SHH and WNT1 pathways, thereby enhancing adipogenesis. In addition, promotes expression of the gluconeogenic enzyme glucose-6-phosphatase (G6PC). {ECO:0000269|PubMed:10910078, ECO:0000269|PubMed:11980910, ECO:0000269|PubMed:14500717, ECO:0000269|PubMed:24827035}. | 15.1 | |||
| kccDYRK2 | Dual specificity tyrosine-phosphorylation-regulated kinase 2 | 5 | 141 | 91.66 | ND | 81.14 | 0.59 | ND | 0.3 | Mammalian | Testis, after the onset of spermatogenesis. {ECO:0000269|PubMed:9748265}. | Kinase | Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser- 641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457', promoting TERT ubiquitination by the EDVP complex. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro). {ECO:0000269|PubMed:11311121, ECO:0000269|PubMed:12588975, ECO:0000269|PubMed:14593110, ECO:0000269|PubMed:15910284, ECO:0000269|PubMed:16511445, ECO:0000269|PubMed:16611631, ECO:0000269|PubMed:17349958, ECO:0000269|PubMed:18455992, ECO:0000269|PubMed:18599021, ECO:0000269|PubMed:19287380, ECO:0000269|PubMed:22307329, ECO:0000269|PubMed:22878263, ECO:0000269|PubMed:23362280, ECO:0000269|PubMed:9748265}. | 15.1 | ||||
| kccDYRK3 | Dual specificity tyrosine-phosphorylation-regulated kinase 3 | 13 | 182 | 93.62 | ND | 88.74 | 0.15 | ND | 1.4 | Mammalian | Isoform 1 and isoform 2 are highly expressed in testis and in hematopoietic tissue such as fetal liver, and bone marrow. Isoform 2 is the predominant form in testis. Isoform 1 is the predominant form in fetal liver and bone marrow. Isoform 1 and isoform 2 are present at low levels in heart, pancreas, lymph node, and thymus. {ECO:0000269|PubMed:10779429}. | Kinase | Negative regulator of EPO-dependent erythropoiesis, may place an upper limit on red cell production during stress erythropoiesis. Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells. May act by regulating CREB/CRE signaling. {ECO:0000269|PubMed:10779429}. | 15.1 | ||||
| kccDYRK4 | Dual specificity tyrosine-phosphorylation-regulated kinase 4 | 7 | 73 | 92.40 | ND | 85.46 | 0.34 | ND | 0.7 | Mammalian | Enzyme | Possible non-essential role in spermiogenesis. {ECO:0000250}. | 15.1 | |||||
| kccE2AK1 | Eukaryotic translation initiation factor 2-alpha kinase 1 | 2 | 88 | 97.28 | ND | 92.64 | 0.27 | ND | 1.1 | Mammalian | Expressed predominantly in erythroid cells. At much lower levels, expressed in hepatocytes (at protein level). {ECO:0000269|PubMed:20071449}. | Kinase | Inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. Exerts its function through the phosphorylation of EIF2S1 at 'Ser- 48' and 'Ser-51', thus preventing its recycling. Binds hemin forming a 1:1 complex through a cysteine thiolate and histidine nitrogenous coordination. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. Thus plays an essential protective role for RBC survival in anemias of iron deficiency. Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes. May also contain ER stress during acute heme-deficient conditions (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccE2AK3 | Eukaryotic translation initiation factor 2-alpha kinase 3 | 5 | 64 | 100.00 | ND | 99.98 | 0.66 | ND | 0.9 | Mammalian | Ubiquitous. A high level expression is seen in secretory tissues. | Kinase | Wolcott-Rallison syndrome (WRS) [MIM:226980]: A rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, mental retardation and cardiovascular abnormalities. {ECO:0000269|PubMed:10932183}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function (By similarity). {ECO:0000250}. | 15.1 | |||
| kccE2AK4 | Eukaryotic translation initiation factor 2-alpha kinase 4 | 1 | 68 | 84.99 | ND | 81.88 | 0.75 | ND | 0.8 | Mammalian | Widely expressed. Expressed in the lung in smooth muscle cells of the pulmonary vessel wall, interstitial tissue and macrophages. {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:24292273}. | Kinase | Pulmonary venoocclusive disease 2, autosomal recessive (PVOD2) [MIM:234810]: A disease characterized by widespread fibrous obstruction and intimal thickening of septal veins and preseptal venules, a low diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and nodular ground-glass opacities, septal lines and lymph node enlargement showed by high-resolution computed tomography of the chest. It is frequently associated with pulmonary capillary dilatation and proliferation, and is a rare and devastating cause of pulmonary hypertension. {ECO:0000269|PubMed:24135949, ECO:0000269|PubMed:24292273}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Can phosphorylate the alpha subunit of EIF2 and may mediate translational control. {ECO:0000250}. | 15.1 | |||
| kccEAA1 | Excitatory amino acid transporter 1 | 2 | 66 | 99.95 | ND | 99.99 | 0.43 | ND | 0.5 | Mammalian | Highly expressed in cerebellum, but also found in frontal cortex, hippocampus and basal ganglia. | Electrochemical transporter | Episodic ataxia 6 (EA6) [MIM:612656]: A disorder characterized by episodic ataxia, seizures, migraine and alternating hemiplegia. {ECO:0000269|PubMed:16116111}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transports L-glutamate and also L- and D-aspartate. Essential for terminating the postsynaptic action of glutamate by rapidly removing released glutamate from the synaptic cleft. Acts as a symport by cotransporting sodium. | Dihydrofolate reductase inhibitor: Methotrexate, Pemetrexed, Pralatrexate, Proguanil, Pyrimethamine, Trimethoprim, Trimetrexate Dihydrofolate reductase substrate: Methotrexate Dihydrofolate reductase unknown: Gentamicin | 15.1 | ||
| kccEAA2 | Excitatory amino acid transporter 2 | 3 | 63 | 99.54 | ND | 99.80 | 0.67 | ND | 0.7 | Mammalian | Electrochemical transporter | Transports L-glutamate and also L- and D-aspartate. Essential for terminating the postsynaptic action of glutamate by rapidly removing released glutamate from the synaptic cleft. Acts as a symport by cotransporting sodium. | Dihydrofolate reductase inhibitor: Methotrexate, Pemetrexed, Pralatrexate, Proguanil, Pyrimethamine, Trimethoprim, Trimetrexate Dihydrofolate reductase substrate: Methotrexate Dihydrofolate reductase unknown: Gentamicin | 15.1 | ||||
| kccEAA3 | Excitatory amino acid transporter 3 | 3 | 67 | 99.98 | ND | 99.90 | 0.72 | ND | 0.5 | Mammalian | Expressed in all tissues tested including liver, muscle, testis, ovary, retinoblastoma cell line, neurons and brain (in which there was dense expression in substantia nigra, red nucleus, hippocampus and in cerebral cortical layers). {ECO:0000269|PubMed:7521911, ECO:0000269|PubMed:7859077, ECO:0000269|PubMed:7914198}. | Electrochemical transporter | Dicarboxylic aminoaciduria (DCBXA) [MIM:222730]: An autosomal recessive disorder characterized by abnormal excretion of urinary glutamate and aspartate, resulting from the incomplete reabsorption of anionic amino acids from the glomerular filtrate in the kidney. It can be associated with mental retardation. {ECO:0000269|PubMed:21123949}. Note=The disease is caused by mutations affecting the gene represented in this entry. Schizophrenia 18 (SCZD18) [MIM:615232]: A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. {ECO:0000269|PubMed:21982423, ECO:0000269|PubMed:23341099}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A deletion at the chromosome 9p24.2 locus, including SLC1A1, has been identified in patients with psychotic disorders (PubMed:21982423). This 84 kb deletion is immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence, extends through exon 1 of the SLC1A1 mRNA, co-segregates with disease in an extended 5-generation pedigree and increases disease risk more than 18-fold for family members (PubMed:23341099). {ECO:0000269|PubMed:21982423, ECO:0000269|PubMed:23341099}. | Transports L-glutamate, L- and D-aspartate and L-cystein (PubMed:21123949). Essential for terminating the postsynaptic action of glutamate by rapidly removing released glutamate from the synaptic cleft. Acts as a symport by cotransporting sodium. Negatively regulated by ARL6IP5 (By similarity). {ECO:0000250|UniProtKB:P51906, ECO:0000250|UniProtKB:P51907, ECO:0000269|PubMed:21123949}. | Excitatory amino acid transporter 3 Other: Pregabalin Excitatory amino acid transporter 3 unknown: L-Aspartic Acid | 15.1 | ||
| kccEBP | 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase | 6 | 129 | 91.90 | ND | 92.10 | 0.26 | ND | 0.9 | Mammalian | Enzyme | Chondrodysplasia punctata 2, X-linked dominant (CDPX2) [MIM:302960]: A clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. The key clinical features of CDPX2 are chondrodysplasia punctata, linear ichthyosis, cataracts and short stature. CDPX2 is a rare disorder of defective cholesterol biosynthesis, biochemically characterized by an increased amount of 8-dehydrocholesterol and cholest-8(9)- en-3-beta-ol in the plasma and tissues. {ECO:0000269|PubMed:10391218, ECO:0000269|PubMed:10391219, ECO:0000269|PubMed:10942423, ECO:0000269|PubMed:11493318}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of Delta(8)-sterols to their corresponding Delta(7)-isomers. | 15.1 | ||||
| kccECE1 | Endothelin-converting enzyme 1 | 15 | 404 | 99.41 | ND | 99.88 | 0.46 | ND | 0.8 | Mammalian | All isoforms are expressed in umbilical vein endothelial cells, polynuclear neutrophils, fibroblasts, atrium cardiomyocytes and ventricles. Isoforms A, B and C are also expressed in placenta, lung, heart, adrenal gland and phaeochromocytoma; isoforms A and C in liver, testis and small intestine; isoform B, C and D in endothelial cells and umbilical vein smooth muscle cells; isoforms C and D in saphenous vein cells, and isoform C in kidney. {ECO:0000269|PubMed:10491078, ECO:0000269|PubMed:9396733}. | Protease | Hirschsprung disease cardiac defects and autonomic dysfunction (HSCRCDAD) [MIM:613870]: A disorder characterized by skip-lesions Hirschsprung disease, craniofacial abnormalities and other dysmorphic features, cardiac defects including ductus arteriosus, small subaortic ventricular septal defect, small atrial septal defect, and autonomic dysfunction. {ECO:0000269|PubMed:9915973}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts big endothelin-1 to endothelin-1. {ECO:0000269|PubMed:9396733}. | Excitatory amino acid transporter 3 Other: Pregabalin Excitatory amino acid transporter 3 unknown: L-Aspartic Acid | 15.1 | ||
| kccEDNRA | Endothelin-1 receptor | 26 | 2009 | 97.77 | ND | 99.17 | 0.66 | ND | 0.7 | Nature11159 | Mammalian | Isoform 1, isoform 3 and isoform 4 are expressed in a variety of tissues, with highest levels in the aorta and cerebellum, followed by lung, atrium and cerebral cortex, lower levels in the placenta, kidney, adrenal gland, duodenum, colon, ventricle and liver but no expression in umbilical vein endothelial cells. Within the placenta, isoform 1, isoform 2, isoform 3 and isoform 4 are expressed in the villi and stem villi vessels. {ECO:0000269|PubMed:8611157, ECO:0000269|PubMed:9284755}. | Family A G protein-coupled receptor | Mandibulofacial dysostosis with alopecia (MFDA) [MIM:616367]: A form of mandibulofacial dysostosis, a disorder characterized by malar and mandibular hypoplasia, typically associated with abnormalities of the ears and eyelids. MFDA features include maxillary dysmorphism with dysplastic zygomatic arch, hypoplastic mandible, scalp alopecia, scant eyebrows and eyelashes, severe hypoplasia or aplasia of eyelids, small cupped dysplastic ears, conductive hearing loss, cleft palate, dental anomalies, micrognathia, and limited jaw mobility. {ECO:0000269|PubMed:25772936}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3. | Endothelin-1 receptor antagonist: Bosentan, MACITENTAN, Sitaxentan Endothelin-1 receptor unknown: Acetylsalicylic acid | 15.1 | |
| kccEDNRB | Endothelin B receptor | 21 | 1471 | 99.02 | ND | 99.60 | 0.76 | ND | 0.6 | Nature11159 | Mammalian | Expressed in placental stem villi vessels, but not in cultured placental villi smooth muscle cells. {ECO:0000269|PubMed:9284755}. | Family A G protein-coupled receptor | Waardenburg syndrome 4A (WS4A) [MIM:277580]: A disorder characterized by the association of Waardenburg features (depigmentation and deafness) with the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease). {ECO:0000269|PubMed:12189494, ECO:0000269|PubMed:8634719}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hirschsprung disease 2 (HSCR2) [MIM:600155]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. {ECO:0000269|PubMed:8001158, ECO:0000269|PubMed:8630503, ECO:0000269|PubMed:8852659, ECO:0000269|PubMed:8852660}. Note=The disease is caused by mutations affecting the gene represented in this entry. ABCD syndrome (ABCDS) [MIM:600501]: An autosomal recessive syndrome characterized by albinism, black lock at temporal occipital region, bilateral deafness, aganglionosis of the large intestine and total absence of neurocytes and nerve fibers in the small intestine. {ECO:0000269|PubMed:11891690}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:7536888}. | Endothelin B receptor antagonist: Bosentan, MACITENTAN, Sitaxentan | 15.1 | |
| kccEGFR | Epidermal growth factor receptor | 146 | 4099 | 96.44 | ND | 96.24 | 0.68 | ND | 0.8 | Mammalian | Ubiquitously expressed. Isoform 2 is also expressed in ovarian cancers. {ECO:0000269|PubMed:17671655}. | Decreased appetite | Kinase | Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:15118125, ECO:0000269|PubMed:16533793, ECO:0000269|PubMed:16672372}. Note=The gene represented in this entry is involved in disease pathogenesis. Inflammatory skin and bowel disease, neonatal, 2 (NISBD2) [MIM:616069]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269|PubMed:24691054}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS- RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin. Isoform 2 may act as an antagonist of EGF action. | Epidermal growth factor receptor antagonist: Erlotinib, Gefitinib, Lapatinib, Lidocaine Epidermal growth factor receptor inhibitor: Afatinib, Vandetanib | 15.1 | |
| kccEGLN1 | Egl nine homolog 1 | 9 | 245 | 95.68 | ND | 97.60 | 0.62 | ND | 1.1 | Mammalian | According to PubMed:11056053, widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to PubMed:12351678 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. According to PubMed:12788921; expressed in adult and fetal heart, brain, liver, lung, skeletal muscle and kidney. Also expressed in placenta. Highest levels in adult heart, brain, lung and liver and fetal brain, heart spleen and skeletal muscle. {ECO:0000269|PubMed:11056053, ECO:0000269|PubMed:12163023, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:12788921}. | Enzyme | Erythrocytosis, familial, 3 (ECYT3) [MIM:609820]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels. {ECO:0000269|PubMed:16407130, ECO:0000269|PubMed:17579185}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:15897452, ECO:0000269|PubMed:19339211, ECO:0000269|PubMed:21792862, ECO:0000269|PubMed:25129147}. | Egl nine homolog 1 unknown: Vitamin C | 15.1 | ||
| kccEGLN2 | Egl nine homolog 2 | 1 | 54 | 100.00 | ND | 100.00 | 0.89 | ND | 0.5 | Mammalian | Expressed in adult and fetal heart, brain, liver, lung, skeletal muscle, and kidney. Also expressed in testis and placenta. Highest levels in adult brain, placenta, lung, kidney, and testis. Expressed in hormone responsive tissues, including normal and cancerous mammary, ovarian and prostate epithelium. {ECO:0000269|PubMed:12163023}. | Enzyme | Anemia
Kidney Disease | Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB activation in hypoxic conditions. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:16509823, ECO:0000269|PubMed:17114296, ECO:0000269|PubMed:19339211, ECO:0000269|PubMed:23932902}. | Egl nine homolog 2 unknown: Vitamin C | 15.1 | ||
| kccEGLN3 | Egl nine homolog 3 | 3 | 67 | 94.85 | ND | 93.22 | 0.01 | ND | 0.5 | Mammalian | Widely expressed at low levels. Expressed at higher levels in adult heart (cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle), lung and placenta, and in fetal spleen, heart and skeletal muscle. Also expressed in pancreas. Localized to pancreatic acini and islet cells. {ECO:0000269|PubMed:12163023, ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:21575608}. | Enzyme | Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:16098468, ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:20849813, ECO:0000269|PubMed:20978507, ECO:0000269|PubMed:21317538, ECO:0000269|PubMed:21483450, ECO:0000269|PubMed:21575608, ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22797300}. | Egl nine homolog 3 unknown: Vitamin C | 15.1 | |||
| kccELNE | Neutrophil elastase | 36 | 1195 | 96.75 | ND | 98.78 | 0.71 | ND | 0.8 | Mammalian | Bone marrow cells. | Protease | Cyclic haematopoiesis (CH) [MIM:162800]: Autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency. {ECO:0000269|PubMed:10581030, ECO:0000269|PubMed:11001877, ECO:0000269|PubMed:14962902, ECO:0000269|PubMed:23463630}. Note=The disease is caused by mutations affecting the gene represented in this entry. Neutropenia, severe congenital 1, autosomal dominant (SCN1) [MIM:202700]: A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. {ECO:0000269|PubMed:11001877, ECO:0000269|PubMed:11675333, ECO:0000269|PubMed:12091371, ECO:0000269|PubMed:14962902, ECO:0000269|PubMed:17436313, ECO:0000269|PubMed:18946670, ECO:0000269|PubMed:19036076, ECO:0000269|PubMed:19415009, ECO:0000269|PubMed:19927291, ECO:0000269|PubMed:20220065, ECO:0000269|PubMed:20803142, ECO:0000269|PubMed:21425445, ECO:0000269|PubMed:23463630}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis. {ECO:0000269|PubMed:15140022}. | Egl nine homolog 3 unknown: Vitamin C | 15.1 | ||
| kccELOV6 | Elongation of very long chain fatty acids protein 6 {ECO:0000305} | 4 | 100 | 99.88 | ND | 99.95 | 0.40 | ND | 0.5 | Mammalian | Ubiquitous. {ECO:0000269|PubMed:20937905}. | Enzyme | Catalyzes the first and rate-limiting reaction of the four that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. Condensing enzyme that elongates fatty acids with 12, 14 and 16 carbons with higher activity toward C16:0 acyl-CoAs. Catalyzes the synthesis of unsaturated C16 long chain fatty acids and, to a lesser extent, C18:0 and those with low desaturation degree. May participate to the production of saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. {ECO:0000269|PubMed:20937905}. | 15.1 | ||||
| kccENPL | Endoplasmin | 3 | 55 | 93.76 | ND | 90.74 | 0.70 | ND | 0.4 | Mammalian | Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors (By similarity). Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity. {ECO:0000250, ECO:0000269|PubMed:18264092}. | Endoplasmin other/unknown: Rifabutin | 15.1 | |||||
| kccENPP2 | Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 | 8 | 140 | 98.72 | ND | 97.98 | 0.62 | ND | 0.6 | Mammalian | Predominantly expressed in brain, placenta, ovary, and small intestine. Expressed in a number of carcinomas such as hepatocellular and prostate carcinoma, neuroblastoma and non-small-cell lung cancer. Expressed in body fluids such as plasma, cerebral spinal fluid (CSF), saliva, follicular and amniotic fluids. Not detected in leukocytes. Isoform 1 is more highly expressed in peripheral tissues than in the central nervous system (CNS). Adipocytes only express isoform 1. Isoform 3 is more highly expressed in the brain than in peripheral tissues. {ECO:0000269|PubMed:18175805, ECO:0000269|PubMed:8579579, ECO:0000269|PubMed:8586446}. | Enzyme | Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility- related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Tumor cell motility-stimulating factor. {ECO:0000269|PubMed:11559573, ECO:0000269|PubMed:1733949, ECO:0000269|PubMed:21240271}. | 15.1 | ||||
| kccENTK | Enteropeptidase | 1 | 100 | 90.24 | ND | 95.87 | 0.00 | ND | 0.9 | Mammalian | Intestinal brush border. | Protease | Enterokinase deficiency (ENTKD) [MIM:226200]: Life- threatening intestinal malabsorption disorder characterized by diarrhea and failure to thrive. {ECO:0000269|PubMed:11719902}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Responsible for initiating activation of pancreatic proteolytic proenzymes (trypsin, chymotrypsin and carboxypeptidase A). It catalyzes the conversion of trypsinogen to trypsin which in turn activates other proenzymes including chymotrypsinogen, procarboxypeptidases, and proelastases. | 15.1 | |||
| kccEPHA2 | Ephrin type-A receptor 2 | 9 | 236 | 91.81 | ND | 88.38 | 0.14 | ND | 1.3 | Mammalian | Expressed in brain and glioma tissue and glioma cell lines (at protein level). Expressed most highly in tissues that contain a high proportion of epithelial cells, e.g. skin, intestine, lung, and ovary. {ECO:0000269|PubMed:17332925}. | Kinase | Cataract 6, multiple types (CTRCT6) [MIM:116600]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT6 includes posterior polar and age- related cortical cataracts, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. Age-related cortical cataract is a developmental punctate opacity restricted to the cortex. The cataract is white or cerulean, increases in number with age, but rarely affects vision. {ECO:0000269|PubMed:19005574, ECO:0000269|PubMed:19306328, ECO:0000269|PubMed:19649315}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Overexpressed in several cancer types and promotes malignancy. {ECO:0000269|PubMed:19573808}. | Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand- independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:16236711, ECO:0000269|PubMed:18339848, ECO:0000269|PubMed:19573808, ECO:0000269|PubMed:20679435, ECO:0000269|PubMed:20861311, ECO:0000269|PubMed:23358419}. | Ephrin type-A receptor 2 antagonist: Dasatinib Ephrin type-A receptor 2 inhibitor: Regorafenib | 15.1 | ||
| kccEPHA3 | Ephrin type-A receptor 3 | 1 | 86 | 88.42 | ND | 88.24 | 0.03 | ND | 1.0 | Mammalian | Widely expressed. Highest level in placenta. | Kinase | Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The gene represented in this entry may be involved in disease pathogenesis. | Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development. {ECO:0000269|PubMed:11870224}. | 15.1 | |||
| kccEPHA6 | Ephrin type-A receptor 6 | 1 | 65 | 94.61 | ND | 91.07 | 0.00 | ND | 1.4 | Mammalian | Expressed in brain and testis. {ECO:0000269|PubMed:14726470}. | Kinase | Receptor tyrosine kinase which binds promiscuously GPI- anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccEPHA8 | Ephrin type-A receptor 8 | 1 | 66 | 95.75 | ND | 89.33 | 0.01 | ND | 1.0 | Mammalian | Kinase | Receptor tyrosine kinase which binds promiscuously GPI- anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. The GPI-anchored ephrin-A EFNA2, EFNA3, and EFNA5 are able to activate EPHA8 through phosphorylation. With EFNA5 may regulate integrin-mediated cell adhesion and migration on fibronectin substrate but also neurite outgrowth. During development of the nervous system plays also a role in axon guidance. Downstream effectors of the EPHA8 signaling pathway include FYN which promotes cell adhesion upon activation by EPHA8 and the MAP kinases in the stimulation of neurite outgrowth (By similarity). {ECO:0000250}. | 15.1 | |||||
| kccEPHB2 | Ephrin type-B receptor 2 | 3 | 102 | 88.90 | ND | 91.59 | 0.05 | ND | 0.8 | Mammalian | Brain, heart, lung, kidney, placenta, pancreas, liver and skeletal muscle. Preferentially expressed in fetal brain. | Kinase | Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:15300251, ECO:0000269|PubMed:16155194}. Note=The gene represented in this entry may be involved in disease pathogenesis. EPHB2 mutations have been found in a prostate cancer cell line derived from a brain metastasis. | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. In addition to axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor. {ECO:0000269|PubMed:15300251}. | Ephrin type-A receptor 2 antagonist: Dasatinib Ephrin type-A receptor 2 inhibitor: Regorafenib | 15.1 | ||
| kccEPHB3 | Ephrin type-B receptor 3 | 1 | 97 | 93.54 | ND | 80.36 | 0.39 | ND | 1.2 | Mammalian | Ubiquitous. | Kinase | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Generally has an overlapping and redundant function with EPHB2. Like EPHB2, functions in axon guidance during development regulating for instance the neurons forming the corpus callosum and the anterior commissure, 2 major interhemispheric connections between the temporal lobes of the cerebral cortex. In addition to its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and the formation of excitatory synapses. Controls other aspects of development through regulation of cell migration and positioning. This includes angiogenesis, palate development and thymic epithelium development for instance. Forward and reverse signaling through the EFNB2/EPHB3 complex also regulate migration and adhesion of cells that tubularize the urethra and septate the cloaca. Finally, plays an important role in intestinal epithelium differentiation segregating progenitor from differentiated cells in the crypt. {ECO:0000269|PubMed:15536074}. | 15.1 | ||||
| kccEPHB4 | Ephrin type-B receptor 4 | 14 | 421 | 98.40 | ND | 96.16 | 0.60 | ND | 0.7 | Mammalian | Abundantly expressed in placenta but also detected in kidney, liver, lung, pancreas, skeletal muscle and heart. Expressed in primitive and myeloid, but not lymphoid, hematopoietic cells. Also observed in cell lines derived from liver, breast, colon, lung, melanocyte and cervix. {ECO:0000269|PubMed:8188704}. | Kinase | Lung Cancer
Solid tumors | Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4- mediated forward signaling controls cellular repulsion and segregation form EFNB2-expressing cells. Plays also a role in postnatal blood vessel remodeling, morphogenesis and permeability and is thus important in the context of tumor angiogenesis. {ECO:0000269|PubMed:12734395, ECO:0000269|PubMed:16424904}. | Ephrin type-A receptor 2 antagonist: Dasatinib Ephrin type-A receptor 2 inhibitor: Regorafenib | 15.1 | ||
| kccEPHB6 | Ephrin type-B receptor 6 | 1 | 60 | 94.66 | ND | 84.37 | 0.06 | ND | 1.2 | Mammalian | Expressed in brain. Expressed in non invasive breast carcinoma cell lines (at protein level). Strong expression in brain and pancreas, and weak expression in other tissues, such as heart, placenta, lung, liver, skeletal muscle and kidney. Expressed in breast non invasive tumors but not in metastatic lesions. Isoform 3 is expressed in cell lines of glioblastomas, anaplastic astrocytomas, gliosarcomas and astrocytomas. Isoform 3 is not detected in normal tissues. {ECO:0000269|PubMed:18754880, ECO:0000269|PubMed:19234485, ECO:0000269|PubMed:9207182}. | Kinase-defective receptor for members of the ephrin-B family. Binds to ephrin-B1 and ephrin-B2. Modulates cell adhesion and migration by exerting both positive and negative effects upon stimulation with ephrin-B2. Inhibits JNK activation, T-cell receptor-induced IL-2 secretion and CD25 expression upon stimulation with ephrin-B2. {ECO:0000269|PubMed:12517763, ECO:0000269|PubMed:15955811}. | 15.1 | |||||
| kccERBB2 | Receptor tyrosine-protein kinase erbB-2 | 53 | 1485 | 98.01 | ND | 97.41 | 0.63 | ND | 0.8 | Mammalian | Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth. {ECO:0000269|PubMed:15380516}. | Kinase | Hereditary diffuse gastric cancer (HDGC) [MIM:137215]: A cancer predisposition syndrome with increased susceptibility to diffuse gastric cancer. Diffuse gastric cancer is a malignant disease characterized by poorly differentiated infiltrating lesions resulting in thickening of the stomach. Malignant tumors start in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. Note=The gene represented in this entry is involved in disease pathogenesis. Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. Note=The gene represented in this entry is involved in disease pathogenesis. Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Note=The gene represented in this entry is involved in disease pathogenesis. Gastric cancer (GASC) [MIM:613659]: A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. Note=The gene represented in this entry is involved in disease pathogenesis. Note=Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2. | Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth. | Receptor tyrosine-protein kinase erbB-2 antagonist: Lapatinib Receptor tyrosine-protein kinase erbB-2 inhibitor: Afatinib | 15.1 | ||
| kccERBB4 | Receptor tyrosine-protein kinase erbB-4 | 8 | 186 | 96.88 | ND | 94.31 | 0.28 | ND | 1.5 | Mammalian | Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart. {ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:9334263}. | Kinase | Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:24119685}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis. {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:10358079, ECO:0000269|PubMed:10722704, ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:11390655, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:8617750, ECO:0000269|PubMed:9135143, ECO:0000269|PubMed:9168115, ECO:0000269|PubMed:9334263}. | Receptor tyrosine-protein kinase erbB-4 inhibitor: Afatinib | 15.1 | ||
| kccERCC5 | DNA repair protein complementing XP-G cells | 5 | 52 | 100.00 | ND | 99.99 | 0.94 | ND | 0.5 | Mammalian | Other nuclear protein | Xeroderma pigmentosum complementation group G (XP-G) [MIM:278780]: An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling and other pigmentation abnormalities. Some XP-G patients present features of Cockayne syndrome, cachectic dwarfism, pigmentary retinopathy, ataxia, decreased nerve conduction velocities. The phenotype combining xeroderma pigmentosum and Cockayne syndrome traits is referred to as XP-CS complex. {ECO:0000269|PubMed:11228268, ECO:0000269|PubMed:11841555, ECO:0000269|PubMed:12060391, ECO:0000269|PubMed:7951246, ECO:0000269|PubMed:9096355}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Single-stranded structure-specific DNA endonuclease involved in DNA excision repair. Makes the 3'incision in DNA nucleotide excision repair (NER). Acts as a cofactor for a DNA glycosylase that removes oxidized pyrimidines from DNA. May also be involved in transcription-coupled repair of this kind of damage, in transcription by RNA polymerase II, and perhaps in other processes too. | 15.1 | ||||
| kccERG | Transcriptional regulator ERG | 4 | 147 | 87.53 | ND | 85.77 | 0.51 | ND | 0.3 | Mammalian | ETS | Ewing sarcoma (ES) [MIM:612219]: A highly malignant, metastatic, primitive small round cell tumor of bone and soft tissue that affects children and adolescents. It belongs to the Ewing sarcoma family of tumors, a group of morphologically heterogeneous neoplasms that share the same cytogenetic features. They are considered neural tumors derived from cells of the neural crest. Ewing sarcoma represents the less differentiated form of the tumors. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving ERG has been found in patients with Erwing sarcoma. Translocation t(21;22)(q22;q12) with EWSR1. Note=Chromosomal aberrations involving ERG have been found in acute myeloid leukemia (AML). Translocation t(16;21)(p11;q22) with FUS. Translocation t(X;21)(q25-26;q22) with ELF4. | Transcriptional regulator. May participate in transcriptional regulation through the recruitment of SETDB1 histone methyltransferase and subsequent modification of local chromatin structure. | 15.1 | ||||
| kccERG1 | Squalene monooxygenase | 4 | 100 | 93.21 | ND | 96.84 | 0.59 | ND | 0.6 | Mammalian | Enzyme | Fungal diseases
Hypercholesterolemia | Catalyzes the first oxygenation step in sterol biosynthesis and is suggested to be one of the rate-limiting enzymes in this pathway. | Squalene monooxygenase inhibitor: Butenafine, Naftifine, Terbinafine | 15.1 | |||
| kccERG7 | Lanosterol synthase | 12 | 144 | 93.92 | ND | 94.09 | 0.17 | ND | 1.2 | Mammalian | Enzyme | Hypercholesterolemia | Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus. {ECO:0000269|PubMed:7639730}. | Squalene monooxygenase inhibitor: Butenafine, Naftifine, Terbinafine | 15.1 | |||
| kccERR1 | Steroid hormone receptor ERR1 | 6 | 98 | 99.70 | ND | 97.47 | 0.64 | ND | 0.4 | Mammalian | Nuclear receptor | Breast cancer
Diabetes mellitus Metabolic disorder, unspecified Obesity | Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle. {ECO:0000269|PubMed:12522104, ECO:0000269|PubMed:16150865, ECO:0000269|PubMed:17676930, ECO:0000269|PubMed:18063693, ECO:0000269|PubMed:23836911, ECO:0000269|PubMed:9271417}. | Squalene monooxygenase inhibitor: Butenafine, Naftifine, Terbinafine | 15.1 | |||
| kccESR1 | Estrogen receptor | 64 | 1902 | 93.51 | ND | 93.73 | 0.66 | ND | 0.8 | Nature11159 VirtualToxLab | Mammalian | Widely expressed. Isoform 3 is not expressed in the pituitary gland. {ECO:0000269|PubMed:10970861}. | Acne Blood urea increased Bone disorder Breast pain Chloasma Depression Electrolyte imbalance Embolism arterial Endometrial cancer Endometrial hyperplasia Epiphyses premature fusion Erythema multiforme Fibrocystic breast disease Gynaecomastia Hepatic function abnormal Hypercalcaemia Jaundice Menstrual disorder Metrorrhagia Neoplasm Oedema Porphyria non-acute Sodium retention Urticaria Uterine inflammation Weight increased | Nuclear receptor | Estrogen resistance (ESTRR) [MIM:615363]: A disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present. {ECO:0000269|PubMed:23841731, ECO:0000269|PubMed:8961262}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA- binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF- kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA- binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1. {ECO:0000269|PubMed:10681512, ECO:0000269|PubMed:10816575, ECO:0000269|PubMed:11477071, ECO:0000269|PubMed:11682626, ECO:0000269|PubMed:14764652, ECO:0000269|PubMed:15078875, ECO:0000269|PubMed:15891768, ECO:0000269|PubMed:16043358, ECO:0000269|PubMed:16617102, ECO:0000269|PubMed:16684779, ECO:0000269|PubMed:17922032, ECO:0000269|PubMed:17932106, ECO:0000269|PubMed:18247370, ECO:0000269|PubMed:19350539, ECO:0000269|PubMed:20074560, ECO:0000269|PubMed:20705611, ECO:0000269|PubMed:21330404, ECO:0000269|PubMed:22083956, ECO:0000269|PubMed:7651415, ECO:0000269|PubMed:9328340}. | Estrogen receptor agonist: Allylestrenol, Conjugated Estrogens, Danazol, Desogestrel, Dienestrol, Diethylstilbestrol, Estradiol, Estramustine, Estriol, Estrone, Estropipate, Ethinyl Estradiol, Ethynodiol, Etonogestrel, Medroxyprogesterone Acetate, Mestranol, Norgestimate, Progesterone, Raloxifene Estrogen receptor agonist;modulator: Quinestrol Estrogen receptor allosteric modulator: Trilostane Estrogen receptor antagonist: Fluoxymesterone, Fulvestrant, Melatonin Estrogen receptor antagonist;agonist: Clomifene, Ospemifene, Tamoxifen Estrogen receptor antagonist;other/unknown: Naloxone Estrogen receptor modulator: Toremifene Estrogen receptor other: Levonorgestrel | 15.1 |
| kccESR2 | Estrogen receptor beta | 49 | 1454 | 94.25 | ND | 96.19 | 0.55 | ND | 0.7 | Nature11159 VirtualToxLab | Mammalian | Isoform beta-1 is expressed in testis and ovary, and at a lower level in heart, brain, placenta, liver, skeletal muscle, spleen, thymus, prostate, colon, bone marrow, mammary gland and uterus. Also found in uterine bone, breast, and ovarian tumor cell lines, but not in colon and liver tumors. Isoform beta-2 is expressed in spleen, thymus, testis and ovary and at a lower level in skeletal muscle, prostate, colon, small intestine, leukocytes, bone marrow, mammary gland and uterus. Isoform beta-3 is found in testis. Isoform beta-4 is expressed in testis, and at a lower level in spleen, thymus, ovary, mammary gland and uterus. Isoform beta-5 is expressed in testis, placenta, skeletal muscle, spleen and leukocytes, and at a lower level in heart, lung, liver, kidney, pancreas, thymus, prostate, colon, small intestine, bone marrow, mammary gland and uterus. Not expressed in brain. | Acne Blood urea increased Bone disorder Breast pain Chloasma Depression Electrolyte imbalance Endometrial cancer Endometrial hyperplasia Epiphyses premature fusion Erythema multiforme Fibrocystic breast disease Gynaecomastia Hepatic function abnormal Hypercalcaemia Jaundice Menstrual disorder Metrorrhagia Neoplasm Oedema Porphyria non-acute Sodium retention Urticaria Uterine inflammation Weight increased | Nuclear receptor | Breast cancer
Cardiovascular disease, unspecified ER beta-positive prostate tumors Neurodegenerative diseases Vascular injury response | Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual. {ECO:0000269|PubMed:20074560}. | Estrogen receptor beta agonist: Diethylstilbestrol, Estradiol, Estriol, Estropipate, Raloxifene Estrogen receptor beta allosteric modulator: Trilostane Estrogen receptor beta antagonist;agonist: Tamoxifen Estrogen receptor beta other/unknown: Estramustine | 15.1 |
| kccEST1 | Liver carboxylesterase 1 | 17 | 374 | 96.25 | ND | 96.78 | 0.50 | ND | 1.0 | Mammalian | Expressed predominantly in liver with lower levels in heart and lung. {ECO:0000269|PubMed:10562416}. | Enzyme | Alzheimer's disease
Atherosclerosis Cardiovascular disease, unspecified Cocaine overdose Hypercholesterolaemia Protection against chemical weapons like Sarin, Soman and VX gas | Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester. Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine. Catalyzes the transesterification of cocaine to form cocaethylene. Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate. {ECO:0000269|PubMed:7980644, ECO:0000269|PubMed:9169443}. | Liver carboxylesterase 1 inhibitor: Benzocaine, Tamoxifen Liver carboxylesterase 1 other: Oseltamivir Liver carboxylesterase 1 substrate: Capecitabine, Ciclesonide, Clopidogrel, Dabigatran etexilate, Indomethacin, Irinotecan, Mycophenolate mofetil, Rufinamide, Trandolapril Liver carboxylesterase 1 unknown: Cyclandelate, L-Carnitine, Probucol | 15.1 | ||
| kccEST2 | Cocaine esterase | 4 | 124 | 97.56 | ND | 99.85 | 0.29 | ND | 1.1 | Mammalian | Preferentially expressed in intestine with moderate expression in liver. Within the intestine, highest expression is found in small intestine with lower expression in colon and rectum. {ECO:0000269|PubMed:9144407}. | Enzyme | Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Shows high catalytic efficiency for hydrolysis of cocaine, 4-methylumbelliferyl acetate, heroin and 6-monoacetylmorphine. {ECO:0000269|PubMed:9169443}. | Cocaine esterase substrate: Dabigatran etexilate, Irinotecan, Prasugrel Cocaine esterase unknown: Mycophenolate mofetil | 15.1 | |||
| kccEZH2 | Histone-lysine N-methyltransferase EZH2 | 2 | 43 | 100.00 | ND | 99.98 | 0.80 | ND | 0.3 | Mammalian | Expressed in many tissues. Overexpressed in numerous tumor types including carcinomas of the breast, colon, larynx, lymphoma and testis. {ECO:0000269|PubMed:14532106}. | Writer | Weaver syndrome (WVS) [MIM:277590]: A syndrome of accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly. Distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand. {ECO:0000269|PubMed:22177091}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys- 27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Compared to EZH2-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-ARNTL/BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription. {ECO:0000269|PubMed:14532106, ECO:0000269|PubMed:15225548, ECO:0000269|PubMed:15231737, ECO:0000269|PubMed:15385962, ECO:0000269|PubMed:16179254, ECO:0000269|PubMed:16357870, ECO:0000269|PubMed:16618801, ECO:0000269|PubMed:16717091, ECO:0000269|PubMed:16936726, ECO:0000269|PubMed:17210787, ECO:0000269|PubMed:17344414, ECO:0000269|PubMed:18285464, ECO:0000269|PubMed:19026781, ECO:0000269|PubMed:20935635, ECO:0000269|PubMed:23063525, ECO:0000269|PubMed:24474760}. | 15.1 | |||
| kccF13A | Coagulation factor XIII A chain | 3 | 86 | 99.91 | ND | 99.98 | 0.74 | ND | 0.5 | Mammalian | Aminoacyltransferase | Factor XIII subunit A deficiency (FA13AD) [MIM:613225]: An autosomal recessive hematologic disorder characterized by a life-long bleeding tendency, impaired wound healing and spontaneous abortion in affected women. {ECO:0000269|PubMed:1353995}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor XIII is activated by thrombin and calcium ion to a transglutaminase that catalyzes the formation of gamma-glutamyl- epsilon-lysine cross-links between fibrin chains, thus stabilizing the fibrin clot. Also cross-link alpha-2-plasmin inhibitor, or fibronectin, to the alpha chains of fibrin. | Coagulation factor XIII A chain substrate: L-Glutamine | 15.1 | |||
| kccF16P1 | Fructose-1,6-bisphosphatase 1 | 12 | 395 | 99.40 | ND | 99.72 | 0.78 | ND | 0.5 | Mammalian | Expressed in pancreatic islets. {ECO:0000269|PubMed:18375435}. | Enzyme | Fructose-1,6-bisphosphatase deficiency (FBPD) [MIM:229700]: Inherited as an autosomal recessive disorder mainly in the liver and causes life-threatening episodes of hypoglycemia and metabolic acidosis (lactacidemia) in newborn infants or young children. {ECO:0000269|PubMed:12126934, ECO:0000269|PubMed:9382095}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations, acting as a rate-limiting enzyme in gluconeogenesis. Plays a role in regulating glucose sensing and insulin secretion of pancreatic beta-cells. Appears to modulate glycerol gluconeogenesis in liver. Important regulator of appetite and adiposity; increased expression of the protein in liver after nutrient excess increases circulating satiety hormones and reduces appetite-stimulating neuropeptides and thus seems to provide a feedback mechanism to limit weight gain. {ECO:0000269|PubMed:16497803, ECO:0000269|PubMed:18375435, ECO:0000269|PubMed:22517657}. | Fructose-1,6-bisphosphatase 1 antagonist;inhibitory allosteric modulator: Adenosine monophosphate | 15.1 | ||
| kccFA10 | Coagulation factor X | 103 | 4335 | 97.97 | ND | 98.91 | 0.75 | ND | 0.7 | Mammalian | Plasma; synthesized in the liver. {ECO:0000269|PubMed:6587384}. | Protease | Factor X deficiency (FA10D) [MIM:227600]: A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis. {ECO:0000269|PubMed:10468877, ECO:0000269|PubMed:10746568, ECO:0000269|PubMed:11248282, ECO:0000269|PubMed:11728527, ECO:0000269|PubMed:12574802, ECO:0000269|PubMed:12945883, ECO:0000269|PubMed:15075089, ECO:0000269|PubMed:15650540, ECO:0000269|PubMed:17393015, ECO:0000269|PubMed:19135706, ECO:0000269|PubMed:1973167, ECO:0000269|PubMed:1985698, ECO:0000269|PubMed:25313940, ECO:0000269|PubMed:2790181, ECO:0000269|PubMed:7669671, ECO:0000269|PubMed:7860069, ECO:0000269|PubMed:8529633, ECO:0000269|PubMed:8845463, ECO:0000269|PubMed:8910490}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting. | Coagulation factor X activator: Menadione Coagulation factor X antagonist: Rivaroxaban Coagulation factor X inhibitor: Apixaban, Edoxaban, Fondaparinux sodium, Heparin | 15.1 | ||
| kccFA11 | Coagulation factor XI | 5 | 153 | 99.60 | ND | 97.84 | 0.66 | ND | 0.8 | Mammalian | Isoform 2 is produced by platelets and megakaryocytes but absent from other blood cells. | Protease | Factor XI deficiency (FA11D) [MIM:612416]: A hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. {ECO:0000269|PubMed:10027710, ECO:0000269|PubMed:10606881, ECO:0000269|PubMed:11895778, ECO:0000269|PubMed:15026311, ECO:0000269|PubMed:15180874, ECO:0000269|PubMed:1547342, ECO:0000269|PubMed:15953011, ECO:0000269|PubMed:16607084, ECO:0000269|PubMed:18005151, ECO:0000269|PubMed:21457405, ECO:0000269|PubMed:21668437, ECO:0000269|PubMed:21999818, ECO:0000269|PubMed:22016685, ECO:0000269|PubMed:22159456, ECO:0000269|PubMed:22322133, ECO:0000269|PubMed:2813350, ECO:0000269|PubMed:7669672, ECO:0000269|PubMed:7888672, ECO:0000269|PubMed:9401068, ECO:0000269|PubMed:9787168}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. | Coagulation factor X activator: Menadione Coagulation factor X antagonist: Rivaroxaban Coagulation factor X inhibitor: Apixaban, Edoxaban, Fondaparinux sodium, Heparin | 15.1 | ||
| kccFA12 | Coagulation factor XII | 7 | 175 | 85.80 | ND | 86.54 | 0.14 | ND | 0.8 | Mammalian | Protease | Factor XII deficiency (FA12D) [MIM:234000]: An asymptomatic anomaly of in vitro blood coagulation. Its diagnosis is based on finding a low plasma activity of the factor in coagulating assays. It is usually only accidentally discovered through pre-operative blood tests. Factor XII deficiency is divided into two categories, a cross-reacting material (CRM)- negative group (negative F12 antigen detection) and a CRM-positive group (positive F12 antigen detection). {ECO:0000269|PubMed:10361128, ECO:0000269|PubMed:11776307, ECO:0000269|PubMed:15205584, ECO:0000269|PubMed:15617741, ECO:0000269|PubMed:2510163, ECO:0000269|PubMed:2882793, ECO:0000269|PubMed:8049433, ECO:0000269|PubMed:8528215, ECO:0000269|PubMed:9354665}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hereditary angioedema 3 (HAE3) [MIM:610618]: An hereditary angioedema occurring only in women. Hereditary angioedema is an autosomal dominant disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. Hereditary angioedema type 3 differs from types 1 and 2 in that both concentration and function of C1 esterase inhibitor are normal. Hereditary angioedema type 3 is precipitated or worsened by high estrogen levels (e.g., during pregnancy or treatment with oral contraceptives). {ECO:0000269|PubMed:16638441, ECO:0000269|PubMed:17186468}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta- factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa. {ECO:0000269|PubMed:21304106}. | Coagulation factor XII activator: Ethanolamine Oleate | 15.1 | |||
| kccFA7 | Coagulation factor VII | 17 | 342 | 99.65 | ND | 99.01 | 0.55 | ND | 0.7 | Mammalian | Plasma. | Protease | Factor VII deficiency (FA7D) [MIM:227500]: A hemorrhagic disease with variable presentation. The clinical picture can be very severe, with the early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, moderate with cutaneous-mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by a surgical intervention. Finally, numerous subjects are completely asymptomatic despite very low factor VII levels. {ECO:0000269|PubMed:10862079, ECO:0000269|PubMed:11091194, ECO:0000269|PubMed:11129332, ECO:0000269|PubMed:12472587, ECO:0000269|PubMed:14717781, ECO:0000269|PubMed:1634227, ECO:0000269|PubMed:18976247, ECO:0000269|PubMed:19432927, ECO:0000269|PubMed:19751712, ECO:0000269|PubMed:2070047, ECO:0000269|PubMed:21206266, ECO:0000269|PubMed:21372693, ECO:0000269|PubMed:7974346, ECO:0000269|PubMed:7981691, ECO:0000269|PubMed:8043443, ECO:0000269|PubMed:8204879, ECO:0000269|PubMed:8364544, ECO:0000269|PubMed:8652821, ECO:0000269|PubMed:8844208, ECO:0000269|PubMed:8883260, ECO:0000269|PubMed:8940045, ECO:0000269|PubMed:9414278, ECO:0000269|PubMed:9452082, ECO:0000269|PubMed:9576180}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium. | Coagulation factor VII activator: Menadione | 15.1 | ||
| kccFA9 | Coagulation factor IX {ECO:0000303|PubMed:3857619} | 8 | 168 | 99.13 | ND | 98.41 | 0.67 | ND | 0.6 | Mammalian | Detected in blood plasma (at protein level) (PubMed:3857619, PubMed:8295821, PubMed:2592373, PubMed:9169594, PubMed:19846852). Synthesized primarily in the liver and secreted in plasma. {ECO:0000269|PubMed:19846852, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:3857619}. | Protease | Hemophilia B (HEMB) [MIM:306900]: An X-linked blood coagulation disorder characterized by a permanent tendency to hemorrhage, due to factor IX deficiency. It is phenotypically similar to hemophilia A, but patients present with fewer symptoms. Many patients are asymptomatic until the hemostatic system is stressed by surgery or trauma. {ECO:0000269|PubMed:10094553, ECO:0000269|PubMed:10698280, ECO:0000269|PubMed:11122099, ECO:0000269|PubMed:12588353, ECO:0000269|PubMed:12604421, ECO:0000269|PubMed:1346975, ECO:0000269|PubMed:1615485, ECO:0000269|PubMed:1902289, ECO:0000269|PubMed:1958666, ECO:0000269|PubMed:2162822, ECO:0000269|PubMed:2339358, ECO:0000269|PubMed:2372509, ECO:0000269|PubMed:2472424, ECO:0000269|PubMed:25470321, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:2713493, ECO:0000269|PubMed:2714791, ECO:0000269|PubMed:2738071, ECO:0000269|PubMed:2753873, ECO:0000269|PubMed:2773937, ECO:0000269|PubMed:2775660, ECO:0000269|PubMed:3009023, ECO:0000269|PubMed:3243764, ECO:0000269|PubMed:3401602, ECO:0000269|PubMed:3790720, ECO:0000269|PubMed:6603618, ECO:0000269|PubMed:7981722, ECO:0000269|PubMed:8076946, ECO:0000269|PubMed:8199596, ECO:0000269|PubMed:8257988, ECO:0000269|PubMed:8295821, ECO:0000269|PubMed:8680410, ECO:0000269|PubMed:9222764, ECO:0000269|PubMed:9452115, ECO:0000269|PubMed:9590153, ECO:0000269|PubMed:9600455}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide, mutation in position 93 (Alabama) probably fails to bind to cell membranes, mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya OR Hilo) prevent cleavage of the activation peptide. Thrombophilia, X-linked, due to factor IX defect (THPH8) [MIM:300807]: A hemostatic disorder characterized by a tendency to thrombosis. {ECO:0000269|PubMed:19846852}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa. {ECO:0000269|PubMed:1730085, ECO:0000269|PubMed:19846852, ECO:0000269|PubMed:20121197, ECO:0000269|PubMed:20121198, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:8295821}. | Coagulation factor IX {ECO:0000303|PubMed:3857619} activator: Menadione | 15.1 | ||
| kccFAAH1 | Fatty-acid amide hydrolase 1 | 68 | 1842 | 96.96 | ND | 97.21 | 0.64 | ND | 0.8 | Mammalian | Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate. {ECO:0000269|PubMed:17015445}. | Enzyme | Analgesics
Anesthetic Anxiety disorder, unspecified Pain Sedation | Degrades bioactive fatty acid amides like oleamide, the endogenous cannabinoid, anandamide and myristic amide to their corresponding acids, thereby serving to terminate the signaling functions of these molecules. Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates. {ECO:0000269|PubMed:17015445}. | Fatty-acid amide hydrolase 1 inhibitor: Thiopental Fatty-acid amide hydrolase 1 substrate: Propofol | 15.1 | ||
| kccFABP4 | Fatty acid-binding protein, adipocyte | 8 | 122 | 99.45 | ND | 97.18 | 0.82 | ND | 0.6 | Mammalian | Fatty acid binding protein family | Atherosclerosis | Lipid transport protein in adipocytes. Binds both long chain fatty acids and retinoic acid. Delivers long-chain fatty acids and retinoic acid to their cognate receptors in the nucleus (By similarity). {ECO:0000250}. | Fatty-acid amide hydrolase 1 inhibitor: Thiopental Fatty-acid amide hydrolase 1 substrate: Propofol | 15.1 | |||
| kccFABPH | Fatty acid-binding protein, heart | 2 | 56 | 91.37 | ND | 92.15 | 0.26 | ND | 0.6 | Mammalian | Fatty acid binding protein family | FABP are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters. | Fatty-acid amide hydrolase 1 inhibitor: Thiopental Fatty-acid amide hydrolase 1 substrate: Propofol | 15.1 | ||||
| kccFAK1 | Focal adhesion kinase 1 | 20 | 579 | 93.91 | ND | 94.38 | 0.23 | ND | 1.1 | Mammalian | Detected in B and T-lymphocytes. Isoform 1 and isoform 6 are detected in lung fibroblasts (at protein level). Ubiquitous. {ECO:0000269|PubMed:20109444, ECO:0000269|PubMed:7692878, ECO:0000269|PubMed:8247543, ECO:0000269|PubMed:8422239}. | Kinase | Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer. | Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:11331870, ECO:0000269|PubMed:11980671, ECO:0000269|PubMed:15166238, ECO:0000269|PubMed:15561106, ECO:0000269|PubMed:15895076, ECO:0000269|PubMed:16919435, ECO:0000269|PubMed:16927379, ECO:0000269|PubMed:17395594, ECO:0000269|PubMed:17431114, ECO:0000269|PubMed:17968709, ECO:0000269|PubMed:18006843, ECO:0000269|PubMed:18206965, ECO:0000269|PubMed:18256281, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:18497331, ECO:0000269|PubMed:18677107, ECO:0000269|PubMed:19138410, ECO:0000269|PubMed:19147981, ECO:0000269|PubMed:19224453, ECO:0000269|PubMed:20332118, ECO:0000269|PubMed:20495381, ECO:0000269|PubMed:21454698}. | Fatty-acid amide hydrolase 1 inhibitor: Thiopental Fatty-acid amide hydrolase 1 substrate: Propofol | 15.1 | ||
| kccFAK2 | Protein-tyrosine kinase 2-beta | 9 | 257 | 90.57 | ND | 84.42 | 0.31 | ND | 1.3 | Mammalian | Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes. {ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:9545257}. | Kinase | Note=Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer. | Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T- cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2. {ECO:0000269|PubMed:10022920, ECO:0000269|PubMed:12771146, ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:15050747, ECO:0000269|PubMed:15166227, ECO:0000269|PubMed:17634955, ECO:0000269|PubMed:18086875, ECO:0000269|PubMed:18339875, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18765415, ECO:0000269|PubMed:19086031, ECO:0000269|PubMed:19207108, ECO:0000269|PubMed:19244237, ECO:0000269|PubMed:19428251, ECO:0000269|PubMed:19648005, ECO:0000269|PubMed:19880522, ECO:0000269|PubMed:20001213, ECO:0000269|PubMed:20381867, ECO:0000269|PubMed:20521079, ECO:0000269|PubMed:21357692, ECO:0000269|PubMed:21533080, ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:8670418, ECO:0000269|PubMed:8849729}. | Protein-tyrosine kinase 2-beta antagonist: Leflunomide | 15.1 | ||
| kccFAS | Fatty acid synthase | 57 | 933 | 89.80 | ND | 88.25 | 0.29 | ND | 0.8 | Mammalian | Ubiquitous. Prominent expression in brain, lung, and liver. {ECO:0000269|PubMed:7567999, ECO:0000269|PubMed:7595075}. | Transferase | Endometrial carcinoma
Leukemia, unspecified Malaria Mesothelioma Metastatic osteosarcoma in the lung Obesity Prostate cancer Tumors | Fatty acid synthetase catalyzes the formation of long- chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein. | Fatty acid synthase inhibitor: Cerulenin, Orlistat | 15.1 | ||
| kccFCER2 | Low affinity immunoglobulin epsilon Fc receptor | 3 | 69 | 99.93 | ND | 99.98 | 0.77 | ND | 0.4 | Mammalian | Membrane receptor | Low-affinity receptor for immunoglobulin E (IgE) and CR2/CD21. Has essential roles in the regulation of IgE production and in the differentiation of B-cells (it is a B-cell-specific antigen). | 15.1 | |||||
| kccFCGRN | IgG receptor FcRn large subunit p51 | 1 | 136 | 99.85 | ND | 99.97 | 0.65 | ND | 0.5 | Mammalian | Autoimmune diseases | Binds to the Fc region of monomeric immunoglobulins gamma. Mediates the uptake of IgG from milk. Possible role in transfer of immunoglobulin G from mother to fetus. | 15.1 | |||||
| kccFDFT | Squalene synthase | 24 | 597 | 97.51 | ND | 98.30 | 0.62 | ND | 0.9 | Mammalian | Enzyme | Hypercholesterolemia
Hyperlipidemia Hypocholesterolemia | 15.1 | |||||
| kccFEN1 | Flap endonuclease 1 {ECO:0000255|HAMAP-Rule:MF_03140} | 14 | 1084 | 84.25 | ND | 90.63 | 0.54 | ND | 0.7 | Mammalian | Enzyme | Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double- stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA. {ECO:0000255|HAMAP-Rule:MF_03140, ECO:0000269|PubMed:10744741, ECO:0000269|PubMed:11986308, ECO:0000269|PubMed:18443037, ECO:0000269|PubMed:20729856, ECO:0000269|PubMed:7961795, ECO:0000269|PubMed:8621570}. | 15.1 | |||||
| kccFER | Tyrosine-protein kinase Fer | 2 | 169 | 93.96 | ND | 90.96 | 0.14 | ND | 1.5 | Mammalian | Isoform 1 is detected in normal colon and in fibroblasts (at protein level). Isoform 3 is detected in normal testis, in colon carcinoma-derived metastases in lung, liver and ovary, and in colon carcinoma and hepato carcinoma cell lines (at protein level). Isoform 3 is not detected in normal colon or in normal fibroblasts (at protein level). Widely expressed. {ECO:0000269|PubMed:18985748, ECO:0000269|PubMed:2156206, ECO:0000269|PubMed:22223638}. | Kinase | Tyrosine-protein kinase that acts downstream of cell surface receptors for growth factors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, lamellipodia formation, cell adhesion, cell migration and chemotaxis. Acts downstream of EGFR, KIT, PDGFRA and PDGFRB. Acts downstream of EGFR to promote activation of NF-kappa-B and cell proliferation. May play a role in the regulation of the mitotic cell cycle. Plays a role in the insulin receptor signaling pathway and in activation of phosphatidylinositol 3-kinase. Acts downstream of the activated FCER1 receptor and plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Plays a role in the regulation of mast cell degranulation. Plays a role in leukocyte recruitment and diapedesis in response to bacterial lipopolysaccharide (LPS). Plays a role in synapse organization, trafficking of synaptic vesicles, the generation of excitatory postsynaptic currents and neuron-neuron synaptic transmission. Plays a role in neuronal cell death after brain damage. Phosphorylates CTTN, CTNND1, PTK2/FAK1, GAB1, PECAM1 and PTPN11. May phosphorylate JUP and PTPN1. Can phosphorylate STAT3, but the biological relevance of this depends on cell type and stimulus. {ECO:0000269|PubMed:12972546, ECO:0000269|PubMed:14517306, ECO:0000269|PubMed:19147545, ECO:0000269|PubMed:19339212, ECO:0000269|PubMed:19738202, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21518868, ECO:0000269|PubMed:22223638, ECO:0000269|PubMed:7623846, ECO:0000269|PubMed:9722593}. | 15.1 | ||||
| kccFES | Tyrosine-protein kinase Fes/Fps | 2 | 126 | 96.29 | ND | 99.24 | 0.25 | ND | 1.2 | Mammalian | Widely expressed. Detected in adult colon epithelium. {ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:19051325}. | Kinase | Note=Has been shown to act as proto-oncogene in some types of cancer, possibly due to abnormal activation of the kinase. Has been shown to act as tumor suppressor in other types of cancer. Expressed and present as activated kinase in a subset of acute myeloid leukemia patients; promotes survival of leukemia cells (PubMed:20111072). Expression is absent in K562 leukemia cells; ectopic expression of FSP/FES restores myeloid differentiation (PubMed:2656706). May function as tumor suppressor in colorectal cancer; expression is reduced or absent in samples from some colon cancer patients (PubMed:16455651). Ectopic expression of FSP/FES suppresses anchorage-independent growth in colon cancer cell lines (PubMed:16455651). Up-regulated in prostate cancer, and might be a predictor of recurrence after radical surgery (PubMed:21563194). May promote growth of renal carcinoma cells (PubMed:19082481). {ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:19082481, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21563194, ECO:0000269|PubMed:2656706}. | Tyrosine-protein kinase that acts downstream of cell surface receptors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, cell attachment and cell spreading. Plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Acts down- stream of the activated FCER1 receptor and the mast/stem cell growth factor receptor KIT. Plays a role in the regulation of mast cell degranulation. Plays a role in the regulation of cell differentiation and promotes neurite outgrowth in response to NGF signaling. Plays a role in cell scattering and cell migration in response to HGF-induced activation of EZR. Phosphorylates BCR and down-regulates BCR kinase activity. Phosphorylates HCLS1/HS1, PECAM1, STAT3 and TRIM28. {ECO:0000269|PubMed:11509660, ECO:0000269|PubMed:15302586, ECO:0000269|PubMed:15485904, ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:17595334, ECO:0000269|PubMed:18046454, ECO:0000269|PubMed:19001085, ECO:0000269|PubMed:19051325, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:2656706, ECO:0000269|PubMed:8955135}. | 15.1 | |||
| kccFFAR1 | Free fatty acid receptor 1 | 15 | 429 | 99.66 | ND | 99.94 | 0.45 | ND | 0.6 | Mammalian | Detected in brain and pancreas. Detected in pancreatic beta cells. {ECO:0000269|PubMed:12496284, ECO:0000269|PubMed:16289108}. | Family A G protein-coupled receptor | G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis. Fatty acid binding increases glucose- stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (By similarity). Ligand binding leads to a conformation change that triggers signaling via G-proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration. Seems to act through a G(q) and G(i)-mediated pathway. {ECO:0000250|UniProtKB:Q76JU9, ECO:0000269|PubMed:12496284, ECO:0000269|PubMed:17699519, ECO:0000269|PubMed:24130766}. | Free fatty acid receptor 1 agonist: Icosapent | 15.1 | |||
| kccFFAR2 | Free fatty acid receptor 2 | 2 | 68 | 99.86 | ND | 99.90 | 0.17 | ND | 0.6 | Mammalian | Expressed at relatively high levels in peripheral blood leukocytes and, to lesser extent, in spleen. {ECO:0000269|PubMed:12496283, ECO:0000269|PubMed:12684041}. | Family A G protein-coupled receptor | G protein-coupled receptor that is activated by a major product of dietary fiber digestion, the short chain fatty acids (SCFAs), and that plays a role in the regulation of whole-body energy homeostasis and in intestinal immunity. In omnivorous mammals, the short chain fatty acids acetate, propionate and butyrate are produced primarily by the gut microbiome that metabolizes dietary fibers. SCFAs serve as a source of energy but also act as signaling molecules. That G protein-coupled receptor is probably coupled to the pertussis toxin-sensitive, G(i/o)-alpha family of G proteins but also to the Gq family (PubMed:12496283, PubMed:12711604, PubMed:23589301). Its activation results in the formation of inositol 1,4,5-trisphosphate, the mobilization of intracellular calcium, the phosphorylation of the MAPK3/ERK1 and MAPK1/ERK2 kinases and the inhibition of intracellular cAMP accumulation. May play a role in glucose homeostasis by regulating the secretion of GLP-1, in response to short-chain fatty acids accumulating in the intestine. May also regulate the production of LEP/Leptin, a hormone acting on the central nervous system to inhibit food intake. Finally, may also regulate whole-body energy homeostasis through adipogenesis regulating both differentiation and lipid storage of adipocytes. In parallel to its role in energy homeostasis, may also mediate the activation of the inflammatory and immune responses by SCFA in the intestine, regulating the rapid production of chemokines and cytokines. May also play a role in the resolution of the inflammatory response and control chemotaxis in neutrophils. In addition to SCFAs, may also be activated by the extracellular lectin FCN1 in a process leading to activation of monocytes and inducing the secretion of interleukin- 8/IL-8 in response to the presence of microbes (PubMed:21037097). Among SCFAs, the fatty acids containing less than 6 carbons, the most potent activators are probably acetate, propionate and butyrate (PubMed:12496283, PubMed:12711604). Exhibits a SCFA- independent constitutive G protein-coupled receptor activity (PubMed:23066016). {ECO:0000269|PubMed:12496283, ECO:0000269|PubMed:12684041, ECO:0000269|PubMed:12711604, ECO:0000269|PubMed:18801738, ECO:0000269|PubMed:21037097, ECO:0000269|PubMed:23066016, ECO:0000269|PubMed:23589301}. | 15.1 | ||||
| kccFFAR4 | Free fatty acid receptor 4 | 4 | 55 | 99.97 | ND | 99.97 | 0.34 | ND | 0.8 | Mammalian | Abundant expression in the intestinal tract. Highly expressed in adipose tissue, small intestine and pancreas. {ECO:0000269|PubMed:15619630, ECO:0000269|PubMed:17250804}. | Family A G protein-coupled receptor | Receptor for medium and long-chain free fatty acids (FFAs). Signals via a G(q)/G(11)-coupled pathway. Acts as a receptor for omega-3 fatty acids and mediates robust anti- inflammatory effects, particularly in macrophages and fat cells. The anti-inflammatory effects involve inhibition of TAK1 through a beta-arrestin 2 (ARRB2)/TAB1-dependent effect, but independent of the G(q)/G(11)-coupled pathway. Mediates potent insulin sensitizing and antidiabetic effects by repressing macrophage- induced tissue inflammation. May mediate the taste of fatty acids. Mediates FFA-induced inhibition of apoptosis in enteroendocrine cells. May play a role in the regulation of adipocyte development and differentiation. {ECO:0000269|PubMed:15619630}. | 15.1 | ||||
| kccFGF1 | Fibroblast growth factor 1 | 1 | 53 | 99.96 | ND | 99.96 | 0.66 | ND | 0.7 | Mammalian | Predominantly expressed in kidney and brain. Detected at much lower levels in heart and skeletal muscle. {ECO:0000269|PubMed:11964394, ECO:0000269|PubMed:7504343}. | Secreted protein | Hepatic fibrosis | Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. {ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:20145243, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor 1 antagonist: Pentosan Polysulfate Fibroblast growth factor 1 inhibitor: Amlexanox, Pazopanib | 15.1 | ||
| kccFGF2 | Fibroblast growth factor 2 | 1 | 45 | 99.42 | ND | 99.74 | 0.02 | ND | 1.1 | Mammalian | Expressed in granulosa and cumulus cells. Expressed in hepatocellular carcinoma cells, but not in non- cancerous liver tissue. {ECO:0000269|PubMed:1417798, ECO:0000269|PubMed:1721615}. | Secreted protein | Hepatic fibrosis
Rheumatoid arthritis, unspecified | Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. {ECO:0000269|PubMed:1721615, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor 2 agonist: Sucralfate Fibroblast growth factor 2 antagonist: Pentosan Polysulfate Fibroblast growth factor 2 other/unknown: Sirolimus | 15.1 | ||
| kccFGFR1 | Fibroblast growth factor receptor 1 | 38 | 1091 | 97.48 | ND | 94.22 | 0.47 | ND | 0.9 | Mammalian | Detected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform 17, isoform 18 and isoform 19 are not detected in these cells. {ECO:0000269|PubMed:1652059}. | Kinase | Pfeiffer syndrome (PS) [MIM:101600]: A syndrome characterized by the association of craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly of the fingers and toes. Three subtypes are known: mild autosomal dominant form (type 1); cloverleaf skull, elbow ankylosis, early death, sporadic (type 2); craniosynostosis, early demise, sporadic (type 3). {ECO:0000269|PubMed:7874169}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:147950]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:12627230, ECO:0000269|PubMed:15001591, ECO:0000269|PubMed:15605412, ECO:0000269|PubMed:15845591, ECO:0000269|PubMed:16606836, ECO:0000269|PubMed:16757108, ECO:0000269|PubMed:16764984, ECO:0000269|PubMed:16882753, ECO:0000269|PubMed:17154279, ECO:0000269|PubMed:19820032, ECO:0000269|PubMed:21700882, ECO:0000269|PubMed:22927827, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FGFR1 also have a mutation other HH- associated genes including DUSP6, FGF8, FGF17, FLRT3, GNRH1, GNRHR, HS6ST1, IL17RD, ANOS1, KISS1R, NSMF, PROKR2, SPRY4 and TACR3 (PubMed:23643382). {ECO:0000269|PubMed:23643382}. Osteoglophonic dysplasia (OGD) [MIM:166250]: Characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant. {ECO:0000269|PubMed:15625620, ECO:0000269|PubMed:16470795}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hartsfield syndrome (HRTFDS) [MIM:615465]: A syndrome characterized by the triad of holoprosencephaly, ectrodactyly, and cleft/lip palate. Profound mental retardation is also present. Multiple other congenital anomalies usually occur. {ECO:0000269|PubMed:23812909, ECO:0000269|PubMed:24888332}. Note=The disease is caused by mutations affecting the gene represented in this entry. Trigonocephaly 1 (TRIGNO1) [MIM:190440]: A keel-shaped deformation of the forehead, caused by premature fusion of the metopic sutures. It results in a triangular shape of the head. {ECO:0000269|PubMed:11173846}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with ZMYM2. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1OP. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity and be responsible for the transforming activity. Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(8;9)(p12;q33) with CNTRL. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein CNTRL-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation. {ECO:0000250|UniProtKB:P16092, ECO:0000269|PubMed:10830168, ECO:0000269|PubMed:11353842, ECO:0000269|PubMed:12181353, ECO:0000269|PubMed:1379697, ECO:0000269|PubMed:1379698, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19261810, ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:20133753, ECO:0000269|PubMed:20139426, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:8622701, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor receptor 1 Inhibitor: Lenvatinib, Nintedanib Fibroblast growth factor receptor 1 inhibitor: Ponatinib, Regorafenib, Sorafenib | 15.1 | ||
| kccFGFR2 | Fibroblast growth factor receptor 2 | 1 | 125 | 95.93 | ND | 95.26 | 0.10 | ND | 1.4 | Mammalian | Kinase | Crouzon syndrome (CS) [MIM:123500]: An autosomal dominant syndrome characterized by craniosynostosis, hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism. {ECO:0000269|PubMed:10574673, ECO:0000269|PubMed:11173845, ECO:0000269|PubMed:11380921, ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7581378, ECO:0000269|PubMed:7655462, ECO:0000269|PubMed:7874170, ECO:0000269|PubMed:7987400, ECO:0000269|PubMed:8528214, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:8946174, ECO:0000269|PubMed:8956050, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9152842, ECO:0000269|PubMed:9521581, ECO:0000269|PubMed:9677057, ECO:0000269|Ref.10}. Note=The disease is caused by mutations affecting the gene represented in this entry. Jackson-Weiss syndrome (JWS) [MIM:123150]: An autosomal dominant craniosynostosis syndrome characterized by craniofacial abnormalities and abnormality of the feet: broad great toes with medial deviation and tarsal-metatarsal coalescence. {ECO:0000269|PubMed:7874170, ECO:0000269|PubMed:8528214, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:9385368, ECO:0000269|PubMed:9677057}. Note=The disease is caused by mutations affecting the gene represented in this entry. Apert syndrome (APRS) [MIM:101200]: A syndrome characterized by facio-cranio-synostosis, osseous and membranous syndactyly of the four extremities, and midface hypoplasia. The craniosynostosis is bicoronal and results in acrocephaly of brachysphenocephalic type. Syndactyly of the fingers and toes may be total (mitten hands and sock feet) or partial affecting the second, third, and fourth digits. Intellectual deficit is frequent and often severe, usually being associated with cerebral malformations. {ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7668257, ECO:0000269|PubMed:7719344, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9452027, ECO:0000269|PubMed:9677057}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pfeiffer syndrome (PS) [MIM:101600]: A syndrome characterized by the association of craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly of the fingers and toes. Three subtypes are known: mild autosomal dominant form (type 1); cloverleaf skull, elbow ankylosis, early death, sporadic (type 2); craniosynostosis, early demise, sporadic (type 3). {ECO:0000269|PubMed:10394936, ECO:0000269|PubMed:10945669, ECO:0000269|PubMed:11173845, ECO:0000269|PubMed:11781872, ECO:0000269|PubMed:7719333, ECO:0000269|PubMed:7719345, ECO:0000269|PubMed:8644708, ECO:0000269|PubMed:9002682, ECO:0000269|PubMed:9150725, ECO:0000269|PubMed:9693549, ECO:0000269|PubMed:9719378}. Note=The disease is caused by mutations affecting the gene represented in this entry. Beare-Stevenson cutis gyrata syndrome (BSTVS) [MIM:123790]: An autosomal dominant disease characterized by craniofacial anomalies, particularly craniosynostosis, and ear defects, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, and prominent umbilical stump. The skin furrows have a corrugated appearance and are widespread. Cutis gyrata variably affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet. {ECO:0000269|PubMed:12000365, ECO:0000269|PubMed:8696350}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial scaphocephaly syndrome (FSPC) [MIM:609579]: An autosomal dominant craniosynostosis syndrome characterized by scaphocephaly, macrocephaly, hypertelorism, maxillary retrusion, and mild intellectual disability. Scaphocephaly is the most common of the craniosynostosis conditions and is characterized by a long, narrow head. It is due to premature fusion of the sagittal suture or from external deformation. {ECO:0000269|PubMed:16061565}. Note=The disease is caused by mutations affecting the gene represented in this entry. Lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]: An autosomal dominant ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Lacrimo-auriculo-dento-digital syndrome is characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. {ECO:0000269|PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry. Antley-Bixler syndrome, without genital anomalies or disordered steroidogenesis (ABS2) [MIM:207410]: A rare syndrome characterized by craniosynostosis, radiohumeral synostosis present from the perinatal period, midface hypoplasia, choanal stenosis or atresia, femoral bowing and multiple joint contractures. Arachnodactyly and/or camptodactyly have also been reported. {ECO:0000269|PubMed:10633130}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bent bone dysplasia syndrome (BBDS) [MIM:614592]: A perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Dysmorphic facial features included low-set ears, hypertelorism, midface hypoplasia, prematurely erupted fetal teeth, and micrognathia. {ECO:0000269|PubMed:22387015}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1. {ECO:0000269|PubMed:12529371, ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:15629145, ECO:0000269|PubMed:16384934, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19103595, ECO:0000269|PubMed:19387476, ECO:0000269|PubMed:19410646, ECO:0000269|PubMed:21596750, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor receptor 2 Inhibitor: Lenvatinib, Nintedanib Fibroblast growth factor receptor 2 antagonist: Thalidomide Fibroblast growth factor receptor 2 inhibitor: Ponatinib, Regorafenib | 15.1 | |||
| kccFGFR3 | Fibroblast growth factor receptor 3 | 8 | 208 | 94.93 | ND | 92.75 | 0.13 | ND | 1.5 | Mammalian | Expressed in brain, kidney and testis. Very low or no expression in spleen, heart, and muscle. In 20- to 22- week old fetuses it is expressed at high level in kidney, lung, small intestine and brain, and to a lower degree in spleen, liver, and muscle. Isoform 2 is detected in epithelial cells. Isoform 1 is not detected in epithelial cells. Isoform 1 and isoform 2 are detected in fibroblastic cells. {ECO:0000269|PubMed:1664411}. | Kinase | Achondroplasia (ACH) [MIM:100800]: A frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. {ECO:0000269|PubMed:7758520, ECO:0000269|PubMed:7847369, ECO:0000269|PubMed:8078586}. Note=The disease is caused by mutations affecting the gene represented in this entry. Crouzon syndrome with acanthosis nigricans (CAN) [MIM:612247]: Classic Crouzon disease which is caused by mutations in the FGFR2 gene is characterized by craniosynostosis (premature fusion of the skull sutures), and facial hypoplasia. Crouzon syndrome with acanthosis nigricans (a skin disorder characterized by pigmentation anomalies), CAN, is considered to be an independent disorder from classic Crouzon syndrome. CAN is characterized by additional more severe physical manifestation, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, and is caused by a specific mutation (Ala-391 to Glu) in the transmembrane domain of FGFR3. It is proposed to have an autosomal dominant mode of inheritance. {ECO:0000269|PubMed:17935505, ECO:0000269|PubMed:7493034}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thanatophoric dysplasia 1 (TD1) [MIM:187600]: A neonatal lethal skeletal dysplasia. Affected individuals manifest severe shortening of the limbs with macrocephaly, narrow thorax, short ribs, and curved femurs. {ECO:0000269|PubMed:10360402, ECO:0000269|PubMed:10671061, ECO:0000269|PubMed:7773297, ECO:0000269|PubMed:8589699, ECO:0000269|PubMed:8845844, ECO:0000269|PubMed:9790257}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thanatophoric dysplasia 2 (TD2) [MIM:187601]: A neonatal lethal skeletal dysplasia causing severe shortening of the limbs, narrow thorax and short ribs. Patients with thanatophoric dysplasia type 2 have straight femurs and cloverleaf skull. {ECO:0000269|PubMed:7773297}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypochondroplasia (HCH) [MIM:146000]: Autosomal dominant disease and is characterized by disproportionate short stature. It resembles achondroplasia, but with a less severe phenotype. {ECO:0000269|PubMed:10215410, ECO:0000269|PubMed:10777366, ECO:0000269|PubMed:11055896, ECO:0000269|PubMed:12707965, ECO:0000269|PubMed:7670477, ECO:0000269|PubMed:9452043}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. {ECO:0000269|PubMed:11314002}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Somatic mutations can constitutively activate FGFR3. Cervical cancer (CERCA) [MIM:603956]: A malignant neoplasm of the cervix, typically originating from a dysplastic or premalignant lesion previously present at the active squamocolumnar junction. The transformation from mild dysplastic to invasive carcinoma generally occurs slowly within several years, although the rate of this process varies widely. Carcinoma in situ is particularly known to precede invasive cervical cancer in most cases. Cervical cancer is strongly associated with infection by oncogenic types of human papillomavirus. Note=The gene represented in this entry is involved in disease pathogenesis. Camptodactyly tall stature and hearing loss syndrome (CATSHL syndrome) [MIM:610474]: Autosomal dominant syndrome characterized by permanent and irreducible flexion of one or more fingers of the hand and/or feet, tall stature, scoliosis and/or a pectus excavatum, and hearing loss. Affected individuals have developmental delay and/or mental retardation, and several of these have microcephaly. Radiographic findings included tall vertebral bodies with irregular borders and broad femoral metaphyses with long tubular shafts. On audiological exam, each tested member have bilateral sensorineural hearing loss and absent otoacoustic emissions. The hearing loss was congenital or developed in early infancy, progressed variably in early childhood, and range from mild to severe. Computed tomography and magnetic resonance imaging reveal that the brain, middle ear, and inner ear are structurally normal. {ECO:0000269|PubMed:17033969}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple myeloma (MM) [MIM:254500]: A malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. {ECO:0000269|PubMed:11529856, ECO:0000269|PubMed:9207791}. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving FGFR3 is found in multiple myeloma. Translocation t(4;14)(p16.3;q32.3) with the IgH locus. Lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]: An autosomal dominant ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Lacrimo-auriculo-dento-digital syndrome is characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. {ECO:0000269|PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry. Keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900]: Epidermal nevi of the common, non-organoid and non- epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. {ECO:0000269|PubMed:16841094}. Note=The disease is caused by mutations affecting the gene represented in this entry. Muenke syndrome (MNKS) [MIM:602849]: A condition characterized by premature closure of coronal suture of skull during development (coronal craniosynostosis), which affects the shape of the head and face. It may be uni- or bilateral. When bilateral, it is characterized by a skull with a small antero- posterior diameter (brachycephaly), often with a decrease in the depth of the orbits and hypoplasia of the maxillae. Unilateral closure of the coronal sutures leads to flattening of the orbit on the involved side (plagiocephaly). The intellect is normal. In addition to coronal craniosynostosis some affected individuals show skeletal abnormalities of hands and feet, sensorineural hearing loss, mental retardation and respiratory insufficiency. {ECO:0000269|PubMed:11746040, ECO:0000269|PubMed:9042914, ECO:0000269|PubMed:9950359}. Note=The disease is caused by mutations affecting the gene represented in this entry. Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:15772091}. Note=The disease is caused by mutations affecting the gene represented in this entry. Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:19855393}. Note=The gene represented in this entry may be involved in disease pathogenesis. | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:14534538, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17145761, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:19286672, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor receptor 3 Inhibitor: Lenvatinib, Nintedanib Fibroblast growth factor receptor 3 inhibitor: Pazopanib, Ponatinib | 15.1 | ||
| kccFGFR4 | Fibroblast growth factor receptor 4 | 1 | 82 | 97.19 | ND | 97.21 | 0.03 | ND | 0.6 | Mammalian | Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. {ECO:0000269|PubMed:10631118}. | Kinase | Obesity | Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645, ECO:0000269|PubMed:8663044}. | Fibroblast growth factor receptor 4 Inhibitor: Lenvatinib Fibroblast growth factor receptor 4 inhibitor: Ponatinib | 15.1 | ||
| kccFKB1A | Peptidyl-prolyl cis-trans isomerase FKBP1A | 8 | 474 | 99.12 | ND | 99.15 | 0.68 | ND | 0.8 | Mammalian | Isomerase | Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. {ECO:0000269|PubMed:16720724, ECO:0000269|PubMed:9233797}. | Peptidyl-prolyl cis-trans isomerase FKBP1A inhibitor: Tacrolimus Peptidyl-prolyl cis-trans isomerase FKBP1A other: Sirolimus Peptidyl-prolyl cis-trans isomerase FKBP1A potentiator: Pimecrolimus | 15.1 | ||||
| kccFKBP4 | Peptidyl-prolyl cis-trans isomerase FKBP4 | 1 | 60 | 99.78 | ND | 99.97 | 0.42 | ND | 0.6 | Mammalian | Widely expressed. {ECO:0000269|PubMed:1279700}. | Enzyme | Neurological diseases | Immunophilin protein with PPIase and co-chaperone activities. Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria. {ECO:0000269|PubMed:1279700, ECO:0000269|PubMed:1376003, ECO:0000269|PubMed:19945390, ECO:0000269|PubMed:21730050, ECO:0000269|PubMed:2378870}. | 15.1 | |||
| kccFKBP5 | Peptidyl-prolyl cis-trans isomerase FKBP5 | 2 | 76 | 99.65 | ND | 99.90 | 0.20 | ND | 0.6 | Mammalian | Widely expressed, enriched in testis compared to other tissues. | Enzyme | Immunophilin protein with PPIase and co-chaperone activities. Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). Plays a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors maintaining the complex into the cytoplasm when unliganded. | 15.1 | ||||
| kccFLT3 | Receptor-type tyrosine-protein kinase FLT3 | 76 | 1224 | 97.16 | ND | 94.65 | 0.46 | ND | 1.1 | Mammalian | Detected in bone marrow, in hematopoietic stem cells, in myeloid progenitor cells and in granulocyte/macrophage progenitor cells (at protein level). Detected in bone marrow, liver, thymus, spleen and lymph node, and at low levels in kidney and pancreas. Highly expressed in T-cell leukemia. {ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:7507245, ECO:0000269|PubMed:8394751, ECO:0000269|PubMed:8637232}. | Kinase | Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:11290608, ECO:0000269|PubMed:11442493, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:18305215, ECO:0000269|PubMed:8946930, ECO:0000269|PubMed:9737679}. Note=The gene represented in this entry may be involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase. | Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways. {ECO:0000269|PubMed:10080542, ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:16627759, ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21067588, ECO:0000269|PubMed:21262971, ECO:0000269|PubMed:21516120, ECO:0000269|PubMed:7507245}. | Receptor-type tyrosine-protein kinase FLT3 Inhibitor: Nintedanib Receptor-type tyrosine-protein kinase FLT3 antagonist: Sorafenib Receptor-type tyrosine-protein kinase FLT3 inhibitor: Ponatinib Receptor-type tyrosine-protein kinase FLT3 multitarget: Sunitinib | 15.1 | ||
| kccFOLH1 | Glutamate carboxypeptidase 2 | 12 | 218 | 97.89 | ND | 98.73 | 0.37 | ND | 1.1 | Mammalian | Highly expressed in prostate epithelium. Detected in urinary bladder, kidney, testis, ovary, fallopian tube, breast, adrenal gland, liver, esophagus, stomach, small intestine, colon and brain (at protein level). Detected in the small intestine, brain, kidney, liver, spleen, colon, trachea, spinal cord and the capillary endothelium of a variety of tumors. Expressed specifically in jejunum brush border membranes. In the brain, highly expressed in the ventral striatum and brain stem. Also expressed in fetal liver and kidney. Isoform PSMA' is the most abundant form in normal prostate. Isoform PSMA-1 is the most abundant form in primary prostate tumors. Isoform PSMA-2 is also found in normal prostate as well as in brain and liver. Isoform PSMA-9 is specifically expressed in prostate cancer. {ECO:0000269|PubMed:14716746, ECO:0000269|PubMed:16555021, ECO:0000269|PubMed:17150306, ECO:0000269|PubMed:9375657}. | Protease | Amyotrophic lateral sclerosis
Prostate cancer Stroke | Has both folate hydrolase and N-acetylated-alpha-linked- acidic dipeptidase (NAALADase) activity. Has a preference for tri- alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N- aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoform PSM-4 and isoform PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression. Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC. | Receptor-type tyrosine-protein kinase FLT3 Inhibitor: Nintedanib Receptor-type tyrosine-protein kinase FLT3 antagonist: Sorafenib Receptor-type tyrosine-protein kinase FLT3 inhibitor: Ponatinib Receptor-type tyrosine-protein kinase FLT3 multitarget: Sunitinib | 15.1 | ||
| kccFPPS | Farnesyl pyrophosphate synthase | 12 | 212 | 99.03 | ND | 98.59 | 0.51 | ND | 0.9 | Mammalian | Transferase | Cancer, unspecific
Chagas' disease Hypercholesterolemia Leishmania infections Myeloma disease Osteoporosis, unspecified Skeletal disorders Toxoplasma infections Trypanosomatid infections | Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate. | Farnesyl pyrophosphate synthase inhibitor: Alendronate, Ibandronate, Pamidronate, Risedronate, Zoledronate | 15.1 | |||
| kccFPR1 | fMet-Leu-Phe receptor | 6 | 198 | 99.67 | ND | 99.91 | 0.53 | ND | 0.5 | Mammalian | Neutrophils. | Family A G protein-coupled receptor | Gastric ulcer | High affinity receptor for N-formyl-methionyl peptides (fMLP), which are powerful neutrophil chemotactic factors (PubMed:2161213, PubMed:2176894, PubMed:10514456, PubMed:15153520). Binding of fMLP to the receptor stimulates intracellular calcium mobilization and superoxide anion release (PubMed:2161213, PubMed:1712023, PubMed:15153520). This response is mediated via a G-protein that activates a phosphatidylinositol- calcium second messenger system (PubMed:1712023, PubMed:10514456). {ECO:0000269|PubMed:10514456, ECO:0000269|PubMed:15153520, ECO:0000269|PubMed:2161213, ECO:0000269|PubMed:2176894, ECO:0000303|PubMed:10514456, ECO:0000303|PubMed:1712023, ECO:0000303|PubMed:2161213, ECO:0000303|PubMed:2176894}. | fMet-Leu-Phe receptor antagonist: Nedocromil | 15.1 | ||
| kccFPR2 | N-formyl peptide receptor 2 | 4 | 96 | 99.93 | ND | 99.91 | 0.66 | ND | 0.5 | Mammalian | Expressed abundantly in the lung and neutrophils. Also found in the spleen and testis. {ECO:0000269|PubMed:9151906}. | Family A G protein-coupled receptor | Alzheimer's disease | Low affinity receptor for N-formyl-methionyl peptides, which are powerful neutrophils chemotactic factors. Binding of FMLP to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The activation of LXA4R could result in an anti-inflammatory outcome counteracting the actions of proinflammatory signals such as LTB4 (leukotriene B4). | 15.1 | |||
| kccFRK | Tyrosine-protein kinase FRK | 10 | 216 | 96.05 | ND | 89.49 | 0.11 | ND | 1.6 | Mammalian | Predominantly expressed in epithelial derived cell lines and tissues, especially normal liver, kidney, breast and colon. {ECO:0000269|PubMed:7696183}. | Kinase | Non-receptor tyrosine-protein kinase that negatively regulates cell proliferation. Positively regulates PTEN protein stability through phosphorylation of PTEN on 'Tyr-336', which in turn prevents its ubiquitination and degradation, possibly by reducing its binding to NEDD4. May function as a tumor suppressor. {ECO:0000269|PubMed:19345329}. | Tyrosine-protein kinase FRK inhibitor: Regorafenib | 15.1 | |||
| kccFSHR | Follicle-stimulating hormone receptor | 3 | 59 | 99.90 | ND | 100.00 | 0.38 | ND | 1.1 | Mammalian | Sertoli cells and ovarian granulosa cells. | Family A G protein-coupled receptor | Ovarian dysgenesis 1 (ODG1) [MIM:233300]: An autosomal recessive disease characterized by primary amenorrhea, variable development of secondary sex characteristics, poorly developed streak ovaries, and high serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). {ECO:0000269|PubMed:10551778, ECO:0000269|PubMed:11889179, ECO:0000269|PubMed:12571157, ECO:0000269|PubMed:12915623, ECO:0000269|PubMed:7553856, ECO:0000269|PubMed:9769327, ECO:0000269|PubMed:9851774}. Note=The disease is caused by mutations affecting the gene represented in this entry. Ovarian hyperstimulation syndrome (OHSS) [MIM:608115]: Disorder which occurs either spontaneously or most often as an iatrogenic complication of ovarian stimulation treatments for in vitro fertilization. The clinical manifestations vary from abdominal distention and discomfort to potentially life- threatening, massive ovarian enlargement and capillary leak with fluid sequestration. Pathologic features of this syndrome include the presence of multiple serous and hemorrhagic follicular cysts lined by luteinized cells, a condition called hyperreactio luteinalis. {ECO:0000269|PubMed:12930927, ECO:0000269|PubMed:12930928, ECO:0000269|PubMed:15080154, ECO:0000269|PubMed:16278261, ECO:0000269|PubMed:17721928}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for follicle-stimulating hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. | Follicle-stimulating hormone receptor antagonist: Suramin | 15.1 | ||
| kccFUCO | Tissue alpha-L-fucosidase | 1 | 100 | 97.60 | ND | 99.72 | 0.12 | ND | 1.5 | Mammalian | Enzyme | Fucosidosis (FUCA1D) [MIM:230000]: An autosomal recessive lysosomal storage disease characterized by accumulation of fucose- containing glycolipids and glycoproteins in various tissues. Clinical signs include facial dysmorphism, dysostosis multiplex, moderate hepatomegaly, severe intellectual deficit, deafness, and according to age, angiokeratomas. {ECO:0000269|PubMed:7874128, ECO:0000269|PubMed:8504303, ECO:0000269|PubMed:9762612}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Alpha-L-fucosidase is responsible for hydrolyzing the alpha-1,6-linked fucose joined to the reducing-end N- acetylglucosamine of the carbohydrate moieties of glycoproteins. | 15.1 | ||||
| kccFURIN | Furin | 2 | 355 | 99.36 | ND | 98.94 | 0.63 | ND | 0.4 | Mammalian | Seems to be expressed ubiquitously. | Protease | Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif. {ECO:0000269|PubMed:7690548}. | Follicle-stimulating hormone receptor antagonist: Suramin | 15.1 | |||
| kccFYN | Tyrosine-protein kinase Fyn | 13 | 440 | 88.43 | ND | 88.34 | 0.18 | ND | 1.2 | Mammalian | Isoform 1 is highly expressed in the brain. Isoform 2 is expressed in cells of hemopoietic lineages, especially T-lymphocytes. {ECO:0000269|PubMed:10196263}. | Kinase | Philadelphia-positive leukemia | Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance. Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain. Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions. Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta- catenin). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT. Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage. Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL and TRPC6. Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein. Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation. Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts. CSK maintains LCK and FYN in an inactive form. Promotes CD28-induced phosphorylation of VAV1. {ECO:0000269|PubMed:11005864, ECO:0000269|PubMed:11162638, ECO:0000269|PubMed:11536198, ECO:0000269|PubMed:12788081, ECO:0000269|PubMed:14707117, ECO:0000269|PubMed:14761972, ECO:0000269|PubMed:15536091, ECO:0000269|PubMed:15557120, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:16841086, ECO:0000269|PubMed:17194753, ECO:0000269|PubMed:18056706, ECO:0000269|PubMed:18258597, ECO:0000269|PubMed:19179337, ECO:0000269|PubMed:19652227, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:22080863, ECO:0000269|PubMed:7568038, ECO:0000269|PubMed:7822789}. | Tyrosine-protein kinase Fyn multitarget: Dasatinib | 15.1 | ||
| kccG6PD | Glucose-6-phosphate 1-dehydrogenase | 2 | 100 | 80.23 | ND | 99.46 | 0.52 | ND | 0.4 | Mammalian | Isoform Long is found in lymphoblasts, granulocytes and sperm. | Enzyme | Anemia, non-spherocytic hemolytic, due to G6PD deficiency (NSHA) [MIM:300908]: A disease characterized by G6PD deficiency, acute hemolytic anemia, fatigue, back pain, and jaundice. In most patients, the disease is triggered by an exogenous agent, such as some drugs, food, or infection. Increased unconjugated bilirubin, lactate dehydrogenase, and reticulocytosis are markers of the disorder. Although G6PD deficiency can be life-threatening, most patients are asymptomatic throughout their life. {ECO:0000269|PubMed:1611091}. Note=The disease is caused by mutations affecting the gene represented in this entry. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of NSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class- IV have near normal activity. | Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis. The main function of this enzyme is to provide reducing power (NADPH) and pentose phosphates for fatty acid and nucleic acid synthesis. {ECO:0000269|PubMed:15858258, ECO:0000269|PubMed:24769394}. | Tyrosine-protein kinase Fyn multitarget: Dasatinib | 15.1 | ||
| kccGAK | Cyclin-G-associated kinase | 1 | 69 | 88.31 | ND | 86.27 | 0.32 | ND | 1.5 | Mammalian | Ubiquitous. Highest in testis. | Kinase | Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin- coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1. {ECO:0000269|PubMed:10625686}. | 15.1 | ||||
| kccGALR1 | Galanin receptor type 1 | 3 | 52 | 99.97 | ND | 99.99 | 0.92 | ND | 0.5 | Mammalian | Family A G protein-coupled receptor | Convulsions
Obesity | Receptor for the hormone galanin. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity. | 15.1 | ||||
| kccGALR2 | Galanin receptor type 2 | 3 | 69 | 91.14 | ND | 93.70 | 0.77 | ND | 0.5 | Mammalian | Expressed abundantly within the central nervous system in both hypothalamus and hippocampus. In peripheral tissues, the strongest expression was observed in heart, kidney, liver, and small intestine. | Family A G protein-coupled receptor | Alzheimer's disease
Central nervous system diseases Cerebral hemorrhage Diabetes mellitus Diarrhea Eating disorders Obesity | Receptor for the hormone galanin and GALP. Receptor for the hormone spexin-1 (PubMed:24517231). The activity of this receptor is mediated by G proteins that activate the phospholipase C/protein kinase C pathway (via G(q)) and that inhibit adenylyl cyclase (via G(i)). {ECO:0000269|PubMed:24517231}. | 15.1 | |||
| kccGASR | Gastrin/cholecystokinin type B receptor | 19 | 1703 | 99.08 | ND | 99.61 | 0.72 | ND | 0.7 | Nature11159 | Mammalian | Isoform 1 is expressed in brain, pancreas, stomach, the colon cancer cell line LoVo and the T-lymphoblastoma Jurkat, but not in heart, placenta, liver, lung, skeletal muscle, kidney or the stomach cancer cell line AGS. Expressed at high levels in the small cell lung cancer cell line NCI-H510, at lower levels in NCI-H345, NCI-H69 and GLC-28 cell lines, not expressed in GLC-19 cell line. Within the stomach, expressed at high levels in the mucosa of the gastric fundus and at low levels in the antrum and duodenum. Isoform 2 is present in pancreatic cancer cells and colorectal cancer cells, but not in normal pancreas or colonic mucosa. Isoform 3 is expressed in brain, pancreas, stomach, the stomach cancer cell line AGS and the colon cancer cell line LoVo. {ECO:0000269|PubMed:10913157, ECO:0000269|PubMed:12429993, ECO:0000269|PubMed:7848914, ECO:0000269|PubMed:7887934, ECO:0000269|PubMed:8185170, ECO:0000269|PubMed:8349705}. | Family A G protein-coupled receptor | Acid-related diseases
Anxiety disorder, unspecified Cocaine dependence Gastrin sensitive tumours Gastrointestinal adenocarcinomas Gastrointestinal motility disorders Malignant gliomas Medullary thyroid cancer Neuroendocrine tumors Small cell lung cancer Stromal ovarian tumors | Receptor for gastrin and cholecystokinin. The CKK-B receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 is constitutively activated and may regulate cancer cell proliferation via a gastrin-independent mechanism. | Gastrin/cholecystokinin type B receptor agonist: Pentagastrin | 15.1 | |
| kccGBA2 | Non-lysosomal glucosylceramidase | 1 | 44 | 99.82 | ND | 99.96 | 0.08 | ND | 1.4 | Mammalian | Widely expressed. Highly expressed in brain, heart, skeletal muscle, kidney and placenta and expressed at lower level in liver. {ECO:0000269|PubMed:11489889}. | Enzyme | Spastic paraplegia 46, autosomal recessive (SPG46) [MIM:614409]: A neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging. {ECO:0000269|PubMed:23332916, ECO:0000269|PubMed:23332917}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-lysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide (GlcCer) to free glucose and ceramide. Involved in sphingomyelin generation and prevention of glycolipid accumulation. May also catalyze the hydrolysis of bile acid 3-O-glucosides, however, the relevance of such activity is unclear in vivo. Plays a role in central nevous system development. Required for proper formation of motor neuron axons. {ECO:0000269|PubMed:17105727, ECO:0000269|PubMed:23332916}. | 15.1 | |||
| kccGBRA1 | Gamma-aminobutyric acid receptor subunit alpha-1 | 13 | 163 | 86.86 | ND | 92.18 | 0.23 | ND | 0.9 | Nature11159 | Mammalian | Agitation Amnesia Apnoea Ataxia Cholestasis Confusional state Dependence Dermatitis exfoliative Dysarthria Erythema multiforme Folate deficiency Gangrene Hiccups Hypoprothrombinaemia Hypotension Incontinence Irritability Jaundice Laryngospasm Libido disorder Necrosis Nystagmus Respiratory depression Respiratory disorder Salivary gland disorder Somnolence Speech disorder Thrombophlebitis Urinary retention | Ligand-gated ion channel | Epilepsy, childhood absence 4 (ECA4) [MIM:611136]: A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood. {ECO:0000269|PubMed:16718694}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Epilepsy, idiopathic generalized 13 (EIG13) [MIM:611136]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:21714819}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Juvenile myoclonic epilepsy 5 (EJM5) [MIM:611136]: A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. {ECO:0000269|PubMed:11992121}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Epileptic encephalopathy, early infantile, 19 (EIEE19) [MIM:615744]: A severe neurologic disorder characterized by onset of seizures in the first months of life and usually associated with EEG abnormalities. Affected infants have convulsive seizures (hemiclonic or generalized) that are often prolonged and triggered by fever. Other seizure types include focal, myoclonic, absence seizures, and drop attacks. Development is normal in the first year of life with later slowing and intellectual disability. {ECO:0000269|PubMed:24623842}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand- gated chloride channel (By similarity). {ECO:0000250}. | Gamma-aminobutyric acid receptor subunit alpha-1 agonist: Ergoloid mesylate, Ethanol, Etomidate, Glutethimide, Isoflurane, Meprobamate, Methoxyflurane, Methyprylon, Progabide, Sevoflurane, Thiamylal, Topiramate Gamma-aminobutyric acid receptor subunit alpha-1 antagonist: Amoxapine, Flumazenil, Methohexital Gamma-aminobutyric acid receptor subunit alpha-1 other/unknown: Halothane Gamma-aminobutyric acid receptor subunit alpha-1 positive allosteric modulator: Alprazolam, Butabarbital, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Desflurane, Enflurane, Ethchlorvynol, Lorazepam, Propofol Gamma-aminobutyric acid receptor subunit alpha-1 positive modulator: Acamprosate Gamma-aminobutyric acid receptor subunit alpha-1 potentiator: Adinazolam, Amobarbital, Aprobarbital, Bromazepam, Butalbital, Butethal, Cinolazepam, Clotiazepam, Diazepam, Estazolam, Eszopiclone, Fludiazepam, Flurazepam, Halazepam, Heptabarbital, Hexobarbital, Ketazolam, Methylphenobarbital, Midazolam, Nitrazepam, Oxazepam, Pentobarbital, Phenobarbital, Prazepam, Primidone, Quazepam, Quinidine barbiturate, Secobarbital, Talbutal, Temazepam, Thiopental, Triazolam, Zaleplon, Zolpidem, Zopiclone Gamma-aminobutyric acid receptor subunit alpha-1 unknown: Olanzapine | 15.1 | |
| kccGBRA2 | Gamma-aminobutyric acid receptor subunit alpha-2 | 10 | 131 | 92.12 | ND | 95.36 | 0.20 | ND | 0.5 | Mammalian | Agitation Amnesia Apnoea Ataxia Bone marrow disorder Cholestasis Confusional state Dependence Dermatitis exfoliative Dysarthria Erythema multiforme Folate deficiency Gangrene Hypoprothrombinaemia Hypotension Incontinence Irritability Jaundice Laryngospasm Libido disorder Nystagmus Respiratory depression Respiratory disorder Salivary gland disorder Somnolence Urinary retention Vertigo | Ligand-gated ion channel | Anxiety disorder, unspecified
Disorders of initiating and maintaining sleep [insomnias] | GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. | Gamma-aminobutyric acid receptor subunit alpha-2 agonist: Ergoloid mesylate, Eszopiclone, Meprobamate, Zolpidem Gamma-aminobutyric acid receptor subunit alpha-2 binder: Amoxapine Gamma-aminobutyric acid receptor subunit alpha-2 positive allosteric modulator: Alprazolam, Butabarbital, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Desflurane, Enflurane, Ethchlorvynol, Etomidate, Flumazenil, Glutethimide, Halothane, Isoflurane, Lorazepam, Methoxyflurane, Methyprylon, Propofol, Sevoflurane, Topiramate Gamma-aminobutyric acid receptor subunit alpha-2 positive modulator: Acamprosate Gamma-aminobutyric acid receptor subunit alpha-2 potentiator: Adinazolam, Amobarbital, Aprobarbital, Bromazepam, Butalbital, Butethal, Cinolazepam, Clotiazepam, Diazepam, Estazolam, Fludiazepam, Flunitrazepam, Flurazepam, Halazepam, Heptabarbital, Hexobarbital, Methylphenobarbital, Midazolam, Nitrazepam, Oxazepam, Pentobarbital, Prazepam, Primidone, Quazepam, Quinidine barbiturate, Secobarbital, Talbutal, Temazepam, Thiopental, Triazolam, Zopiclone Gamma-aminobutyric acid receptor subunit alpha-2 unknown: Ethanol, Olanzapine | 15.1 | ||
| kccGBRA3 | Gamma-aminobutyric acid receptor subunit alpha-3 | 7 | 95 | 87.62 | ND | 92.09 | 0.79 | ND | 0.2 | Mammalian | Agitation Amnesia Apnoea Ataxia Bone marrow disorder Cholestasis Confusional state Dependence Dermatitis exfoliative Dysarthria Erythema multiforme Folate deficiency Gangrene Hypoprothrombinaemia Hypotension Incontinence Irritability Jaundice Laryngospasm Libido disorder Nystagmus Respiratory depression Respiratory disorder Salivary gland disorder Somnolence Speech disorder Urinary retention | Ligand-gated ion channel | Anxiety disorder, unspecified
Disorders of initiating and maintaining sleep [insomnias] | GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. | Gamma-aminobutyric acid receptor subunit alpha-3 agonist: Ergoloid mesylate, Eszopiclone, Meprobamate, Zolpidem Gamma-aminobutyric acid receptor subunit alpha-3 binder: Amoxapine Gamma-aminobutyric acid receptor subunit alpha-3 positive allosteric modulator: Alprazolam, Butabarbital, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Desflurane, Enflurane, Ethchlorvynol, Etomidate, Flumazenil, Glutethimide, Halothane, Isoflurane, Lorazepam, Methoxyflurane, Methyprylon, Propofol, Sevoflurane, Topiramate Gamma-aminobutyric acid receptor subunit alpha-3 positive modulator: Acamprosate Gamma-aminobutyric acid receptor subunit alpha-3 potentiator: Adinazolam, Amobarbital, Aprobarbital, Bromazepam, Butalbital, Butethal, Cinolazepam, Clotiazepam, Diazepam, Estazolam, Fludiazepam, Flunitrazepam, Flurazepam, Halazepam, Heptabarbital, Hexobarbital, Methylphenobarbital, Midazolam, Nitrazepam, Oxazepam, Pentobarbital, Prazepam, Primidone, Quazepam, Secobarbital, Talbutal, Temazepam, Thiopental, Triazolam, Zopiclone Gamma-aminobutyric acid receptor subunit alpha-3 unknown: Ethanol, Olanzapine | 15.1 | ||
| kccGBRA5 | Gamma-aminobutyric acid receptor subunit alpha-5 | 11 | 127 | 84.43 | ND | 92.44 | 0.00 | ND | 1.4 | Mammalian | Agitation Amnesia Apnoea Ataxia Bone marrow disorder Cholestasis Confusional state Dependence Dermatitis exfoliative Dysarthria Erythema multiforme Folate deficiency Gangrene Hypoprothrombinaemia Hypotension Incontinence Irritability Jaundice Laryngospasm Libido disorder Nystagmus Respiratory depression Respiratory disorder Salivary gland disorder Somnolence Speech disorder Urinary retention | Ligand-gated ion channel | Alzheimer's Disease
Central nervous system diseases Cognitive deficits Delirium Dementia | GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. | Gamma-aminobutyric acid receptor subunit alpha-5 agonist: Ergoloid mesylate, Eszopiclone, Meprobamate Gamma-aminobutyric acid receptor subunit alpha-5 antagonist: Flumazenil Gamma-aminobutyric acid receptor subunit alpha-5 binder: Amoxapine Gamma-aminobutyric acid receptor subunit alpha-5 positive allosteric modulator: Alprazolam, Butabarbital, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Desflurane, Enflurane, Ethchlorvynol, Etomidate, Glutethimide, Halothane, Isoflurane, Lorazepam, Methoxyflurane, Methyprylon, Propofol, Sevoflurane, Topiramate Gamma-aminobutyric acid receptor subunit alpha-5 positive modulator: Acamprosate Gamma-aminobutyric acid receptor subunit alpha-5 potentiator: Adinazolam, Amobarbital, Aprobarbital, Bromazepam, Butalbital, Butethal, Cinolazepam, Clotiazepam, Diazepam, Estazolam, Fludiazepam, Flunitrazepam, Flurazepam, Halazepam, Heptabarbital, Hexobarbital, Methylphenobarbital, Midazolam, Nitrazepam, Oxazepam, Pentobarbital, Prazepam, Primidone, Quazepam, Secobarbital, Talbutal, Temazepam, Thiopental, Triazolam, Zopiclone Gamma-aminobutyric acid receptor subunit alpha-5 unknown: Ethanol, Olanzapine | 15.1 | ||
| kccGCKR | Glucokinase regulatory protein | 2 | 50 | 100.00 | ND | 100.00 | 0.73 | ND | 0.4 | Mammalian | Found in liver and pancreas. Not detected in muscle, brain, heart, thymus, intestine, uterus, adipose tissue, kidney, adrenal, lung or spleen. {ECO:0000269|PubMed:19643913, ECO:0000269|PubMed:9570959}. | Inhibits glucokinase (GCK) by forming an inactive complex with this enzyme. The affinity of GCKR for GCK is modulated by fructose metabolites: GCKR with bound fructose 6- phosphate has increased affinity for GCK, while GCKR with bound fructose 1-phosphate has strongly decreased affinity for GCK and does not inhibit GCK activity. {ECO:0000269|PubMed:23621087, ECO:0000269|PubMed:23733961}. | 15.1 | |||||
| kccGCR | Glucocorticoid receptor | 57 | 1802 | 96.84 | ND | 97.74 | 0.65 | ND | 0.7 | Nature11159 VirtualToxLab | Mammalian | Widely expressed. In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart. {ECO:0000269|PubMed:10902803}. | Acne Adrenal disorder Adrenal insufficiency Adrenal suppression Amenorrhoea Bone disorder Calcium metabolism disorder Cataract Cushingoid Depression Dysphonia Embolism arterial Endocrine disorder Epidural lipomatosis Epistaxis Euphoric mood Fluid retention Foot and mouth disease Fracture Fungal infection Glaucoma Growth retardation Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Impaired healing Increased appetite Intracranial pressure increased Menstrual disorder Muscular weakness Nitrogen balance negative Oedema Oral candidiasis Osteonecrosis Osteoporosis Pancreatic disorder Pancreatitis acute Peptic ulcer Phosphorus metabolism disorder Sepsis Skin atrophy Skin striae Superinfection Telangiectasia | Nuclear receptor | Glucocorticoid resistance, generalized (GCCR) [MIM:615962]: An autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of Cushing syndrome typical signs. Clinical features include hypoglycemia, hypertension, metabolic alkalosis, chronic fatigue and profound anxiety. {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946}. Note=The disease is caused by mutations affecting the gene represented in this entry. Glucocorticoid resistance (GCRES) [MIM:138040]: Hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant. {ECO:0000269|PubMed:11589680, ECO:0000269|PubMed:12050230, ECO:0000269|PubMed:7683692}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic genes expression. {ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:17635946, ECO:0000269|PubMed:19141540, ECO:0000269|PubMed:21664385}. | Glucocorticoid receptor agonist: Alclometasone, Amcinonide, Beclomethasone, Betamethasone, Ciclesonide, Clobetasol propionate, Clocortolone, Cortisone acetate, Desonide, Desoximetasone, Dexamethasone, Diflorasone, Difluprednate, Fludrocortisone, Flumethasone Pivalate, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluorometholone, Flurandrenolide, Fluticasone Propionate, Fluticasone furoate, Halobetasol Propionate, Hydrocortamate, Hydrocortisone, Loteprednol, Medrysone, Megestrol acetate, Methylprednisolone, Mometasone, Paramethasone, Prednicarbate, Prednisolone, Prednisone, Rimexolone, Triamcinolone Glucocorticoid receptor antagonist: Budesonide, Fluoxymesterone, Mifepristone, Spironolactone | 15.1 |
| kccGGPPS | Geranylgeranyl pyrophosphate synthase | 5 | 77 | 99.63 | ND | 99.91 | 0.00 | ND | 0.7 | Mammalian | Abundantly expressed in testis. Found in other tissues to a lower extent. | Enzyme | Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins. | Geranylgeranyl pyrophosphate synthase inhibitor: Zoledronate | 15.1 | |||
| kccGHRL | Appetite-regulating hormone | 1 | 42 | 99.98 | ND | 100.00 | 0.37 | ND | 0.4 | Mammalian | Highest level in stomach. All forms are found in serum as well. Other tissues compensate for the loss of ghrelin synthesis in the stomach following gastrectomy. {ECO:0000269|PubMed:12414809}. | motilin | Anorexia nervosa
Cachexia Noninsulin-dependent diabetes mellitus Obesity | Ghrelin is the ligand for growth hormone secretagogue receptor type 1 (GHSR). Induces the release of growth hormone from the pituitary. Has an appetite-stimulating effect, induces adiposity and stimulates gastric acid secretion. Involved in growth regulation. Obestatin may be the ligand for GPR39. May have an appetite-reducing effect resulting in decreased food intake. May reduce gastric emptying activity and jejunal motility (By similarity). {ECO:0000250}. | 15.1 | |||
| kccGHSR | Growth hormone secretagogue receptor type 1 | 26 | 1073 | 99.40 | ND | 99.45 | 0.60 | ND | 0.7 | Nature11159 | Mammalian | Pituitary and hypothalamus. | Family A G protein-coupled receptor | Growth hormone deficiency, isolated partial (GHDP) [MIM:615925]: A disorder characterized by partial growth hormone deficiency resulting in growth delay and short stature, sometimes associated with recurrent episodes of abdominal pain, vomiting, ketosis and hypoglycemia. {ECO:0000269|PubMed:16511605, ECO:0000269|PubMed:19789204}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine). {ECO:0000269|PubMed:10604470, ECO:0000269|PubMed:11322507}. | 15.1 | ||
| kccGIPR | Gastric inhibitory polypeptide receptor | 6 | 99 | 99.98 | ND | 99.97 | 0.37 | ND | 0.4 | Mammalian | Family B G protein-coupled receptor | This is a receptor for GIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. | 15.1 | |||||
| kccGLCM | Glucosylceramidase | 20 | 535 | 92.31 | ND | 95.27 | 0.40 | ND | 0.8 | Mammalian | Enzyme | Gaucher disease (GD) [MIM:230800]: A lysosomal storage disease due to deficient activity of beta-glucocerebrosidase and characterized by accumulation of glucosylceramide in the reticulo- endothelial system. Different clinical forms are recognized depending on the presence (neuronopathic forms) or absence of central nervous system involvement, severity and age of onset. {ECO:0000269|PubMed:10352942, ECO:0000269|PubMed:10360404, ECO:0000269|PubMed:10447266, ECO:0000269|PubMed:10744424, ECO:0000269|PubMed:10796875, ECO:0000269|PubMed:11933202, ECO:0000269|PubMed:11992489, ECO:0000269|PubMed:12204005, ECO:0000269|PubMed:15292921, ECO:0000269|PubMed:1972019, ECO:0000269|PubMed:1974409, ECO:0000269|PubMed:7627184, ECO:0000269|PubMed:7627192, ECO:0000269|PubMed:7916532, ECO:0000269|PubMed:8076951, ECO:0000269|PubMed:8112750, ECO:0000269|PubMed:8294033, ECO:0000269|PubMed:8432537, ECO:0000269|PubMed:8790604, ECO:0000269|PubMed:8829654, ECO:0000269|PubMed:8829663, ECO:0000269|PubMed:8937765, ECO:0000269|PubMed:9061570, ECO:0000269|PubMed:9153297, ECO:0000269|PubMed:9182788, ECO:0000269|PubMed:9217217, ECO:0000269|PubMed:9279145, ECO:0000269|PubMed:9516376, ECO:0000269|PubMed:9554454, ECO:0000269|PubMed:9554746, ECO:0000269|PubMed:9650766, ECO:0000269|PubMed:9683600}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease 1 (GD1) [MIM:230800]: A form of Gaucher disease characterized by hepatosplenomegaly with consequent anemia and thrombopenia, and bone involvement. The central nervous system is not involved. {ECO:0000269|PubMed:10206680, ECO:0000269|PubMed:10340647, ECO:0000269|PubMed:15605411, ECO:0000269|PubMed:8889591, ECO:0000269|Ref.14}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease 2 (GD2) [MIM:230900]: The most severe form of Gaucher disease. It manifests soon after birth, with death generally occurring before patients reach two years of age. {ECO:0000269|PubMed:9637431, ECO:0000269|PubMed:9851895}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease 3 (GD3) [MIM:231000]: A subacute form of neuronopathic Gaucher disease. It has later onset and slower progression compared to the acute form of neuronopathic Gaucher disease 2. {ECO:0000269|PubMed:8780099}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease 3C (GD3C) [MIM:231005]: A variant of subacute neuronopathic Gaucher disease 3 associated with cardiovascular calcifications. Note=The disease is caused by mutations affecting the gene represented in this entry. Gaucher disease perinatal lethal (GDPL) [MIM:608013]: Distinct form of Gaucher disease type 2, characterized by fetal onset. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. Parkinson disease (PARK) [MIM:168600]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. {ECO:0000269|PubMed:12847165, ECO:0000269|PubMed:16148263, ECO:0000269|PubMed:19286695}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. | Geranylgeranyl pyrophosphate synthase inhibitor: Zoledronate | 15.1 | ||||
| kccGLR | Glucagon receptor | 29 | 659 | 99.58 | ND | 99.25 | 0.66 | ND | 0.7 | Mammalian | Family B G protein-coupled receptor | Hyperglycemia
Insulin-dependent diabetes mellitus Lipid metabolic disorders Noninsulin-dependent diabetes mellitus Obesity | G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. Regulates the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis. Plays an important role in mediating the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase. Besides, plays a role in signaling via a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:19657311, ECO:0000269|PubMed:22908259, ECO:0000269|PubMed:23863937, ECO:0000269|PubMed:7507321, ECO:0000269|PubMed:9287038}. | Glucagon receptor agonist: Glucagon, Glucagon Hydrochloride, Glucagon Hydrochloride Recombinant | 15.1 | |||
| kccGLRA1 | Glycine receptor subunit alpha-1 | 3 | 78 | 80.81 | ND | 84.61 | 0.73 | ND | 0.6 | Mammalian | Respiratory depression | Ligand-gated ion channel | Hyperekplexia 1 (HKPX1) [MIM:149400]: A neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to unexpected acoustic or tactile stimuli. {ECO:0000269|PubMed:10514101, ECO:0000269|PubMed:7611730, ECO:0000269|PubMed:7881416, ECO:0000269|PubMed:7981700, ECO:0000269|PubMed:8298642, ECO:0000269|PubMed:8571969, ECO:0000269|PubMed:8733061, ECO:0000269|PubMed:9067762, ECO:0000269|PubMed:9920650, ECO:0000269|Ref.10}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing). | Glycine receptor subunit alpha-1 agonist: Desflurane, Enflurane, Ethanol, Isoflurane, Methoxyflurane, Sevoflurane Glycine receptor subunit alpha-1 allosteric modulator: Halothane Glycine receptor subunit alpha-1 antagonist: Lindane Glycine receptor subunit alpha-1 unknown: Glycine | 15.1 | ||
| kccGNRHR | Gonadotropin-releasing hormone receptor | 16 | 1436 | 99.75 | ND | 99.93 | 0.65 | ND | 0.7 | Mammalian | Pituitary, ovary, testis, breast and prostate but not in liver and spleen. | Flushing | Family A G protein-coupled receptor | Hypogonadotropic hypogonadism 7 with or without anosmia (HH7) [MIM:146110]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:10022417, ECO:0000269|PubMed:10084584, ECO:0000269|PubMed:10523035, ECO:0000269|PubMed:11318785, ECO:0000269|PubMed:11397842, ECO:0000269|PubMed:11397871, ECO:0000269|PubMed:12679486, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900, ECO:0000269|PubMed:9371856, ECO:0000269|PubMed:9425890}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in GNRHR as well as in other HH-associated genes including FGFR1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}. | Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle- stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol- calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling. | Gonadotropin-releasing hormone receptor agonist: Gonadorelin, Goserelin, Nafarelin Gonadotropin-releasing hormone receptor antagonist: Cetrorelix, Degarelix Gonadotropin-releasing hormone receptor negative modulator: Danazol | 15.1 | |
| kccGP119 | Glucose-dependent insulinotropic receptor | 30 | 543 | 99.81 | ND | 99.11 | 0.43 | ND | 0.6 | Mammalian | Predominantly expressed in the pancreas, especially in the islets. {ECO:0000269|PubMed:15607732}. | Family A G protein-coupled receptor | Diabetes Mellitus Type 2 | Receptor for the endogenous fatty-acid ethanolamide oleoylethanolamide (OEA) and lysophosphatidylcholine (LPC). Functions as a glucose-dependent insulinotropic receptor. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Seems to act through a G(s) mediated pathway. {ECO:0000269|PubMed:16517404}. | 15.1 | |||
| kccGP142 | Probable G-protein coupled receptor 142 | 10 | 85 | 99.99 | ND | 99.99 | 0.35 | ND | 0.5 | Mammalian | Exclusively expressed in the central nervous system, most abundantly in the ventrolateral region of caudate putamen, the habenular nucleus, the zona incerta, and the medial mammillary nucleus. {ECO:0000269|PubMed:15845401}. | Family A G protein-coupled receptor | Orphan receptor. | 15.1 | ||||
| kccGPBAR | G-protein coupled bile acid receptor 1 | 14 | 373 | 99.38 | ND | 99.87 | 0.57 | ND | 0.7 | Mammalian | Ubiquitously expressed. Expressed at higher level in spleen and placenta. Expressed at lower level in other tissues. In digestive tissues, it is expressed in stomach, duodenum, ileocecum, ileum, jejunum, ascending colon, transverse colon, descending colon, cecum and liver, but not in esophagus and rectum. {ECO:0000269|PubMed:12044878, ECO:0000269|PubMed:12419312, ECO:0000269|PubMed:12524422}. | Family A G protein-coupled receptor | Type 2 Diabetes | Receptor for bile acid. Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids. {ECO:0000269|PubMed:12419312, ECO:0000269|PubMed:12524422}. | 15.1 | |||
| kccGPR35 | G-protein coupled receptor 35 | 6 | 228 | 90.22 | ND | 92.97 | 0.29 | ND | 1.2 | Mammalian | Predominantly expressed in immune and gastrointestinal tissues. {ECO:0000269|PubMed:16754668}. | Family A G protein-coupled receptor | Acts as a receptor for kynurenic acid, an intermediate in the tryptophan metabolic pathway. The activity of this receptor is mediated by G-proteins that elicit calcium mobilization and inositol phosphate production through G(qi/o) proteins. {ECO:0000269|PubMed:16754668}. | 15.1 | ||||
| kccGRB2 | Growth factor receptor-bound protein 2 | 4 | 228 | 99.84 | ND | 99.91 | 0.55 | ND | 0.8 | Mammalian | Other cytosolic protein | Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death. | Gonadotropin-releasing hormone receptor agonist: Gonadorelin, Goserelin, Nafarelin Gonadotropin-releasing hormone receptor antagonist: Cetrorelix, Degarelix Gonadotropin-releasing hormone receptor negative modulator: Danazol | 15.1 | ||||
| kccGRIA1 | Glutamate receptor 1 | 6 | 158 | 92.88 | ND | 95.97 | 0.68 | ND | 0.8 | Mammalian | Widely expressed in brain. | Ligand-gated ion channel | Schizophrenia | Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:20805473, ECO:0000269|PubMed:21172611}. | Glutamate receptor 1 antagonist: Desflurane, Enflurane, Isoflurane, Methoxyflurane, Sevoflurane Glutamate receptor 1 unknown: Ethanol | 15.1 | ||
| kccGRIA2 | Glutamate receptor 2 | 8 | 256 | 87.08 | ND | 95.52 | 0.24 | ND | 1.0 | Mammalian | Ligand-gated ion channel | Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:20614889}. | Glutamate receptor 2 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Quinidine barbiturate, Secobarbital, Talbutal, Thiopental Glutamate receptor 2 unknown: Ethanol | 15.1 | ||||
| kccGRIA3 | Glutamate receptor 3 | 2 | 48 | 83.88 | ND | 91.45 | 0.44 | ND | 1.3 | Mammalian | Ligand-gated ion channel | Mental retardation, X-linked 94 (MRX94) [MIM:300699]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX94 patients have moderate mental retardation. Other variable features are macrocephaly, seizures, myoclonic jerks, autistic behavior, asthenic body habitus, distal muscle weakness and hyporeflexia. {ECO:0000269|PubMed:17989220}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:21172611}. | Glutamate receptor 3 potentiator: Lithium Glutamate receptor 3 unknown: Ethanol | 15.1 | |||
| kccGRIA4 | Glutamate receptor 4 | 3 | 121 | 84.75 | ND | 97.52 | 0.48 | ND | 0.8 | Mammalian | Ligand-gated ion channel | Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:21172611}. | Glutamate receptor 4 unknown: Ethanol | 15.1 | ||||
| kccGRIK1 | Glutamate receptor ionotropic, kainate 1 | 11 | 257 | 91.52 | ND | 94.98 | 0.48 | ND | 0.8 | Mammalian | Most abundant in the cerebellum and the suprachiasmatic nuclei (SCN) of the hypothalamus. | Ligand-gated ion channel | Analgesics
Epilepsy Pain | Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus. | Glutamate receptor ionotropic, kainate 1 antagonist: Topiramate | 15.1 | ||
| kccGRIK2 | Glutamate receptor ionotropic, kainate 2 | 3 | 169 | 80.58 | ND | 94.38 | 0.63 | ND | 0.9 | Mammalian | Expression is higher in cerebellum than in cerebral cortex. | Ligand-gated ion channel | Mental retardation, autosomal recessive 6 (MRT6) [MIM:611092]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. In contrast to syndromic or specific mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic mental retardation. MRT6 patients display mild to severe mental retardation and psychomotor development delay in early childhood. Patients do not have neurologic problems, congenital malformations, or facial dysmorphism. Body height, weight, and head circumference are normal. {ECO:0000269|PubMed:17847003}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus. Modulates cell surface expression of NETO2 (By similarity). {ECO:0000250}. | Glutamate receptor ionotropic, kainate 2 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Talbutal, Thiopental | 15.1 | ||
| kccGRK5 | G protein-coupled receptor kinase 5 | 2 | 136 | 83.58 | ND | 81.49 | 0.00 | ND | 1.3 | Mammalian | Highest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney. {ECO:0000269|PubMed:7685906}. | Kinase | Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein- coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70- interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2- mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G- protein-coupled receptor, LRP6 during Wnt signaling (in vitro). {ECO:0000269|PubMed:19661922, ECO:0000269|PubMed:19801552, ECO:0000269|PubMed:20038610, ECO:0000269|PubMed:20124405, ECO:0000269|PubMed:21728385}. | 15.1 | ||||
| kccGRM1 | Metabotropic glutamate receptor 1 | 28 | 701 | 96.79 | ND | 97.91 | 0.69 | ND | 0.7 | Mammalian | Detected in brain. | Family C G protein-coupled receptor | Spinocerebellar ataxia, autosomal recessive, 13 (SCAR13) [MIM:614831]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR13 is characterized by delayed psychomotor development beginning in infancy. Affected individuals show mild to profound mental retardation with poor or absent speech as well as gait and stance ataxia and hyperreflexia. {ECO:0000269|PubMed:22901947}. Note=The disease is caused by mutations affecting the gene represented in this entry. | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum. {ECO:0000269|PubMed:24603153, ECO:0000269|PubMed:7476890}. | Glutamate receptor ionotropic, kainate 2 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Talbutal, Thiopental | 15.1 | ||
| kccGRM2 | Metabotropic glutamate receptor 2 | 29 | 812 | 99.61 | ND | 99.46 | 0.60 | ND | 0.7 | Mammalian | Detected in brain cortex (at protein level). Widely expressed in different regions of the adult brain as well as in fetal brain. {ECO:0000269|PubMed:18297054}. | Family C G protein-coupled receptor | Alzheimer's disease
Analgesics Anxiety disorder, unspecified Epilepsy Pain, unspecified Traumatic brain injury | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization. {ECO:0000269|PubMed:18297054, ECO:0000269|PubMed:22300836, ECO:0000269|PubMed:23129762, ECO:0000269|PubMed:7620613}. | 15.1 | |||
| kccGRM3 | Metabotropic glutamate receptor 3 | 5 | 192 | 91.84 | ND | 99.86 | 0.56 | ND | 0.7 | Mammalian | Detected in brain cortex, thalamus, subthalamic nucleus, substantia nigra, hypothalamus, hippocampus, corpus callosum, caudate nucleus and amygdala. {ECO:0000269|PubMed:8840013}. | Family C G protein-coupled receptor | Alzheimer's disease
Analgesics Epilepsy Pain Psychosis Schizophrenia and Schizoaffective Disorders Traumatic brain injury | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:8840013}. | 15.1 | |||
| kccGRM4 | Metabotropic glutamate receptor 4 | 9 | 305 | 88.94 | ND | 99.69 | 0.50 | ND | 0.6 | Mammalian | Strongly expressed in the cerebellum. Expressed at low levels in hippocampus, hypothalamus and thalamus. No expression detected in liver. {ECO:0000269|PubMed:7617140, ECO:0000269|PubMed:8738157}. | Family C G protein-coupled receptor | Parkinson's disease | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:7617140, ECO:0000269|PubMed:8738157, ECO:0000269|PubMed:9473604}. | Glutamate receptor ionotropic, kainate 2 antagonist: Amobarbital, Aprobarbital, Butabarbital, Butalbital, Butethal, Heptabarbital, Hexobarbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Talbutal, Thiopental | 15.1 | ||
| kccGRM5 | Metabotropic glutamate receptor 5 | 90 | 2236 | 98.63 | ND | 98.72 | 0.54 | ND | 0.7 | Mammalian | Family C G protein-coupled receptor | Analgesics
Anxiety Disorders Convulsions Depression Drug dependence Gastroesophageal Reflux Disease (GERD) Inflammatory pain Migraine and Cluster Headaches Neuronal injury Parkinson's disease | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. Plays an important role in the regulation of synaptic plasticity and the modulation of the neural network activity. {ECO:0000269|PubMed:7908515, ECO:0000269|Ref.7}. | Metabotropic glutamate receptor 5 antagonist: Acamprosate Metabotropic glutamate receptor 5 inhibitor: Rufinamide | 15.1 | |||
| kccGRM7 | Metabotropic glutamate receptor 7 | 2 | 58 | 98.59 | ND | 89.97 | 0.94 | ND | 0.2 | Mammalian | Expressed in many areas of the brain, especially in the cerebral cortex, hippocampus, and cerebellum. Expression of GRM7 isoforms in non-neuronal tissues appears to be restricted to isoform 3 and isoform 4. {ECO:0000269|PubMed:12052533, ECO:0000269|PubMed:8840028}. | Family C G protein-coupled receptor | Convulsions | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:9473604}. | Metabotropic glutamate receptor 5 antagonist: Acamprosate Metabotropic glutamate receptor 5 inhibitor: Rufinamide | 15.1 | ||
| kccGRM8 | Metabotropic glutamate receptor 8 | 4 | 82 | 96.34 | ND | 92.68 | 0.10 | ND | 0.7 | Mammalian | Family C G protein-coupled receptor | Analgesics
Epilepsy Pain | G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. {ECO:0000269|PubMed:9473604}. | Metabotropic glutamate receptor 5 antagonist: Acamprosate Metabotropic glutamate receptor 5 inhibitor: Rufinamide | 15.1 | |||
| kccGRPR | Gastrin-releasing peptide receptor | 3 | 124 | 99.99 | ND | 100.00 | 0.80 | ND | 0.7 | Mammalian | Highly expressed in pancreas. Also expressed in stomach, adrenal cortex and brain. {ECO:0000269|PubMed:11245983}. | Family A G protein-coupled receptor | Small cell lung cancer | Receptor for gastrin releasing peptide (GRP). This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. | 15.1 | |||
| kccGSHR | Glutathione reductase, mitochondrial | 2 | 118 | 91.34 | ND | 91.28 | 0.57 | ND | 0.5 | Mammalian | Oxidoreductase | Maintains high levels of reduced glutathione in the cytosol. | Glutathione reductase, mitochondrial inhibitor: Carmustine Glutathione reductase, mitochondrial unknown: Flavin adenine dinucleotide, Glutathione | 15.1 | ||||
| kccGSK3A | Glycogen synthase kinase-3 alpha | 31 | 664 | 95.30 | ND | 94.61 | 0.39 | ND | 1.2 | Mammalian | Kinase | Not Available | Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. {ECO:0000269|PubMed:12761548, ECO:0000269|PubMed:17229088}. | 15.1 | ||||
| kccGSK3B | Glycogen synthase kinase-3 beta | 109 | 2337 | 96.73 | ND | 94.31 | 0.50 | ND | 0.9 | Mammalian | Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Colocalizes with EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain. {ECO:0000269|PubMed:21029237}. | Kinase | Alzheimer's disease
Bipolar affective disorder Brain injury Immunodeficiency Ischemia Noninsulin-dependent diabetes mellitus | Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation. Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). {ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20932480, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:8397507, ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}. | Glycogen synthase kinase-3 beta inhibitor: Lithium | 15.1 | ||
| kccGSTP1 | Glutathione S-transferase P | 3 | 83 | 99.77 | ND | 99.85 | 0.57 | ND | 0.6 | Mammalian | Enzyme | Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration. {ECO:0000269|PubMed:21668448}. | Glutathione S-transferase P inhibitor: Clomipramine, Vitamin E Glutathione S-transferase P substrate: Busulfan, Carboplatin, Chlorambucil, Cisplatin, Etoposide, Oxaliplatin Glutathione S-transferase P unknown: Glutathione | 15.1 | ||||
| kccGTR1 | Solute carrier family 2, facilitated glucose transporter member 1 | 24 | 1170 | 98.89 | ND | 99.54 | 0.61 | ND | 0.8 | Mammalian | Detected in erythrocytes (at protein level). Expressed at variable levels in many human tissues. {ECO:0000269|PubMed:23219802}. | Electrochemical transporter | GLUT1 deficiency syndrome 1 (GLUT1DS1) [MIM:606777]: A neurologic disorder showing wide phenotypic variability. The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe mental retardation. {ECO:0000269|PubMed:10227690, ECO:0000269|PubMed:10980529, ECO:0000269|PubMed:11136715, ECO:0000269|PubMed:11603379, ECO:0000269|PubMed:12325075, ECO:0000269|PubMed:15622525, ECO:0000269|PubMed:19901175, ECO:0000269|PubMed:20129935, ECO:0000269|PubMed:20221955, ECO:0000269|PubMed:20574033}. Note=The disease is caused by mutations affecting the gene represented in this entry. GLUT1 deficiency syndrome 2 (GLUT1DS2) [MIM:612126]: A clinically variable disorder characterized primarily by onset in childhood of paroxysmal exercise-induced dyskinesia. The dyskinesia involves transient abnormal involuntary movements, such as dystonia and choreoathetosis, induced by exercise or exertion, and affecting the exercised limbs. Some patients may also have epilepsy, most commonly childhood absence epilepsy. Mild mental retardation may also occur. In some patients involuntary exertion- induced dystonic, choreoathetotic, and ballistic movements may be associated with macrocytic hemolytic anemia. {ECO:0000269|PubMed:14605501, ECO:0000269|PubMed:18451999, ECO:0000269|PubMed:19630075, ECO:0000269|PubMed:19798636, ECO:0000269|PubMed:20129935, ECO:0000269|PubMed:20574033, ECO:0000269|PubMed:20621801, ECO:0000269|PubMed:20830593, ECO:0000269|PubMed:21204808}. Note=The disease is caused by mutations affecting the gene represented in this entry. Epilepsy, idiopathic generalized 12 (EIG12) [MIM:614847]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. In some EIG12 patients seizures may remit with age. {ECO:0000269|PubMed:19798636, ECO:0000269|PubMed:22282645}. Note=The disease is caused by mutations affecting the gene represented in this entry. Dystonia 9 (DYT9) [MIM:601042]: An autosomal dominant neurologic disorder characterized by childhood onset of paroxysmal choreoathetosis and progressive spastic paraplegia. Most patients show some degree of cognitive impairment. Other variable features may include seizures, migraine headaches, and ataxia. {ECO:0000269|PubMed:21832227}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Facilitative glucose transporter. This isoform may be responsible for constitutive or basal glucose uptake. Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses. {ECO:0000269|PubMed:18245775, ECO:0000269|PubMed:19449892}. | Solute carrier family 2, facilitated glucose transporter member 1 inhibitor: Etomidate | 15.1 | ||
| kccHCAR2 | Hydroxycarboxylic acid receptor 2 | 14 | 466 | 96.67 | ND | 98.59 | 0.47 | ND | 0.7 | Mammalian | Expression largely restricted to adipose tissue and spleen. Expressed on mature neutrophils but not on immature neutrophils or eosinophils. {ECO:0000269|PubMed:12522134, ECO:0000269|PubMed:17932499}. | Family A G protein-coupled receptor | Type IV and V hyperlipidemia | Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5- methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide. {ECO:0000269|PubMed:17932499}. | Hydroxycarboxylic acid receptor 2 agonist: Niacin | 15.1 | ||
| kccHCAR3 | Hydroxycarboxylic acid receptor 3 | 2 | 43 | 97.78 | ND | 99.95 | 0.34 | ND | 0.7 | Mammalian | Expression largely restricted to adipose tissue and spleen. {ECO:0000269|PubMed:12522134}. | Family A G protein-coupled receptor | Type IV and V hyperlipidemia | Receptor for 3-OH-octanoid acid mediates a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. Acts as a low affinity receptor for nicotinic acid. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. {ECO:0000269|PubMed:12522134, ECO:0000269|PubMed:19561068}. | Hydroxycarboxylic acid receptor 3 agonist: Niacin | 15.1 | ||
| kccHCK | Tyrosine-protein kinase HCK | 9 | 326 | 98.88 | ND | 96.11 | 0.50 | ND | 0.8 | Mammalian | Detected in monocytes and neutrophils (at protein level). Expressed predominantly in cells of the myeloid and B-lymphoid lineages. Highly expressed in granulocytes. Detected in tonsil. {ECO:0000269|PubMed:3453117, ECO:0000269|PubMed:8064233, ECO:0000269|PubMed:8995234}. | Kinase | Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity. Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation. | Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS. {ECO:0000269|PubMed:10092522, ECO:0000269|PubMed:10779760, ECO:0000269|PubMed:10973280, ECO:0000269|PubMed:11741929, ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:12411494, ECO:0000269|PubMed:15010462, ECO:0000269|PubMed:15952790, ECO:0000269|PubMed:15998323, ECO:0000269|PubMed:17310994, ECO:0000269|PubMed:17535448, ECO:0000269|PubMed:19114024, ECO:0000269|PubMed:19903482, ECO:0000269|PubMed:20452982, ECO:0000269|PubMed:21338576, ECO:0000269|PubMed:7535819, ECO:0000269|PubMed:8132624, ECO:0000269|PubMed:9406996, ECO:0000269|PubMed:9407116}. | Tyrosine-protein kinase HCK inhibitor: Bosutinib | 15.1 | ||
| kccHDA10 | Histone deacetylase 10 | 9 | 142 | 97.95 | ND | 95.47 | 0.22 | ND | 1.3 | Mammalian | Ubiquitous. High expression in liver, spleen, pancreas and kidney. | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. | 15.1 | ||||
| kccHDA11 | Histone deacetylase 11 | 5 | 114 | 91.77 | ND | 87.07 | 0.75 | ND | 0.8 | Mammalian | Weakly expressed in most tissues. Strongly expressed in brain, heart, skeletal muscle, kidney and testis. | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. {ECO:0000269|PubMed:11948178}. | 15.1 | ||||
| kccHDAC1 | Histone deacetylase 1 | 107 | 1777 | 98.57 | ND | 98.88 | 0.65 | ND | 0.7 | Mammalian | Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain. | Eraser | Cancer, unspecific
Proliferative diseases Prostate cancer (hormone refractory) | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST- mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation. {ECO:0000269|PubMed:12837748, ECO:0000269|PubMed:16478997, ECO:0000269|PubMed:17000776, ECO:0000269|PubMed:17704056, ECO:0000269|PubMed:17996965, ECO:0000269|PubMed:19081374, ECO:0000269|PubMed:19343227}. | Histone deacetylase 1 inhibitor: Vorinostat | 15.1 | ||
| kccHDAC2 | Histone deacetylase 2 | 32 | 461 | 97.56 | ND | 98.35 | 0.56 | ND | 0.8 | Mammalian | Widely expressed; lower levels in brain and lung. | Eraser | Colon cancer | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation. Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A. {ECO:0000269|PubMed:19343227, ECO:0000269|PubMed:21965678}. | Histone deacetylase 2 activator: Aminophylline, Oxtriphylline, Theophylline Histone deacetylase 2 inhibitor: Vorinostat Histone deacetylase 2 other: Lovastatin Histone deacetylase 2 unknown: Valproic Acid | 15.1 | ||
| kccHDAC3 | Histone deacetylase 3 | 23 | 392 | 94.03 | ND | 92.00 | 0.48 | ND | 0.9 | Mammalian | Widely expressed. | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys- 27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803). {ECO:0000269|PubMed:21444723, ECO:0000269|PubMed:23911289, ECO:0000269|PubMed:25190803}. | Histone deacetylase 3 inhibitor: Vorinostat | 15.1 | |||
| kccHDAC4 | Histone deacetylase 4 | 22 | 363 | 96.34 | ND | 96.39 | 0.55 | ND | 0.9 | Mammalian | Ubiquitous. | Eraser | Brachydactyly-mental retardation syndrome (BDMR) [MIM:600430]: A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism. {ECO:0000269|PubMed:20691407}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. {ECO:0000269|PubMed:10523670, ECO:0000269|PubMed:24413532}. | Histone deacetylase 3 inhibitor: Vorinostat | 15.1 | ||
| kccHDAC5 | Histone deacetylase 5 | 7 | 168 | 83.03 | ND | 84.13 | 0.25 | ND | 1.2 | Mammalian | Ubiquitous. | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. {ECO:0000269|PubMed:24413532}. | 15.1 | ||||
| kccHDAC6 | Histone deacetylase 6 | 70 | 944 | 97.55 | ND | 95.51 | 0.59 | ND | 0.8 | Mammalian | Eraser | Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia (CDP-PBHM) [MIM:300863]: A disease characterized by chondrodysplasia, severe platyspondyly, hydrocephaly, and facial features with microphthalmia. Bone abnormalities include a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges. Affected females show a milder phenotype with small stature, sometimes associated with body asymmetry and mild mental retardation. {ECO:0000269|PubMed:20181727}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. {ECO:0000250}. In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy. | Histone deacetylase 6 inhibitor: Vorinostat | 15.1 | |||
| kccHDAC7 | Histone deacetylase 7 | 6 | 168 | 85.67 | ND | 83.04 | 0.17 | ND | 1.0 | Mammalian | Eraser | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565). {ECO:0000250|UniProtKB:Q8C2B3, ECO:0000269|PubMed:12239305, ECO:0000269|PubMed:17360565}. | Histone deacetylase 6 inhibitor: Vorinostat | 15.1 | ||||
| kccHDAC8 | Histone deacetylase 8 | 32 | 669 | 94.63 | ND | 96.97 | 0.68 | ND | 0.6 | Mammalian | Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney. {ECO:0000269|PubMed:10926844, ECO:0000269|PubMed:14701748, ECO:0000269|PubMed:15772115, ECO:0000269|PubMed:16538051}. | Eraser | Cornelia de Lange syndrome 5 (CDLS5) [MIM:300882]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:22885700}. Note=The disease is caused by mutations affecting the gene represented in this entry. Wilson-Turner X-linked mental retardation syndrome (WTS) [MIM:309585]: A neurologic disorder characterized by severe intellectual disability, dysmorphic facial features, hypogonadism, short stature, and truncal obesity. Affected females have a milder phenotype than affected males. {ECO:0000269|PubMed:22889856}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. {ECO:0000269|PubMed:10748112, ECO:0000269|PubMed:10922473, ECO:0000269|PubMed:10926844, ECO:0000269|PubMed:14701748, ECO:0000269|PubMed:22885700}. | Histone deacetylase 8 unknown: Vorinostat | 15.1 | ||
| kccHDAC9 | Histone deacetylase 9 | 4 | 131 | 90.30 | ND | 87.48 | 0.28 | ND | 1.1 | Mammalian | Broadly expressed, with highest levels in brain, heart, muscle and testis. Isoform 3 is present in human bladder carcinoma cells (at protein level). {ECO:0000269|PubMed:10655483, ECO:0000269|PubMed:11535832, ECO:0000269|PubMed:12590135, ECO:0000269|PubMed:12706107}. | Eraser | Note=A chromosomal aberration involving HDAC9 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with TGFB2 resulting in lack of HDAC9 protein. | Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Represses MEF2-dependent transcription. Isoform 3 lacks active site residues and therefore is catalytically inactive. Represses MEF2-dependent transcription by recruiting HDAC1 and/or HDAC3. Seems to inhibit skeletal myogenesis and to be involved in heart development. Protects neurons from apoptosis, both by inhibiting JUN phosphorylation by MAPK10 and by repressing JUN transcription via HDAC1 recruitment to JUN promoter. | Histone deacetylase 9 inhibitor: Valproic Acid | 15.1 | ||
| kccHIPK2 | Homeodomain-interacting protein kinase 2 | 15 | 287 | 94.07 | ND | 88.68 | 0.37 | ND | 1.2 | Mammalian | Highly expressed in heart, muscle and kidney. Weakly expressed in a ubiquitous way. Down-regulated in several thyroid and breast tumors. {ECO:0000269|PubMed:11267674, ECO:0000269|PubMed:11798164}. | Kinase | Serine/threonine-protein kinase involved in transcription regulation, p53/TP53-mediated cellular apoptosis and regulation of the cell cycle. Acts as a corepressor of several transcription factors, including SMAD1 and POU4F1/Brn3a and probably NK homeodomain transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1 and ZBTB4. Inhibits cell growth and promotes apoptosis through the activation of p53/TP53 both at the transcription level and at the protein level (by phosphorylation and indirect acetylation). The phosphorylation of p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates transcriptional activation of TP73. In response to TGFB, cooperates with DAXX to activate JNK. Negative regulator through phosphorylation and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an intermediate kinase between MAP3K7/TAK1 and NLK to promote the proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and promotes its E3 SUMO- protein ligase activity. Activates CREB1 and ATF1 transcription factors by phosphorylation in response to genotoxic stress. In response to DNA damage, stabilizes PML by phosphorylation. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53- dependent transactivation. Promotes angiogenesis, and is involved in erythroid differentiation, especially during fetal liver erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300 transcription regulation activity. Triggers ZBTB4 protein degradation in response to DNA damage. Modulates HMGA1 DNA-binding affinity. In response to high glucose, triggers phosphorylation- mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis. {ECO:0000269|PubMed:11740489, ECO:0000269|PubMed:11925430, ECO:0000269|PubMed:12851404, ECO:0000269|PubMed:12874272, ECO:0000269|PubMed:14678985, ECO:0000269|PubMed:17018294, ECO:0000269|PubMed:17960875, ECO:0000269|PubMed:18695000, ECO:0000269|PubMed:18809579, ECO:0000269|PubMed:19015637, ECO:0000269|PubMed:19046997, ECO:0000269|PubMed:19448668, ECO:0000269|PubMed:20307497, ECO:0000269|PubMed:20573984, ECO:0000269|PubMed:20637728, ECO:0000269|PubMed:20980392, ECO:0000269|PubMed:21192925, ECO:0000269|PubMed:22825850}. | 15.1 | ||||
| kccHIPK4 | Homeodomain-interacting protein kinase 4 | 15 | 273 | 96.25 | ND | 86.47 | 0.22 | ND | 1.3 | Mammalian | Kinase | Protein kinase that phosphorylates human TP53 at Ser-9, and thus induces TP53 repression of BIRC5 promoter (By similarity). May act as a corepressor of transcription factors (Potential). {ECO:0000250, ECO:0000305}. | 15.1 | |||||
| kccHKDC1 | Putative hexokinase HKDC1 | 1 | 178 | 84.74 | ND | 88.27 | 0.03 | ND | 1.0 | Mammalian | Enzyme | 15.1 | ||||||
| kccHMDH | 3-hydroxy-3-methylglutaryl-coenzyme A reductase | 15 | 734 | 98.35 | ND | 98.77 | 0.68 | ND | 0.7 | Mammalian | Myalgia | Oxidoreductase | Atherosclerosis
Cardiovascular disease, unspecified Cervical cancer Coronary heart disease Dyslipidemia Head and neck squamous cell carcinomas Hypercholesterolemia Hypertriglyceridemia Myocardial infarction | Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins. | 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor: Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin | 15.1 | ||
| kccHMOX1 | Heme oxygenase 1 | 2 | 106 | 99.94 | ND | 99.90 | 0.50 | ND | 0.7 | Mammalian | Expressed at higher levels in renal cancer tissue than in normal tissue (at protein level). {ECO:0000269|PubMed:20855888}. | Enzyme | Heme oxygenase 1 deficiency (HMOX1D) [MIM:614034]: A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly. {ECO:0000269|PubMed:9884342}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed. Exhibits cytoprotective effects since excess of free heme sensitizes cells to undergo apoptosis. | Heme oxygenase 1 inducer: Vitamin E | 15.1 | ||
| kccHMOX2 | Heme oxygenase 2 | 2 | 89 | 99.82 | ND | 99.74 | 0.41 | ND | 0.4 | Mammalian | Enzyme | Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed. Heme oxygenase 2 could be implicated in the production of carbon monoxide in brain where it could act as a neurotransmitter. | Heme oxygenase 1 inducer: Vitamin E | 15.1 | ||||
| kccHNF4A | Hepatocyte nuclear factor 4-alpha | 7 | 115 | 87.59 | ND | 82.38 | 0.32 | ND | 0.5 | Mammalian | nuclear hormone receptor | Maturity-onset diabetes of the young 1 (MODY1) [MIM:125850]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:17407387, ECO:0000269|PubMed:9243109, ECO:0000269|PubMed:9313765}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:9449683}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (FRTS4) [MIM:616026]: A disease characterized by Fanconi syndrome associated with a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Fanconi syndrome is a proximal tubulopathy resulting in generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricemia. Some FRTS4 patients have nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcemia, and hypermagnesemia. {ECO:0000269|PubMed:22802087, ECO:0000269|PubMed:24285859}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1- antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1- alpha. May be essential for development of the liver, kidney and intestine. | Heme oxygenase 1 inducer: Vitamin E | 15.1 | |||
| kccHPGDS | Hematopoietic prostaglandin D synthase | 1 | 57 | 84.65 | ND | 93.49 | 0.58 | ND | 0.8 | Mammalian | Expressed in a number of megakaryocytic cell lines but not in platelets. Highly expressed in adipose tissue, macrophages and placenta. Also expressed at lower levels in lung, heart, lymph nodes, appendix, bone marrow and fetal liver. {ECO:0000269|PubMed:10824118, ECO:0000269|PubMed:11672424, ECO:0000269|PubMed:9353279, ECO:0000269|PubMed:9425264}. | Enzyme | Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide. {ECO:0000269|PubMed:10824118, ECO:0000269|PubMed:11672424, ECO:0000269|PubMed:12627223, ECO:0000269|PubMed:15113825, ECO:0000269|PubMed:16547010, ECO:0000269|PubMed:19939518, ECO:0000269|PubMed:9353279, ECO:0000269|PubMed:9425264}. | Hematopoietic prostaglandin D synthase unknown: Glutathione | 15.1 | |||
| kccHPPD | 4-hydroxyphenylpyruvate dioxygenase | 3 | 51 | 94.76 | ND | 98.72 | 0.42 | ND | 0.9 | Mammalian | Oxidoreductase | Tyrosinemia 3 (TYRSN3) [MIM:276710]: An inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, seizures and mild mental retardation. {ECO:0000269|PubMed:10942115, ECO:0000269|PubMed:11073718}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hawkinsinuria (HAWK) [MIM:140350]: An inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin, in the urine. {ECO:0000269|PubMed:11073718}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Key enzyme in the degradation of tyrosine. | 4-hydroxyphenylpyruvate dioxygenase inhibitor: Nitisinone | 15.1 | |||
| kccHPRT | Hypoxanthine-guanine phosphoribosyltransferase | 1 | 87 | 90.36 | ND | 95.14 | 0.22 | ND | 0.5 | Mammalian | Enzyme | Lesch-Nyhan syndrome (LNS) [MIM:300322]: Characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self- mutilation. {ECO:0000269|PubMed:15571223, ECO:0000269|PubMed:17027311, ECO:0000269|PubMed:2071157, ECO:0000269|PubMed:2246854, ECO:0000269|PubMed:2347587, ECO:0000269|PubMed:2358296, ECO:0000269|PubMed:24940672, ECO:0000269|PubMed:2910902, ECO:0000269|PubMed:3265398, ECO:0000269|PubMed:3384338, ECO:0000269|PubMed:6853716, ECO:0000269|PubMed:7627191, ECO:0000269|PubMed:9452051}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gout HPRT-related (GOUT-HPRT) [MIM:300323]: Characterized by partial enzyme activity and hyperuricemia. {ECO:0000269|PubMed:15571223, ECO:0000269|PubMed:17027311, ECO:0000269|PubMed:20544509, ECO:0000269|PubMed:24940672, ECO:0000269|PubMed:2909537, ECO:0000269|PubMed:3198771, ECO:0000269|PubMed:3358423, ECO:0000269|PubMed:6572373, ECO:0000269|PubMed:6706936, ECO:0000269|PubMed:6853490, ECO:0000269|PubMed:7987318}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5- phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway. | Hypoxanthine-guanine phosphoribosyltransferase inhibitor: Azathioprine, Mercaptopurine Hypoxanthine-guanine phosphoribosyltransferase substrate: Tioguanine | 15.1 | |||
| kccHPSE | Heparanase | 5 | 168 | 98.80 | ND | 98.37 | 0.50 | ND | 0.5 | Mammalian | Highly expressed in placenta and spleen and weakly expressed in lymph node, thymus, peripheral blood leukocytes, bone marrow, endothelial cells, fetal liver and tumor tissues. Also expressed in hair follicles, specifically in both Henle's and Huxley's layers of inner the root sheath (IRS) at anagen phase. {ECO:0000269|PubMed:10395326, ECO:0000269|PubMed:10405343, ECO:0000269|PubMed:10764835, ECO:0000269|PubMed:18557927, ECO:0000269|PubMed:20309870}. | Enzyme | Hepatocellular Cancer Following Curative Resection
Lung Cancer Prostate cancer | Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up- regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis. {ECO:0000269|PubMed:12213822, ECO:0000269|PubMed:12773484, ECO:0000269|PubMed:15044433, ECO:0000269|PubMed:16452201, ECO:0000269|PubMed:18557927, ECO:0000269|PubMed:18798279, ECO:0000269|PubMed:19244131, ECO:0000269|PubMed:20097882, ECO:0000269|PubMed:20181948, ECO:0000269|PubMed:20309870, ECO:0000269|PubMed:20561914, ECO:0000269|PubMed:21131364}. | Heparanase substrate: Heparin | 15.1 | ||
| kccHRH1 | Histamine H1 receptor | 86 | 1487 | 96.02 | ND | 95.94 | 0.68 | ND | 0.8 | Nature11159 | Mammalian | Agranulocytosis Akathisia Anticholinergic syndrome Ataxia Bladder disorder Bone marrow disorder Central nervous system stimulation Chest discomfort Conduction disorder Constipation Convulsion Cycloplegia Dermatitis allergic Diabetic eye disease Dry mouth Dystonia Dysuria Euphoric mood Extrapyramidal disorder Galactorrhoea Haemolytic anaemia Hypercholesterolaemia Hyperthermia Hyporeflexia Increased appetite Increased viscosity of bronchial secretion Insomnia Muscular weakness Myopathy Nervousness Parkinsonism Photosensitivity reaction Sedation Skin sensitisation Somnolence Tachycardia Tardive dyskinesia Tinnitus Tremor Urinary retention Urinary tract disorder Vision blurred Weight increased | Family A G protein-coupled receptor | Acute lymphoblastic leukaemia (therapy-refractory)
Allergic diseases Allergic rhinitis, unspecified Anxiety disorder, unspecified Chronic rhinitis Chronic urticaria Epidermal hyperplasia Epilepsy Hypotension Intimal hyperplasia Ischemia Motion sickness Nausea and vomiting Seasonal allergic rhinitis Systemic arterial vasodilation | In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system. | Histamine H1 receptor agonist: Betahistine, Histamine Phosphate, Paliperidone, Tolazoline Histamine H1 receptor antagonist: Aceprometazine, Alcaftadine, Alimemazine, Amitriptyline, Amoxapine, Antazoline, Aripiprazole, Asenapine, Astemizole, Azatadine, Azelastine, Benzatropine, Bepotastine, Bromodiphenhydramine, Brompheniramine, Buclizine, Butriptyline, Carbinoxamine, Cetirizine, Chlorcyclizine, Chloropyramine, Chlorphenamine, Chlorpromazine, Chlorprothixene, Cinnarizine, Clemastine, Clofedanol, Clozapine, Cyclizine, Cyproheptadine, Desipramine, Desloratadine, Dexbrompheniramine, Dimenhydrinate, Dimetindene, Diphenhydramine, Diphenylpyraline, Doxepin, Doxylamine, Emedastine, Epinastine, Escitalopram, Fexofenadine, Flunarizine, Hydroxyzine, Iloperidone, Imipramine, Isothipendyl, Ketotifen, Levocabastine, Loratadine, Maprotiline, Meclizine, Mepyramine, Mequitazine, Methdilazine, Methotrimeprazine, Mianserin, Mirtazapine, Nortriptyline, Olanzapine, Olopatadine, Orphenadrine, Phenindamine, Pheniramine, Promazine, Promethazine, Propiomazine, Quetiapine, Risperidone, Trazodone, Trimipramine, Tripelennamine, Triprolidine, Ziprasidone Histamine H1 receptor binder: Citalopram, Loxapine | 15.1 | |
| kccHRH2 | Histamine H2 receptor | 19 | 546 | 94.26 | ND | 94.48 | 0.40 | ND | 0.9 | Nature11159 | Mammalian | Anticholinergic syndrome Cycloplegia | Family A G protein-coupled receptor | Epidermal hyperplasia
Lasting tachycardia Peptic ulcer Systemic arterial vasodilation Zollinger-Ellison syndrome | The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and differentiation. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and, through a separate G protein-dependent mechanism, the phosphoinositide/protein kinase (PKC) signaling pathway (By similarity). {ECO:0000250}. | Histamine H2 receptor agonist: Betazole, Histamine Phosphate, Tolazoline Histamine H2 receptor antagonist: Asenapine, Cimetidine, Doxepin, Epinastine, Famotidine, Methantheline, Nizatidine, Olanzapine, Ranitidine, Roxatidine acetate Histamine H2 receptor binder: Loxapine Histamine H2 receptor blocker: Amitriptyline | 15.1 | |
| kccHRH3 | Histamine H3 receptor | 130 | 3143 | 98.75 | ND | 99.07 | 0.58 | ND | 0.7 | Nature11159 | Mammalian | Expressed predominantly in the CNS, with the greatest expression in the thalamus and caudate nucleus. The various isoforms are mainly coexpressed in brain, but their relative expression level varies in a region-specific manner. Isoform 3 and isoform 7 are highly expressed in the thalamus, caudate nucleus and cerebellum while isoform 5 and isoform 6 show a poor expression. Isoform 5 and isoform 6 show a high expression in the amygdala, substantia nigra, cerebral cortex and hypothalamus. Isoform 7 is not found in hypothalamus or substantia nigra. | Family A G protein-coupled receptor | Acid-related diseases
Allergic rhinitis, unspecified Alzheimer's disease Attention-deficit hyperactivity disorder Central nervous system diseases Inflammatory diseases Schizophrenia | The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization. | Histamine H3 receptor agonist: Histamine Phosphate Histamine H3 receptor antagonist: Betahistine, Mirtazapine | 15.1 | |
| kccHRH4 | Histamine H4 receptor | 26 | 840 | 98.48 | ND | 97.61 | 0.51 | ND | 0.7 | Mammalian | Expressed primarily in the bone marrow and eosinophils. Shows preferential distribution in cells of immunological relevance such as T-cells, dendritic cells, monocytes, mast cells, neutrophils. Also expressed in a wide variety of peripheral tissues, including the heart, kidney, liver, lung, pancreas, skeletal muscle, prostate, small intestine, spleen, testis, colon, fetal liver and lymph node. {ECO:0000269|PubMed:12503632}. | Anticholinergic syndrome | Family A G protein-coupled receptor | Allergic diseases
Allergy, unspecified Asthma | The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist). {ECO:0000269|PubMed:12503632}. | Histamine H4 receptor agonist: Histamine Phosphate Histamine H4 receptor antagonist: Clozapine, Olanzapine Histamine H4 receptor binder: Amitriptyline, Amoxapine, Chlorpromazine, Doxepin, Loxapine, Mianserin | 15.1 | |
| kccHS90A | Heat shock protein HSP 90-alpha | 50 | 1199 | 84.34 | ND | 86.02 | 0.49 | ND | 1.1 | Mammalian | Other cytosolic protein | Breast cancer
Chronic Myelogenous Leukemia (CML) Gastrointestinal Stromal Tumors (GIST) Hematological Malignancies HER2-positive Metastatic Breast Cancer Melanoma Multiple Myeloma Non-small Cell Lung Cancer Ovarian cancer Prostate cancer Refractory Hematological Malignancies Solid tumors | Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes. {ECO:0000269|PubMed:11274138, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:15577939, ECO:0000269|PubMed:15937123}. | Heat shock protein HSP 90-alpha other/unknown: Rifabutin Heat shock protein HSP 90-alpha unknown: Nedocromil | 15.1 | |||
| kccHS90B | Heat shock protein HSP 90-beta | 16 | 379 | 99.30 | ND | 99.16 | 0.70 | ND | 0.7 | Mammalian | Other cytosolic protein | Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. {ECO:0000269|PubMed:16478993, ECO:0000269|PubMed:19696785}. | Heat shock protein HSP 90-alpha other/unknown: Rifabutin Heat shock protein HSP 90-alpha unknown: Nedocromil | 15.1 | ||||
| kccHXK4 | Glucokinase | 25 | 564 | 99.73 | ND | 99.46 | 0.44 | ND | 0.5 | Mammalian | Isoform 1 is expressed in pancreas. Isoform 2 and isoform 3 is expressed in liver. | Enzyme | Maturity-onset diabetes of the young 2 (MODY2) [MIM:125851]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:10588527, ECO:0000269|PubMed:10694920, ECO:0000269|PubMed:11106831, ECO:0000269|PubMed:11372010, ECO:0000269|PubMed:1303265, ECO:0000269|PubMed:1464666, ECO:0000269|PubMed:1502186, ECO:0000269|PubMed:8168652, ECO:0000269|PubMed:8325892, ECO:0000269|PubMed:8495817, ECO:0000269|PubMed:9049484, ECO:0000269|PubMed:9662401}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperinsulinemic hypoglycemia 3 (HHF3) [MIM:602485]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269|PubMed:9435328}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage. | Heat shock protein HSP 90-alpha other/unknown: Rifabutin Heat shock protein HSP 90-alpha unknown: Nedocromil | 15.1 | ||
| kccHYEP | Epoxide hydrolase 1 | 3 | 82 | 98.64 | ND | 99.93 | 0.46 | ND | 0.5 | Mammalian | Found in liver. {ECO:0000269|PubMed:12878321}. | Protease | Note=In some populations, the high activity haplotype tyr113/his139 is overrepresented among women suffering from pregnancy-induced hypertension (pre-eclampsia) when compared with healthy controls. {ECO:0000269|PubMed:12173035}. Familial hypercholanemia (FHCA) [MIM:607748]: A disorder characterized by elevated serum bile acid concentrations, itching, and fat malabsorption. Note=The disease is caused by mutations affecting the gene represented in this entry. | Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water. | 15.1 | |||
| kccHYES | Bifunctional epoxide hydrolase 2 | 50 | 1186 | 97.56 | ND | 98.49 | 0.56 | ND | 0.8 | Mammalian | Protease | Cardiovascular disease, unspecified
Hypertension Renal diseases | Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo- 9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro- 9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy- octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate. {ECO:0000269|PubMed:12574508, ECO:0000269|PubMed:12574510}. | Heat shock protein HSP 90-alpha other/unknown: Rifabutin Heat shock protein HSP 90-alpha unknown: Nedocromil | 15.1 | |||
| kccI23O1 | Indoleamine 2,3-dioxygenase 1 | 8 | 263 | 84.08 | ND | 93.29 | 0.40 | ND | 0.7 | Mammalian | Expressed in mature dendritic cells located in lymphoid organs (including lymph nodes, spleen, tonsils, Peyers's patches, the gut lamina propria, and the thymic medulla), in some epithelial cells of the female genital tract, as well as in endothelial cells of term placenta and in lung parenchyma (PubMed:25691885). Weakly or not expressed in most normal tissues, but mostly inducible in most tissues (PubMed:25691885). Expressed in more than 50% of tumors, either by tumoral, stromal, or endothelial cells (expression in tumor is associated with a worse clinical outcome) (PubMed:18418598). Not overexpressed in tumor- draining lymph nodes (PubMed:26155395, PubMed:25691885). {ECO:0000269|PubMed:18418598, ECO:0000269|PubMed:25691885, ECO:0000269|PubMed:26155395}. | Enzyme | Depression | Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway (PubMed:17671174). Involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses (PubMed:25691885). Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells (PubMed:25691885). Acts as a suppressor of anti-tumor immunity (PubMed:23103127, PubMed:25157255, PubMed:14502282, PubMed:25691885). Limits the growth of intracellular pathogens by depriving tryptophan (PubMed:25691885). Protects the fetus from maternal immune rejection (PubMed:25691885). {ECO:0000269|PubMed:14502282, ECO:0000269|PubMed:17671174, ECO:0000303|PubMed:23103127, ECO:0000303|PubMed:25157255, ECO:0000303|PubMed:25691885}. | Indoleamine 2,3-dioxygenase 1 substrate: L-Tryptophan, Melatonin | 15.1 | ||
| kccICAM1 | Intercellular adhesion molecule 1 | 4 | 130 | 99.86 | ND | 99.91 | 0.43 | ND | 0.8 | Mammalian | Adhesion | Asthma
Autoimmune diseases Inflammation Multiple sclerosis | ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). During leukocyte trans- endothelial migration, ICAM1 engagement promotes the assembly of endothelial apical cups through ARHGEF26/SGEF and RHOG activation. {ECO:0000269|PubMed:11173916, ECO:0000269|PubMed:17875742}. (Microbial infection) Acts as a receptor for major receptor group rhinovirus A-B capsid proteins (PubMed:1968231, PubMed:2538243). Acts as a receptor for Coxsackievirus A21 capsid proteins (PubMed:11160747, PubMed:16004874, PubMed:9539703). Upon Kaposi's sarcoma-associated herpesvirus/HHV-8 infection, is degraded by viral E3 ubiquitin ligase MIR2, presumably to prevent lysis of infected cells by cytotoxic T-lymphocytes and NK cell (PubMed:11413168). {ECO:0000269|PubMed:11160747, ECO:0000269|PubMed:11413168, ECO:0000269|PubMed:16004874, ECO:0000269|PubMed:1968231, ECO:0000269|PubMed:2538243, ECO:0000269|PubMed:9539703}. | 15.1 | ||||
| kccICMT | Protein-S-isoprenylcysteine O-methyltransferase | 3 | 201 | 94.39 | ND | 94.77 | 0.50 | ND | 0.6 | Mammalian | Ubiquitously expressed. Expressed at higher levels in the cerebellum and putamen than in other brain regions. Abundant expression seen in the Purkinje cells and pontine neurons. {ECO:0000269|PubMed:10649571}. | Enzyme | Catalyzes the post-translational methylation of isoprenylated C-terminal cysteine residues. | 15.1 | ||||
| kccIF4E | Eukaryotic translation initiation factor 4E | 1 | 123 | 92.67 | ND | 91.22 | 0.57 | ND | 0.3 | Mammalian | Other nuclear protein | Autism 19 (AUTS19) [MIM:615091]: A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate mental retardation. {ECO:0000269|PubMed:19556253}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A heterozygous single-nucleotide insertion has been found in families affected by autism. The variant results in increased promoter activity and is involved in disease pathogenesis through EIF4E deregulation (PubMed:19556253). {ECO:0000269|PubMed:19556253}. Note=A chromosomal aberration involving EIF4E has been found in a patient with classic autism. Translocation t(45)(q23q31.3). The breakpoint on chromosome 4 is located 56 kb downstream of EIF4E (PubMed:19556253). {ECO:0000269|PubMed:19556253}. | Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap. {ECO:0000269|PubMed:16271312, ECO:0000269|PubMed:22578813}. | Insulin-degrading enzyme inhibitor: Bacitracin | 15.1 | |||
| kccIF4H | Eukaryotic translation initiation factor 4H | 1 | 86 | 87.67 | ND | 99.60 | 0.09 | ND | 0.8 | Mammalian | The short isoform is the predominant isoform and is expressed alone in liver and skeletal muscle. Both isoforms are expressed in fibroblast, spleen, testis and bone marrow. Levels are high in lung and pancreas and low in heart, frontal cortex and kidney. {ECO:0000269|PubMed:11003705, ECO:0000269|PubMed:8812460}. | Note=EIF4H is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of EIF4H may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease. | Stimulates the RNA helicase activity of EIF4A in the translation initiation complex. Binds weakly mRNA. {ECO:0000269|PubMed:10585411, ECO:0000269|PubMed:11418588}. | 15.1 | ||||
| kccIGF1R | Insulin-like growth factor 1 receptor | 35 | 1176 | 95.15 | ND | 95.79 | 0.76 | ND | 0.7 | Mammalian | Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney. {ECO:0000269|PubMed:12019176, ECO:0000269|PubMed:8247543, ECO:0000269|PubMed:9202395, ECO:0000269|PubMed:9355755}. | Kinase | Insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]: A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels. {ECO:0000269|PubMed:14657428, ECO:0000269|PubMed:15928254}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K- driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R. When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. | Insulin-degrading enzyme inhibitor: Bacitracin | 15.1 | ||
| kccIKBA | NF-kappa-B inhibitor alpha | 3 | 42 | 100.00 | ND | 100.00 | 0.82 | ND | 0.2 | Mammalian | Other cytosolic protein | Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency autosomal dominant (ADEDAID) [MIM:612132]: A form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. This form of ectodermal dysplasia is associated with decreased production of pro-inflammatory cytokines and certain interferons, rendering patients susceptible to infection. {ECO:0000269|PubMed:14523047, ECO:0000269|PubMed:18412279}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL dimers in the cytoplasm through masking of their nuclear localization signals. On cellular stimulation by immune and proinflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription. {ECO:0000269|PubMed:7479976}. | NF-kappa-B inhibitor alpha unknown: Acetylsalicylic acid | 15.1 | |||
| kccIKKA | Inhibitor of nuclear factor kappa-B kinase subunit alpha | 18 | 393 | 97.83 | ND | 96.30 | 0.25 | ND | 1.0 | Mammalian | Widely expressed. | Kinase | Cocoon syndrome (COCOS) [MIM:613630]: A lethal syndrome characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin. {ECO:0000269|PubMed:20961246}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine kinase that plays an essential role in the NF- kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa- B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. {ECO:0000269|PubMed:12789342, ECO:0000269|PubMed:17434128, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20501937, ECO:0000269|PubMed:21765415}. | Inhibitor of nuclear factor kappa-B kinase subunit alpha inhibitor: Acetylcysteine, Aminosalicylic Acid, Mesalazine, Sulfasalazine | 15.1 | ||
| kccIKKB | Inhibitor of nuclear factor kappa-B kinase subunit beta | 30 | 897 | 97.96 | ND | 96.40 | 0.70 | ND | 0.6 | Mammalian | Highly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood. | Kinase | Immunodeficiency 15 (IMD15) [MIM:615592]: An autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T- cells, and impaired differentiation and activation of immune cells. {ECO:0000269|PubMed:24369075}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine kinase that plays an essential role in the NF- kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation. {ECO:0000269|PubMed:11297557, ECO:0000269|PubMed:17213322, ECO:0000269|PubMed:19716809, ECO:0000269|PubMed:20410276, ECO:0000269|PubMed:20434986, ECO:0000269|PubMed:20797629, ECO:0000269|PubMed:21138416}. | Inhibitor of nuclear factor kappa-B kinase subunit beta inducer: Arsenic trioxide Inhibitor of nuclear factor kappa-B kinase subunit beta inhibitor: Acetylcysteine, Auranofin, Mesalazine, Sulfasalazine Inhibitor of nuclear factor kappa-B kinase subunit beta unknown: Acetylsalicylic acid | 15.1 | ||
| kccIKKE | Inhibitor of nuclear factor kappa-B kinase subunit epsilon | 8 | 240 | 93.28 | ND | 87.92 | 0.36 | ND | 1.2 | Mammalian | Highly expressed in spleen followed by thymus, peripheral blood leukocytes, pancreas, placenta. Weakly expressed in lung, kidney, prostate, ovary and colon. | Kinase | Analgesics
Herpes virus infection Inflammation Inflammatory diseases Pain, unspecified Rheumatoid arthritis, unspecified | Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG- I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1. {ECO:0000269|PubMed:17568778, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:19153231, ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:22532683, ECO:0000269|PubMed:23453969, ECO:0000269|PubMed:23478265}. | 15.1 | |||
| kccIMDH1 | Inosine-5'-monophosphate dehydrogenase 1 {ECO:0000255|HAMAP-Rule:MF_03156} | 5 | 129 | 99.89 | ND | 99.94 | 0.52 | ND | 0.7 | Mammalian | IMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor. | Oxidoreductase | Retinitis pigmentosa 10 (RP10) [MIM:180105]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:11875049, ECO:0000269|PubMed:11875050, ECO:0000269|PubMed:16384941}. Note=The disease is caused by mutations affecting the gene represented in this entry. Leber congenital amaurosis 11 (LCA11) [MIM:613837]: A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. {ECO:0000269|PubMed:16384941}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate- limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors. | Inosine-5'-monophosphate dehydrogenase 1 {ECO:0000255|HAMAP-Rule:MF_03156} Inhibitor: Mercaptopurine Inosine-5'-monophosphate dehydrogenase 1 {ECO:0000255|HAMAP-Rule:MF_03156} inhibitor: Mycophenolate mofetil, Mycophenolic acid, Ribavirin | 15.1 | ||
| kccIMDH2 | Inosine-5'-monophosphate dehydrogenase 2 {ECO:0000255|HAMAP-Rule:MF_03156} | 13 | 619 | 98.10 | ND | 98.80 | 0.58 | ND | 0.6 | Mammalian | IMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor. | Oxidoreductase | Leukemia, unspecified | Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate- limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors. | Inosine-5'-monophosphate dehydrogenase 2 {ECO:0000255|HAMAP-Rule:MF_03156} Inhibitor: Mercaptopurine Inosine-5'-monophosphate dehydrogenase 2 {ECO:0000255|HAMAP-Rule:MF_03156} inhibitor: Mycophenolate mofetil, Mycophenolic acid | 15.1 | ||
| kccIMPA1 | Inositol monophosphatase 1 | 9 | 602 | 83.20 | ND | 85.37 | 0.01 | ND | 0.8 | Mammalian | Hydrolase | Responsible for the provision of inositol required for synthesis of phosphatidylinositol and polyphosphoinositides and has been implicated as the pharmacological target for lithium action in brain. Has broad substrate specificity and can use myo- inositol monophosphates, myo-inositol 1,3-diphosphate, myo- inositol 1,4-diphosphate, scyllo-inositol-phosphate, D-galactose 1-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1- phosphate, beta-glycerophosphate, and 2'-AMP as substrates. {ECO:0000269|PubMed:17068342, ECO:0000269|PubMed:8718889, ECO:0000269|PubMed:9462881}. | Inositol monophosphatase 1 inhibitor: Lithium | 15.1 | ||||
| kccINMT | Indolethylamine N-methyltransferase | 2 | 61 | 98.70 | ND | 92.61 | 0.05 | ND | 0.5 | Mammalian | Widely expressed. The highest levels were in thyroid, adrenal gland, adult and fetal lung. Intermediate levels in heart, placenta, skeletal muscle, testis, small intestine, pancreas, stomach, spinal cord, lymph node and trachea. Very low levels in adult and fetal kidney and liver, in adult spleen, thymus, ovary, colon and bone marrow. Not expressed in peripheral blood leukocytes and brain. {ECO:0000269|PubMed:10552930}. | Enzyme | Functions as thioether S-methyltransferase and is active with a variety of thioethers and the corresponding selenium and tellurium compounds, including 3-methylthiopropionaldehyde, dimethyl selenide, dimethyl telluride, 2-methylthioethylamine, 2- methylthioethanol, methyl-n-propyl sulfide and diethyl sulfide. Plays an important role in the detoxification of selenium compounds (By similarity). Catalyzes the N-methylation of tryptamine and structurally related compounds. {ECO:0000250, ECO:0000269|PubMed:10552930}. | 15.1 | ||||
| kccINSR | Insulin receptor | 37 | 884 | 96.72 | ND | 96.48 | 0.44 | ND | 0.9 | Mammalian | Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas. {ECO:0000269|PubMed:10207053, ECO:0000269|PubMed:2369896, ECO:0000269|PubMed:9202395, ECO:0000269|PubMed:9355755}. | Kinase | Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10443650, ECO:0000269|PubMed:12023989, ECO:0000269|PubMed:17201797, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:8314008}. Note=The disease is caused by mutations affecting the gene represented in this entry. Leprechaunism (LEPRCH) [MIM:246200]: Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive. {ECO:0000269|PubMed:12538626, ECO:0000269|PubMed:12970295, ECO:0000269|PubMed:1607067, ECO:0000269|PubMed:1730625, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2479553, ECO:0000269|PubMed:2834824, ECO:0000269|PubMed:7538143, ECO:0000269|PubMed:7815442, ECO:0000269|PubMed:8188715, ECO:0000269|PubMed:8326490, ECO:0000269|PubMed:8419945, ECO:0000269|PubMed:8636294, ECO:0000269|PubMed:9249867, ECO:0000269|PubMed:9703342}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:1470163, ECO:0000269|PubMed:1607076, ECO:0000269|PubMed:7657032}. Note=The gene represented in this entry may be involved in disease pathogenesis. Familial hyperinsulinemic hypoglycemia 5 (HHF5) [MIM:609968]: Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. {ECO:0000269|PubMed:15161766}. Note=The disease is caused by mutations affecting the gene represented in this entry. Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]: Characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. {ECO:0000269|PubMed:10733238, ECO:0000269|PubMed:11260230, ECO:0000269|PubMed:12107746, ECO:0000269|PubMed:12970295, ECO:0000269|PubMed:1563582, ECO:0000269|PubMed:1963473, ECO:0000269|PubMed:2002058, ECO:0000269|PubMed:2168397, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2544998, ECO:0000269|PubMed:3283938, ECO:0000269|PubMed:8243830, ECO:0000269|PubMed:8288049, ECO:0000269|PubMed:8314008, ECO:0000269|PubMed:8388389, ECO:0000269|PubMed:9175790}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src- homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti- apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K- AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. {ECO:0000269|PubMed:12138094, ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16831875, ECO:0000269|PubMed:8257688, ECO:0000269|PubMed:8276809, ECO:0000269|PubMed:8452530, ECO:0000269|PubMed:9428692}. | Inositol monophosphatase 1 inhibitor: Lithium | 15.1 | ||
| kccIRAK1 | Interleukin-1 receptor-associated kinase 1 | 16 | 244 | 92.74 | ND | 87.08 | 0.06 | ND | 1.2 | Mammalian | Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2. {ECO:0000269|PubMed:11397809}. | Kinase | Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor- signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3. {ECO:0000269|PubMed:11397809, ECO:0000269|PubMed:12860405, ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:15465816, ECO:0000269|PubMed:15767370, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509}. | 15.1 | ||||
| kccIRAK4 | Interleukin-1 receptor-associated kinase 4 | 18 | 375 | 96.20 | ND | 93.56 | 0.19 | ND | 1.3 | Mammalian | Kinase | Recurrent isolated invasive pneumococcal disease 1 (IPD1) [MIM:610799]: Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. {ECO:0000269|PubMed:16950813}. Note=The disease is caused by mutations affecting the gene represented in this entry. IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. {ECO:0000269|PubMed:12637671, ECO:0000269|PubMed:12925671, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:19663824, ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino- mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA- IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. {ECO:0000269|PubMed:11960013, ECO:0000269|PubMed:12538665, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:17217339, ECO:0000269|PubMed:17337443, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509, ECO:0000269|PubMed:24316379}. | Inositol monophosphatase 1 inhibitor: Lithium | 15.1 | |||
| kccITA2B | Integrin alpha-IIb | 3 | 41 | 99.89 | ND | 99.99 | 0.37 | ND | 0.3 | Mammalian | Isoform 1 and isoform 2 were identified in platelets and megakaryocytes, but not in reticulocytes or in Jurkat and U-937 white blood cell line. Isoform 3 is expressed by leukemia, prostate adenocarcinoma and melanoma cells but not by platelets or normal prostate or breast epithelial cells. | Membrane receptor | Glanzmann thrombasthenia (GT) [MIM:273800]: A common inherited disease of platelet aggregation. It is characterized by mucocutaneous bleeding of mild-to-moderate severity. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb-IIIa complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the GPIIb-IIIa complex at reduced levels, have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. {ECO:0000269|PubMed:10607701, ECO:0000269|PubMed:11798398, ECO:0000269|PubMed:12083483, ECO:0000269|PubMed:12181054, ECO:0000269|PubMed:12424194, ECO:0000269|PubMed:12506038, ECO:0000269|PubMed:15099289, ECO:0000269|PubMed:15219201, ECO:0000269|PubMed:17018384, ECO:0000269|PubMed:20020534, ECO:0000269|PubMed:7508443, ECO:0000269|PubMed:7706461, ECO:0000269|PubMed:8282784, ECO:0000269|PubMed:8704171, ECO:0000269|PubMed:9215749, ECO:0000269|PubMed:9473221, ECO:0000269|PubMed:9722314, ECO:0000269|PubMed:9734640, ECO:0000269|PubMed:9763559, ECO:0000269|PubMed:9920835}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bleeding disorder, platelet-type 16 (BDPLT16) [MIM:187800]: An autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities. {ECO:0000269|PubMed:21454453, ECO:0000269|PubMed:9834222}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha- IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface. | Integrin alpha-IIb antagonist: Tirofiban | 15.1 | ||
| kccITA4 | Integrin alpha-4 | 8 | 170 | 97.88 | ND | 97.47 | 0.86 | ND | 0.4 | Mammalian | Membrane receptor | Not Available | Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are also receptors for VCAM1. Integrin alpha- 4/beta-1 recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha- 4/beta-7 is also a receptor for MADCAM1. It recognizes the sequence L-D-T in MADCAM1. On activated endothelial cells integrin VLA-4 triggers homotypic aggregation for most VLA-4-positive leukocyte cell lines. It may also participate in cytolytic T-cell interactions with target cells. {ECO:0000269|PubMed:19064666}. | Integrin alpha-4/beta-7 inhibitor: Natalizumab | 15.1 | |||
| kccITAL | Integrin alpha-L | 6 | 138 | 99.03 | ND | 99.98 | 0.67 | ND | 0.7 | Mammalian | Leukocytes. | Membrane receptor | Inflammatory diseases | Integrin alpha-L/beta-2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. It is involved in a variety of immune phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell mediated killing, and antibody dependent killing by granulocytes and monocytes. | Integrin alpha-L other/unknown: Lovastatin | 15.1 | ||
| kccITAV | Integrin alpha-V | 3 | 55 | 99.35 | ND | 99.99 | 0.75 | ND | 0.6 | Mammalian | Membrane receptor | Brain tumors | The alpha-V (ITGAV) integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. (Microbial infection) Integrin ITGAV:ITGB5 acts as a receptor for adenovirus type C (PubMed:20615244). Integrin ITGAV:ITGB5 and ITGAV:ITGB3 act as receptors for coxsackievirus A9 and B1 (PubMed:9426447, PubMed:15194773, PubMed:7519807). Integrin ITGAV:ITGB3 acts as a receptor for herpes virus 8/HHV-8 (PubMed:18045938). Integrin ITGAV:ITGB6 acts as a receptor for herpes simplex 1/HHV-1 (PubMed:24367260). Integrin ITGAV:ITGB3 acts as a receptor for Human parechovirus 1 (PubMed:11160695). Integrin ITGAV:ITGB3 acts as a receptor for West nile virus (PubMed:23658209). In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions (PubMed:10397733). {ECO:0000269|PubMed:10397733, ECO:0000269|PubMed:11160695, ECO:0000269|PubMed:15194773, ECO:0000269|PubMed:18045938, ECO:0000269|PubMed:20615244, ECO:0000269|PubMed:23658209, ECO:0000269|PubMed:24367260, ECO:0000269|PubMed:7519807, ECO:0000269|PubMed:9426447}. | Integrin alpha-V/beta-3 inhibitor: Abciximab | 15.1 | |||
| kccITK | Tyrosine-protein kinase ITK/TSK | 21 | 683 | 98.67 | ND | 96.68 | 0.38 | ND | 1.1 | Mammalian | T-cell lines and natural killer cell lines. | Kinase | Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011]: A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma. {ECO:0000269|PubMed:19425169}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. {ECO:0000269|PubMed:12186560, ECO:0000269|PubMed:12682224, ECO:0000269|PubMed:21725281}. | Tyrosine-protein kinase ITK/TSK inhibitor: Pazopanib | 15.1 | ||
| kccJAK1 | Tyrosine-protein kinase JAK1 | 20 | 482 | 98.65 | ND | 97.44 | 0.69 | ND | 0.8 | Mammalian | Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue. {ECO:0000269|PubMed:7896447}. | Kinase | Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. {ECO:0000269|PubMed:11909529}. | Tyrosine-protein kinase JAK1 inhibitor: Ruxolitinib | 15.1 | |||
| kccJAK2 | Tyrosine-protein kinase JAK2 | 58 | 1284 | 95.73 | ND | 93.15 | 0.52 | ND | 1.1 | Mammalian | Ubiquitously expressed throughout most tissues. {ECO:0000269|PubMed:16424865}. | Kinase | Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Budd-Chiari syndrome (BDCHS) [MIM:600880]: A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. {ECO:0000269|PubMed:16707754}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Polycythemia vera (PV) [MIM:263300]: A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly. {ECO:0000269|PubMed:15781101, ECO:0000269|PubMed:15793561, ECO:0000269|PubMed:15858187, ECO:0000269|PubMed:16603627}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thrombocythemia 3 (THCYT3) [MIM:614521]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. {ECO:0000269|PubMed:16325696, ECO:0000269|PubMed:22397670}. Note=The disease may be caused by mutations affecting the gene represented in this entry. Myelofibrosis (MYELOF) [MIM:254450]: A disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry. Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:16247455}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin. {ECO:0000269|PubMed:12023369, ECO:0000269|PubMed:19783980, ECO:0000269|PubMed:20098430, ECO:0000269|PubMed:21423214}. | Tyrosine-protein kinase JAK2 inhibitor: Ruxolitinib | 15.1 | ||
| kccJAK3 | Tyrosine-protein kinase JAK3 | 37 | 877 | 97.85 | ND | 96.31 | 0.39 | ND | 1.0 | Mammalian | In NK cells and an NK-like cell line but not in resting T-cells or in other tissues. The S-form is more commonly seen in hematopoietic lines, whereas the B-form is detected in cells both of hematopoietic and epithelial origins. {ECO:0000269|PubMed:7535338}. | Kinase | Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:600802]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:10982185, ECO:0000269|PubMed:14615376, ECO:0000269|PubMed:7659163, ECO:0000269|PubMed:9354668, ECO:0000269|PubMed:9753072}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion. {ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:20440074, ECO:0000269|PubMed:7662955, ECO:0000269|PubMed:8022485}. | Tyrosine-protein kinase JAK2 inhibitor: Ruxolitinib | 15.1 | ||
| kccJUN | Transcription factor AP-1 | 4 | 90 | 90.47 | ND | 92.74 | 0.40 | ND | 0.6 | Mammalian | Transcription factor | Allergic airway inflammation
Breast cancer Cancer (multidrug resistant) Cancer, unspecific Melanoma Rheumatoid arthritis Vascular disease | Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'. Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. {ECO:0000269|PubMed:10995748, ECO:0000269|PubMed:17210646}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | |||
| kccKAPCA | cAMP-dependent protein kinase catalytic subunit alpha | 26 | 546 | 94.95 | ND | 90.67 | 0.36 | ND | 1.1 | Mammalian | Isoform 1 is ubiquitous. Isoform 2 is sperm- specific and is enriched in pachytene spermatocytes but is not detected in round spermatids. {ECO:0000269|PubMed:10906071, ECO:0000269|PubMed:21812984}. | Kinase | Primary pigmented nodular adrenocortical disease 4 (PPNAD4) [MIM:615830]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:24571724, ECO:0000269|PubMed:24700472, ECO:0000269|PubMed:24747643, ECO:0000269|PubMed:24855271}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose- mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B- alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha- difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. {ECO:0000269|PubMed:15642694, ECO:0000269|PubMed:15905176, ECO:0000269|PubMed:16387847, ECO:0000269|PubMed:17333334, ECO:0000269|PubMed:17565987, ECO:0000269|PubMed:17693412, ECO:0000269|PubMed:18836454, ECO:0000269|PubMed:19949837, ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:21423175, ECO:0000269|PubMed:21514275, ECO:0000269|PubMed:21812984}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | ||
| kccKAT2B | Histone acetyltransferase KAT2B | 3 | 81 | 94.70 | ND | 99.88 | 0.48 | ND | 0.3 | Mammalian | Ubiquitously expressed but most abundant in heart and skeletal muscle. {ECO:0000269|PubMed:8684459}. | Writer | Functions as a histone acetyltransferase (HAT) to promote transcriptional activation. Has significant histone acetyltransferase activity with core histones (H3 and H4), and also with nucleosome core particles. Also acetylates non-histone proteins, such as ACLY. Inhibits cell-cycle progression and counteracts the mitogenic activity of the adenoviral oncoprotein E1A. In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers. {ECO:0000269|PubMed:10675335, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:23932781, ECO:0000269|PubMed:8684459, ECO:0000269|PubMed:9707565}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | |||
| kccKC1A | Casein kinase I isoform alpha | 20 | 408 | 95.79 | ND | 92.81 | 0.18 | ND | 1.3 | Mammalian | Kinase | Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates CTNNB1 at 'Ser-45'. May phosphorylate PER1 and PER2. May play a role in segregating chromosomes during mitosis. {ECO:0000269|PubMed:11955436, ECO:0000269|PubMed:1409656, ECO:0000269|PubMed:18305108}. | 15.1 | |||||
| kccKC1D | Casein kinase I isoform delta | 33 | 463 | 96.36 | ND | 93.47 | 0.27 | ND | 1.2 | Mammalian | Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. However, kinase activity is not uniform, with highest kinase activity in splenocytes. In blood, highly expressed in hemopoietic cells and mature granulocytes. Also found in monocytes and lymphocytes. {ECO:0000269|PubMed:15070676, ECO:0000269|PubMed:16027726}. | Kinase | Advanced sleep phase syndrome, familial, 2 (FASPS2) [MIM:615224]: A disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. {ECO:0000269|PubMed:15800623, ECO:0000269|PubMed:23636092}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In balance with PP1, determines the circadian period length through the regulation of the speed and rhythmicity of PER1 and PER2 phospohorylation. Controls PER1 and PER2 nuclear transport and degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate. {ECO:0000269|PubMed:10606744, ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16027726, ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:19043076, ECO:0000269|PubMed:19339517, ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20637175, ECO:0000269|PubMed:20696890, ECO:0000269|PubMed:20699359, ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092}. | 15.1 | |||
| kccKC1G1 | Casein kinase I isoform gamma-1 | 11 | 231 | 97.88 | ND | 95.70 | 0.25 | ND | 1.2 | Mammalian | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Regulates fast synaptic transmission mediated by glutamate (By similarity). Phosphorylates CLSPN. {ECO:0000250, ECO:0000269|PubMed:21680713}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | ||||
| kccKC1G2 | Casein kinase I isoform gamma-2 | 18 | 270 | 94.01 | ND | 92.68 | 0.41 | ND | 1.1 | Mammalian | Testis. | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates COL4A3BP/CERT, MTA1 and SMAD3. Involved in brain development and vesicular trafficking and neurotransmitter releasing from small synaptic vesicles. Regulates fast synaptic transmission mediated by glutamate. SMAD3 phosphorylation promotes its ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Hyperphosphorylation of the serine-repeat motif of COL4A3BP/CERT leads to its inactivation by dissociation from the Golgi complex, thus down-regulating ER-to-Golgi transport of ceramide and sphingomyelin synthesis. Triggers PER1 proteasomal degradation probably through phosphorylation. {ECO:0000269|PubMed:15077195, ECO:0000269|PubMed:15342122, ECO:0000269|PubMed:15917222, ECO:0000269|PubMed:18794808, ECO:0000269|PubMed:19005213}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | |||
| kccKC1G3 | Casein kinase I isoform gamma-3 | 15 | 193 | 93.44 | ND | 88.39 | 0.32 | ND | 1.1 | Mammalian | Kinase | Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Regulates fast synaptic transmission mediated by glutamate (By similarity). {ECO:0000250}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | ||||
| kccKCC1A | Calcium/calmodulin-dependent protein kinase type 1 | 7 | 127 | 89.29 | ND | 91.97 | 0.29 | ND | 1.1 | Mammalian | Widely expressed. Expressed in cells of the zona glomerulosa of the adrenal cortex. {ECO:0000269|PubMed:12193581, ECO:0000269|PubMed:17056143}. | Kinase | Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca(2+) elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser- 694', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser-92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser- 498' in the regulation of muscle cell differentiation. Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-276' and 'Ser-295'. Involved in the regulation of basal and estrogen- stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation (By similarity). Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K(+) and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I. {ECO:0000250, ECO:0000269|PubMed:11114197, ECO:0000269|PubMed:12193581, ECO:0000269|PubMed:14507913, ECO:0000269|PubMed:14754892, ECO:0000269|PubMed:17056143, ECO:0000269|PubMed:17442826, ECO:0000269|PubMed:18184567, ECO:0000269|PubMed:20181577}. | 15.1 | ||||
| kccKCC2A | Calcium/calmodulin-dependent protein kinase type II subunit alpha | 3 | 145 | 83.65 | ND | 80.08 | 0.07 | ND | 1.1 | Mammalian | Kinase | CaM-kinase II (CAMK2) is a prominent kinase in the central nervous system that may function in long-term potentiation and neurotransmitter release. Member of the NMDAR signaling complex in excitatory synapses it may regulate NMDAR-dependent potentiation of the AMPAR and synaptic plasticity (By similarity). {ECO:0000250}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | ||||
| kccKCC2B | Calcium/calmodulin-dependent protein kinase type II subunit beta | 10 | 224 | 92.60 | ND | 88.07 | 0.18 | ND | 1.0 | Mammalian | Widely expressed. Expressed in adult and fetal brain. Expression is slightly lower in fetal brain. Expressed in skeletal muscle. {ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic reticulum Ca(2+) transport in skeletal muscle. In neurons, plays an essential structural role in the reorganization of the actin cytoskeleton during plasticity by binding and bundling actin filaments in a kinase-independent manner. This structural function is required for correct targeting of CaMK2A, which acts downstream of NMDAR to promote dendritic spine and synapse formation and maintain synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. In developing hippocampal neurons, promotes arborization of the dendritic tree and in mature neurons, promotes dendritic remodeling. Participates in the modulation of skeletal muscle function in response to exercise. In slow-twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of triadin, a ryanodine receptor-coupling factor, and phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2. {ECO:0000269|PubMed:16690701}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | |||
| kccKCC2D | Calcium/calmodulin-dependent protein kinase type II subunit delta | 19 | 338 | 95.65 | ND | 92.58 | 0.32 | ND | 1.3 | Mammalian | Expressed in cardiac muscle and skeletal muscle. Isoform Delta 3, isoform Delta 2, isoform Delta 8 and isoform Delta 9 are expressed in cardiac muscle. Isoform Delta 11 is expressed in skeletal muscle. {ECO:0000269|PubMed:10189359, ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser- 2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program. Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis. May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor- coupling factor. {ECO:0000269|PubMed:16690701, ECO:0000269|PubMed:17179159}. | Transcription factor AP-1 inducer: Arsenic trioxide Transcription factor AP-1 other/unknown: Irbesartan, Vinblastine Transcription factor AP-1 unknown: Pseudoephedrine | 15.1 | |||
| kccKCC2G | Calcium/calmodulin-dependent protein kinase type II subunit gamma | 10 | 233 | 92.16 | ND | 95.50 | 0.38 | ND | 1.2 | Mammalian | Expressed in skeletal muscle. {ECO:0000269|PubMed:16690701}. | Kinase | Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in sarcoplsamic reticulum Ca(2+) transport in skeletal muscle and may function in dendritic spine and synapse formation and neuronal plasticity. In slow- twitch muscles, is involved in regulation of sarcoplasmic reticulum (SR) Ca(2+) transport and in fast-twitch muscle participates in the control of Ca(2+) release from the SR through phosphorylation of the ryanodine receptor-coupling factor triadin. In neurons, may participate in the promotion of dendritic spine and synapse formation and maintenance of synaptic plasticity which enables long-term potentiation (LTP) and hippocampus-dependent learning. {ECO:0000269|PubMed:16690701}. | Calcium/calmodulin-dependent protein kinase type II subunit gamma inhibitor: Bosutinib | 15.1 | |||
| kccKCJ11 | ATP-sensitive inward rectifier potassium channel 11 | 1 | 43 | 99.98 | ND | 99.99 | 0.20 | ND | 0.6 | Mammalian | Voltage-gated ion channel | Familial hyperinsulinemic hypoglycemia 2 (HHF2) [MIM:601820]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269|PubMed:10204114, ECO:0000269|PubMed:12364426, ECO:0000269|PubMed:15562009, ECO:0000269|PubMed:15579781, ECO:0000269|PubMed:15807877, ECO:0000269|PubMed:15998776, ECO:0000269|PubMed:16332676, ECO:0000269|PubMed:16357843, ECO:0000269|PubMed:18596924, ECO:0000269|PubMed:19357197, ECO:0000269|PubMed:7847376, ECO:0000269|PubMed:8923010}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes mellitus, permanent neonatal (PNDM) [MIM:606176]: A rare form of diabetes distinct from childhood- onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy. {ECO:0000269|PubMed:15115830, ECO:0000269|PubMed:15292329, ECO:0000269|PubMed:15448106, ECO:0000269|PubMed:15448107, ECO:0000269|PubMed:15580558, ECO:0000269|PubMed:16609879, ECO:0000269|PubMed:16731833, ECO:0000269|PubMed:17213273, ECO:0000269|PubMed:17652641, ECO:0000269|PubMed:20022885}. Note=The disease is caused by mutations affecting the gene represented in this entry. Transient neonatal diabetes mellitus 3 (TNDM3) [MIM:610582]: Neonatal diabetes mellitus, defined as insulin- requiring hyperglycemia within the first month of life, is a rare entity. In about half of the neonates, diabetes is transient and resolves at a median age of 3 months, whereas the rest have a permanent form of diabetes. In a significant number of patients with transient neonatal diabetes mellitus, diabetes type 2 appears later in life. The onset and severity of TNDM3 is variable with childhood-onset diabetes, gestational diabetes or adult-onset diabetes described. {ECO:0000269|PubMed:15718250, ECO:0000269|PubMed:15784703}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Defects in KCNJ11 may contribute to non-insulin- dependent diabetes mellitus (NIDDM), also known as diabetes mellitus type 2. Maturity-onset diabetes of the young 13 (MODY13) [MIM:616329]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:22701567}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium (By similarity). Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation. {ECO:0000250, ECO:0000269|PubMed:17855752, ECO:0000269|PubMed:9831708}. | 15.1 | ||||
| kccKCMA1 | Calcium-activated potassium channel subunit alpha-1 | 5 | 85 | 98.04 | ND | 93.73 | 0.07 | ND | 1.3 | Mammalian | Widely expressed. Except in myocytes, it is almost ubiquitously expressed. {ECO:0000269|PubMed:11880513}. | Voltage-gated ion channel | Generalized epilepsy and paroxysmal dyskinesia (GEPD) [MIM:609446]: Epilepsy is one of the most common and debilitating neurological disorders. Paroxysmal dyskinesias are neurological disorders characterized by sudden, unpredictable, disabling attacks of involuntary movement often requiring life-long treatment. The coexistence of epilepsy and paroxysmal dyskinesia in the same individual or family is an increasingly recognized phenomenon. Patients manifest absence seizures, generalized tonic- clonic seizures, paroxysmal nonkinesigenic dyskinesia, involuntary dystonic or choreiform movements. Onset is usually in childhood and patients may have seizures only, dyskinesia only, or both. {ECO:0000269|PubMed:15937479}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX). | Calcium-activated potassium channel subunit alpha-1 binder: Procaine Calcium-activated potassium channel subunit alpha-1 inducer: Bendroflumethiazide Calcium-activated potassium channel subunit alpha-1 inhibitor: Cromoglicic acid, Halothane, Miconazole Calcium-activated potassium channel subunit alpha-1 other: Diazoxide Calcium-activated potassium channel subunit alpha-1 other/unknown: Hydrochlorothiazide, Hydroflumethiazide Calcium-activated potassium channel subunit alpha-1 unknown: Chlorzoxazone | 15.1 | ||
| kccKCNA3 | Potassium voltage-gated channel subfamily A member 3 | 12 | 353 | 97.66 | ND | 98.38 | 0.48 | ND | 0.5 | Mammalian | Voltage-gated ion channel | Autoimmune diseases
Immunosuppression Multiple Sclerosis T cell-mediated autoimmune diseases | Mediates the voltage-dependent potassium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a potassium-selective channel through which potassium ions may pass in accordance with their electrochemical gradient. | Potassium voltage-gated channel subfamily A member 3 antagonist: Dalfampridine | 15.1 | |||
| kccKCNA5 | Potassium voltage-gated channel subfamily A member 5 | 34 | 479 | 98.99 | ND | 97.75 | 0.27 | ND | 0.6 | Mammalian | Pancreatic islets and insulinoma. | Voltage-gated ion channel | Atrial fibrillation, familial, 7 (ATFB7) [MIM:612240]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:16772329}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:8505626, PubMed:12130714). May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform 2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation (PubMed:11524461). {ECO:0000269|PubMed:11524461, ECO:0000269|PubMed:12130714, ECO:0000269|PubMed:8505626}. | Potassium voltage-gated channel subfamily A member 5 antagonist: Dalfampridine | 15.1 | ||
| kccKCNH2 | Potassium voltage-gated channel subfamily H member 2 | 177 | 5619 | 87.10 | ND | 88.86 | 0.48 | ND | 0.7 | Nature11159 VirtualToxLab | Mammalian | Highly expressed in heart and brain. Isoforms USO are frequently overexpressed in cancer cells. {ECO:0000269|PubMed:18559421}. | Electrocardiogram QT prolonged | Voltage-gated ion channel | Long QT syndrome 2 (LQT2) [MIM:613688]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. Deafness is often associated with long QT syndrome type 2. {ECO:0000269|PubMed:10086971, ECO:0000269|PubMed:10187793, ECO:0000269|PubMed:10220144, ECO:0000269|PubMed:10517660, ECO:0000269|PubMed:10735633, ECO:0000269|PubMed:10862094, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:12062363, ECO:0000269|PubMed:12354768, ECO:0000269|PubMed:12621127, ECO:0000269|PubMed:15051636, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:16922724, ECO:0000269|PubMed:22314138, ECO:0000269|PubMed:7889573, ECO:0000269|PubMed:8635257, ECO:0000269|PubMed:8877771, ECO:0000269|PubMed:8914737, ECO:0000269|PubMed:9024139, ECO:0000269|PubMed:9452080, ECO:0000269|PubMed:9544837, ECO:0000269|PubMed:9600240, ECO:0000269|PubMed:9693036}. Note=The disease is caused by mutations affecting the gene represented in this entry. Short QT syndrome 1 (SQT1) [MIM:609620]: A heart disorder characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. It causes syncope and sudden death. {ECO:0000269|PubMed:14676148, ECO:0000269|PubMed:15828882}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation. {ECO:0000269|PubMed:18559421}. | Potassium voltage-gated channel subfamily H member 2 inhibitor: Amiodarone, Amsacrine, Astemizole, Carvedilol, Cisapride, Dofetilide, Doxazosin, Halofantrine, Ibutilide, Imipramine, Miconazole, Pimozide, Prazosin, Propafenone, Quinidine, Sertindole, Sotalol, Terazosin, Thioridazine, Verapamil Potassium voltage-gated channel subfamily H member 2 unknown: Alfuzosin, Chlorpromazine, Ciprofloxacin, Clarithromycin, Doxepin, Dronedarone, Erythromycin | 15.1 |
| kccKCNJ1 | ATP-sensitive inward rectifier potassium channel 1 | 2 | 58 | 99.97 | ND | 99.96 | 0.14 | ND | 0.4 | Mammalian | In the kidney and pancreatic islets. Lower levels in skeletal muscle, pancreas, spleen, brain, heart and liver. {ECO:0000269|PubMed:7635463}. | Voltage-gated ion channel | Bartter syndrome 2 (BS2) [MIM:241200]: An autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. Bartter syndrome type 2 is a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia. {ECO:0000269|PubMed:8841184, ECO:0000269|PubMed:9002665, ECO:0000269|PubMed:9727001}. Note=The disease is caused by mutations affecting the gene represented in this entry. | In the kidney, probably plays a major role in potassium homeostasis. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This channel is activated by internal ATP and can be blocked by external barium. | 15.1 | |||
| kccKCNN3 | Small conductance calcium-activated potassium channel protein 3 | 5 | 125 | 99.91 | ND | 99.93 | 0.77 | ND | 0.5 | Mammalian | Voltage-gated ion channel | Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. The channel is blocked by apamin. | Small conductance calcium-activated potassium channel protein 3 binder: Procaine Small conductance calcium-activated potassium channel protein 3 inhibitor: Miconazole | 15.1 | ||||
| kccKCNN4 | Intermediate conductance calcium-activated potassium channel protein 4 | 2 | 52 | 84.48 | ND | 99.87 | 0.83 | ND | 0.5 | Mammalian | Widely expressed in non-excitable tissues. | Voltage-gated ion channel | Forms a voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization which promotes calcium influx. Required for maximal calcium influx and proliferation during the reactivation of naive T-cells. The channel is blocked by clotrimazole and charybdotoxin but is insensitive to apamin. {ECO:0000269|PubMed:17157250, ECO:0000269|PubMed:18796614}. | Intermediate conductance calcium-activated potassium channel protein 4 binder: Procaine Intermediate conductance calcium-activated potassium channel protein 4 inhibitor: Clotrimazole, Enflurane, Halothane, Miconazole, Quinine | 15.1 | |||
| kccKCNQ1 | Potassium voltage-gated channel subfamily KQT member 1 | 4 | 94 | 97.87 | ND | 99.92 | 0.47 | ND | 0.9 | Mammalian | Abundantly expressed in heart, pancreas, prostate, kidney, small intestine and peripheral blood leukocytes. Less abundant in placenta, lung, spleen, colon, thymus, testis and ovaries. | Voltage-gated ion channel | Long QT syndrome 1 (LQT1) [MIM:192500]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:10024302, ECO:0000269|PubMed:10220144, ECO:0000269|PubMed:10220146, ECO:0000269|PubMed:10367071, ECO:0000269|PubMed:10482963, ECO:0000269|PubMed:10728423, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:19540844, ECO:0000269|PubMed:21241800, ECO:0000269|PubMed:8528244, ECO:0000269|PubMed:8818942, ECO:0000269|PubMed:8872472, ECO:0000269|PubMed:9024139, ECO:0000269|PubMed:9272155, ECO:0000269|PubMed:9302275, ECO:0000269|PubMed:9386136, ECO:0000269|PubMed:9482580, ECO:0000269|PubMed:9570196, ECO:0000269|PubMed:9641694, ECO:0000269|PubMed:9693036, ECO:0000269|PubMed:9702906, ECO:0000269|PubMed:9799083, ECO:0000269|PubMed:9927399, ECO:0000269|Ref.22}. Note=The disease is caused by mutations affecting the gene represented in this entry. Jervell and Lange-Nielsen syndrome 1 (JLNS1) [MIM:220400]: An autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death. {ECO:0000269|PubMed:10090886, ECO:0000269|PubMed:10728423, ECO:0000269|PubMed:9781056}. Note=The disease is caused by mutations affecting the gene represented in this entry. Atrial fibrillation, familial, 3 (ATFB3) [MIM:607554]: An autosomal dominant form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:12522251}. Note=The disease is caused by mutations affecting the gene represented in this entry. Short QT syndrome 2 (SQT2) [MIM:609621]: A heart disorder characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. It causes syncope and sudden death. {ECO:0000269|PubMed:15159330}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:18711366, ECO:0000269|PubMed:18711367, ECO:0000269|PubMed:24390345}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Probably important in cardiac repolarization. Associates with KCNE1 (MinK) to form the I(Ks) cardiac potassium current. Elicits a rapidly activating, potassium-selective outward current. Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current in CHO cells in which cloned KCNQ1/KCNE1 channels were coexpressed with M1 muscarinic receptors. May associate also with KCNE3 (MiRP2) to form the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions, which is reduced in cystic fibrosis and pathologically stimulated in cholera and other forms of secretory diarrhea. | Potassium voltage-gated channel subfamily KQT member 1 inhibitor: Bepridil, Indapamide | 15.1 | ||
| kccKCNQ2 | Potassium voltage-gated channel subfamily KQT member 2 | 8 | 174 | 94.70 | ND | 93.19 | 0.01 | ND | 1.2 | Mammalian | In adult and fetal brain. Highly expressed in areas containing neuronal cell bodies, low in spinal chord and corpus callosum. Isoform 2 is preferentially expressed in differentiated neurons. Isoform 6 is prominent in fetal brain, undifferentiated neuroblastoma cells and brain tumors. {ECO:0000269|PubMed:10781098}. | Voltage-gated ion channel | Seizures, benign familial neonatal 1 (BFNS1) [MIM:121200]: A disorder characterized by clusters of seizures occurring in the first days of life. Most patients have spontaneous remission by 12 months of age and show normal psychomotor development. Some rare cases manifest an atypical severe phenotype associated with epileptic encephalopathy and psychomotor retardation. The disorder is distinguished from benign familial infantile seizures by an earlier age at onset. In some patients, neonatal convulsions are followed later in life by myokymia, a benign condition characterized by spontaneous involuntary contractions of skeletal muscles fiber groups that can be observed as vermiform movement of the overlying skin. Electromyography typically shows continuous motor unit activity with spontaneous oligo- and multiplet-discharges of high intraburst frequency (myokymic discharges). Some patients may have isolated myokymia. {ECO:0000269|PubMed:11175290, ECO:0000269|PubMed:11572947, ECO:0000269|PubMed:14534157, ECO:0000269|PubMed:15249611, ECO:0000269|PubMed:9425895}. Note=The disease is caused by mutations affecting the gene represented in this entry. Epileptic encephalopathy, early infantile, 7 (EIEE7) [MIM:613720]: An autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. {ECO:0000269|PubMed:12742592, ECO:0000269|PubMed:15249611}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Probably important in the regulation of neuronal excitability. Associates with KCNQ3 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. KCNQ2/KCNQ3 current is blocked by linopirdine and XE991, and activated by the anticonvulsant retigabine. Muscarinic agonist oxotremorine-M strongly suppress KCNQ2/KCNQ3 current in cells in which cloned KCNQ2/KCNQ3 channels were coexpressed with M1 muscarinic receptors. | Potassium voltage-gated channel subfamily KQT member 2 inhibitor: Amitriptyline Potassium voltage-gated channel subfamily KQT member 2 other: Diclofenac, Meclofenamic acid Potassium voltage-gated channel subfamily KQT member 2 unknown: Ezogabine | 15.1 | ||
| kccKDM1A | Lysine-specific histone demethylase 1A | 7 | 145 | 89.22 | ND | 91.21 | 0.73 | ND | 0.4 | Mammalian | Ubiquitously expressed. {ECO:0000269|PubMed:16079795}. | Eraser | Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr- 6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Effector of SNAI1-mediated transcription repression of E- cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7. {ECO:0000269|PubMed:12032298, ECO:0000269|PubMed:15620353, ECO:0000269|PubMed:16079795, ECO:0000269|PubMed:17805299, ECO:0000269|PubMed:20228790, ECO:0000269|PubMed:20562920}. | 15.1 | ||||
| kccKGP1 | cGMP-dependent protein kinase 1 | 10 | 192 | 93.43 | ND | 93.17 | 0.37 | ND | 1.3 | Mammalian | Primarily expressed in lung and placenta. {ECO:0000269|PubMed:9192852}. | Kinase | Aortic aneurysm, familial thoracic 8 (AAT8) [MIM:615436]: A disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance. {ECO:0000269|PubMed:23910461}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine protein kinase that acts as key mediator of the nitric oxide (NO)/cGMP signaling pathway. GMP binding activates PRKG1, which phosphorylates serines and threonines on many cellular proteins. Numerous protein targets for PRKG1 phosphorylation are implicated in modulating cellular calcium, but the contribution of each of these targets may vary substantially among cell types. Proteins that are phosphorylated by PRKG1 regulate platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes involved in several aspects of the CNS like axon guidance, hippocampal and cerebellar learning, circadian rhythm and nociception. Smooth muscle relaxation is mediated through lowering of intracellular free calcium, by desensitization of contractile proteins to calcium, and by decrease in the contractile state of smooth muscle or in platelet activation. Regulates intracellular calcium levels via several pathways: phosphorylates MRVI1/IRAG and inhibits IP3- induced Ca(2+) release from intracellular stores, phosphorylation of KCNMA1 (BKCa) channels decreases intracellular Ca(2+) levels, which leads to increased opening of this channel. PRKG1 phosphorylates the canonical transient receptor potential channel (TRPC) family which inactivates the associated inward calcium current. Another mode of action of NO/cGMP/PKGI signaling involves PKGI-mediated inactivation of the Ras homolog gene family member A (RhoA). Phosphorylation of RHOA by PRKG1 blocks the action of this protein in myriad processes: regulation of RHOA translocation; decreasing contraction; controlling vesicle trafficking, reduction of myosin light chain phosphorylation resulting in vasorelaxation. Activation of PRKG1 by NO signaling alters also gene expression in a number of tissues. In smooth muscle cells, increased cGMP and PRKG1 activity influence expression of smooth muscle-specific contractile proteins, levels of proteins in the NO/cGMP signaling pathway, down-regulation of the matrix proteins osteopontin and thrombospondin-1 to limit smooth muscle cell migration and phenotype. Regulates vasodilator-stimulated phosphoprotein (VASP) functions in platelets and smooth muscle. {ECO:0000269|PubMed:10567269, ECO:0000269|PubMed:11162591, ECO:0000269|PubMed:11723116, ECO:0000269|PubMed:12082086, ECO:0000269|PubMed:14608379, ECO:0000269|PubMed:15194681, ECO:0000269|PubMed:16990611, ECO:0000269|PubMed:8182057}. | 15.1 | |||
| kccKGP2 | cGMP-dependent protein kinase 2 | 6 | 131 | 92.43 | ND | 90.54 | 0.48 | ND | 1.4 | Mammalian | Highly concentrated in brain, lung and intestinal mucosa. | Kinase | 15.1 | |||||
| kccKHK | Ketohexokinase {ECO:0000312|HGNC:HGNC:6315} | 3 | 85 | 99.94 | ND | 99.98 | 0.36 | ND | 0.5 | Mammalian | Most abundant in liver, kidney, gut, spleen and pancreas. Low levels also found in adrenal, muscle, brain and eye. {ECO:0000269|PubMed:9799106}. | Enzyme | Fructosuria (FRUCT) [MIM:229800]: Benign defect of intermediary metabolism. {ECO:0000269|PubMed:12941785, ECO:0000269|PubMed:7833921}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate. {ECO:0000269|PubMed:12941785}. | 15.1 | |||
| kccKIF11 | Kinesin-like protein KIF11 | 33 | 758 | 98.56 | ND | 99.31 | 0.57 | ND | 0.7 | Mammalian | Other cytosolic protein | Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:152950]: An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes. {ECO:0000269|PubMed:22284827}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays. {ECO:0000269|PubMed:19001501}. | Potassium voltage-gated channel subfamily KQT member 2 inhibitor: Amitriptyline Potassium voltage-gated channel subfamily KQT member 2 other: Diclofenac, Meclofenamic acid Potassium voltage-gated channel subfamily KQT member 2 unknown: Ezogabine | 15.1 | |||
| kccKISSR | KiSS-1 receptor | 2 | 158 | 99.97 | ND | 99.97 | 0.73 | ND | 0.6 | Mammalian | Most highly expressed in the pancreas, placenta and spinal cord, with lower-level of expression in peripheral blood leukocytes, kidney, lung, fetal liver, stomach, small intestine, testes, spleen, thymus, adrenal glands and lymph nodes. In the adult brain, expressed in the superior frontal gyrus, putamen, caudate nucleus, cingulate gyrus, nucleus accumbens, hippocampus, pons and amygdala, as well as the hypothalamus and pituitary. Expression levels are higher in early (7-9 weeks) than term placentas. Expression levels were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells. Expressed at higher levels in first trimester trophoblasts than at term of gestation. Also found in the extravillous trophoblast suggesting endocrine/paracrine activation mechanism. {ECO:0000269|PubMed:11385580, ECO:0000269|PubMed:11387329, ECO:0000269|PubMed:11414709, ECO:0000269|PubMed:11457843, ECO:0000269|PubMed:12414911, ECO:0000269|PubMed:15020672}. | Family A G protein-coupled receptor | Hypogonadotropic hypogonadism 8 with or without anosmia (HH8) [MIM:614837]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:12944565, ECO:0000269|PubMed:14573733, ECO:0000269|PubMed:15598687, ECO:0000269|PubMed:17164310, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in KISS1R as well as in other HH- associated genes including FGFR1 and IL17RD (PubMed:23643382). {ECO:0000269|PubMed:23643382}. Precocious puberty, central 1 (CPPB1) [MIM:176400]: A condition defined as the development of secondary sexual characteristics in boys and girls at a chronological age that is 2.5 standard deviations below the mean age at onset of puberty in the population. Central precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis. {ECO:0000269|PubMed:18272894}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for metastin (kisspeptin-54 or kp-54), a C- terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein that suppresses metastases in malignant melanomas and in some breast carcinomas without affecting tumorigenicity. The metastasis suppressor properties may be mediated in part by cell cycle arrest and induction of apoptosis in malignant cells. The receptor is essential for normal gonadotropin-released hormone physiology and for puberty. The hypothalamic KiSS1/KISS1R system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood. The receptor is also probably involved in the regulation and fine- tuning of trophoblast invasion generated by the trophoblast itself. Analysis of the transduction pathways activated by the receptor identifies coupling to phospholipase C and intracellular calcium release through pertussis toxin-insensitive G(q) proteins. {ECO:0000269|PubMed:15020672}. | 15.1 | |||
| kccKIT | Mast/stem cell growth factor receptor Kit | 42 | 807 | 98.45 | ND | 95.69 | 0.33 | ND | 1.2 | Mammalian | Isoform 1 and isoform 2 are detected in spermatogonia and Leydig cells. Isoform 3 is detected in round spermatids, elongating spermatids and spermatozoa (at protein level). Widely expressed. Detected in the hematopoietic system, the gastrointestinal system, in melanocytes and in germ cells. {ECO:0000269|PubMed:20601678, ECO:0000269|PubMed:2448137}. | Kinase | Piebald trait (PBT) [MIM:172800]: Autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. {ECO:0000269|PubMed:11074500, ECO:0000269|PubMed:1370874, ECO:0000269|PubMed:1376329, ECO:0000269|PubMed:1717985, ECO:0000269|PubMed:7687267, ECO:0000269|PubMed:8680409, ECO:0000269|PubMed:9450866, ECO:0000269|PubMed:9699740}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gastrointestinal stromal tumor (GIST) [MIM:606764]: Common mesenchymal neoplasms arising in the gastrointestinal tract, most often in the stomach. They are histologically, immunohistochemically, and genetically different from typical leiomyomas, leiomyosarcomas, and schwannomas. Most GISTs are composed of a fairly uniform population of spindle-shaped cells. Some tumors are dominated by epithelioid cells or contain a mixture of spindle and epithelioid morphologies. Primary GISTs in the gastrointestinal tract commonly metastasize in the omentum and mesenteries, often as multiple nodules. However, primary tumors may also occur outside of the gastrointestinal tract, in other intra-abdominal locations, especially in the omentum and mesentery. {ECO:0000269|PubMed:11505412, ECO:0000269|PubMed:15824741, ECO:0000269|PubMed:9438854, ECO:0000269|PubMed:9697690}. Note=The gene represented in this entry is involved in disease pathogenesis. Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. Note=The gene represented in this entry may be involved in disease pathogenesis. Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. Note=The gene represented in this entry is involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase. | Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1. {ECO:0000269|PubMed:10397721, ECO:0000269|PubMed:12444928, ECO:0000269|PubMed:12511554, ECO:0000269|PubMed:12878163, ECO:0000269|PubMed:17904548, ECO:0000269|PubMed:19265199, ECO:0000269|PubMed:21135090, ECO:0000269|PubMed:21640708, ECO:0000269|PubMed:7520444, ECO:0000269|PubMed:9528781}. | Mast/stem cell growth factor receptor Kit Inhibitor: Lenvatinib Mast/stem cell growth factor receptor Kit antagonist: Dasatinib, Nilotinib, Sorafenib, Sunitinib Mast/stem cell growth factor receptor Kit antagonist;multitarget: Imatinib Mast/stem cell growth factor receptor Kit inhibitor: Pazopanib, Ponatinib, Regorafenib | 15.1 | ||
| kccKITH | Thymidine kinase, cytosolic | 3 | 93 | 98.82 | ND | 99.28 | 0.19 | ND | 0.4 | Mammalian | Enzyme | Thymidine kinase, cytosolic substrate: Trifluridine, Zidovudine | 15.1 | |||||
| kccKKCC1 | Calcium/calmodulin-dependent protein kinase kinase 1 | 1 | 66 | 80.02 | ND | 97.29 | 0.07 | ND | 0.7 | Mammalian | Kinase | Calcium/calmodulin-dependent protein kinase that belongs to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1, CAMK1D, CAMK1G and CAMK4. Involved in regulating cell apoptosis. Promotes cell survival by phosphorylating AKT1/PKB that inhibits pro-apoptotic BAD/Bcl2-antagonist of cell death. {ECO:0000269|PubMed:12935886}. | 15.1 | |||||
| kccKLK | Kallikrein-10 | 2 | 59 | 99.68 | ND | 91.58 | 0.47 | ND | 0.4 | Mammalian | Expressed in breast, ovary and prostate. | Has a tumor-suppressor role for NES1 in breast and prostate cancer. | 15.1 | |||||
| kccKLK1 | Kallikrein-1 | 5 | 102 | 96.32 | ND | 99.93 | 0.68 | ND | 0.6 | Mammalian | Isoform 2 is expressed in pancreas, salivary glands, kidney, colon, prostate gland, testis, spleen and the colon adenocarcinoma cell line T84. {ECO:0000269|PubMed:7749372}. | Protease | Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin. | 15.1 | ||||
| kccKLK3 | Prostate-specific antigen | 2 | 55 | 91.18 | ND | 94.31 | 0.42 | ND | 0.3 | Mammalian | Protease | Prostate cancer | Hydrolyzes semenogelin-1 thus leading to the liquefaction of the seminal coagulum. | 15.1 | ||||
| kccKLKB1 | Plasma kallikrein | 9 | 164 | 93.95 | ND | 97.87 | 0.57 | ND | 0.8 | Mammalian | Protease | Prekallikrein deficiency (PKK deficiency) [MIM:612423]: This disorder is a blood coagulation defect. {ECO:0000269|PubMed:14652634, ECO:0000269|PubMed:17598838}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. | Plasma kallikrein inhibitor: Aprotinin, Ecallantide | 15.1 | |||
| kccKMO | Kynurenine 3-monooxygenase {ECO:0000255|HAMAP-Rule:MF_03018} | 4 | 54 | 99.97 | ND | 99.97 | 0.03 | ND | 0.7 | Mammalian | Highest levels in placenta and liver. Detectable in kidney. {ECO:0000269|PubMed:9237672}. | Enzyme | Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid, a neurotoxic NMDA receptor antagonist and potential endogenous inhibitor of NMDA receptor signaling in axonal targeting, synaptogenesis and apoptosis during brain development. Quinolinic acid may also affect NMDA receptor signaling in pancreatic beta cells, osteoblasts, myocardial cells, and the gastrointestinal tract. | 15.1 | ||||
| kccKPCA | Protein kinase C alpha type | 6 | 945 | 93.08 | ND | 97.34 | 0.67 | ND | 0.8 | Mammalian | Kinase | Leukemia, unspecified
Prostate cancer | Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation, migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activating signaling cascade involving MAPK1/3 (ERK1/2) and RAP1GAP. Involved in cell proliferation and cell growth arrest by positive and negative regulation of the cell cycle. Can promote cell growth by phosphorylating and activating RAF1, which mediates the activation of the MAPK/ERK signaling cascade, and/or by up-regulating CDKN1A, which facilitates active cyclin-dependent kinase (CDK) complex formation in glioma cells. In intestinal cells stimulated by the phorbol ester PMA, can trigger a cell cycle arrest program which is associated with the accumulation of the hyper-phosphorylated growth-suppressive form of RB1 and induction of the CDK inhibitors CDKN1A and CDKN1B. Exhibits anti-apoptotic function in glioma cells and protects them from apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, and in leukemia cells mediates anti-apoptotic action by phosphorylating BCL2. During macrophage differentiation induced by macrophage colony-stimulating factor (CSF1), is translocated to the nucleus and is associated with macrophage development. After wounding, translocates from focal contacts to lamellipodia and participates in the modulation of desmosomal adhesion. Plays a role in cell motility by phosphorylating CSPG4, which induces association of CSPG4 with extensive lamellipodia at the cell periphery and polarization of the cell accompanied by increases in cell motility. Is highly expressed in a number of cancer cells where it can act as a tumor promoter and is implicated in malignant phenotypes of several tumors such as gliomas and breast cancers. Negatively regulates myocardial contractility and positively regulates angiogenesis, platelet aggregation and thrombus formation in arteries. Mediates hypertrophic growth of neonatal cardiomyocytes, in part through a MAPK1/3 (ERK1/2)- dependent signaling pathway, and upon PMA treatment, is required to induce cardiomyocyte hypertrophy up to heart failure and death, by increasing protein synthesis, protein-DNA ratio and cell surface area. Regulates cardiomyocyte function by phosphorylating cardiac troponin T (TNNT2/CTNT), which induces significant reduction in actomyosin ATPase activity, myofilament calcium sensitivity and myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation of kinase activation and vascular tube formation. Involved in the stabilization of VEGFA mRNA at post-transcriptional level and mediates VEGFA-induced cell proliferation. In the regulation of calcium-induced platelet aggregation, mediates signals from the CD36/GP4 receptor for granule release, and activates the integrin heterodimer ITGA2B- ITGB3 through the RAP1GAP pathway for adhesion. During response to lipopolysaccharides (LPS), may regulate selective LPS-induced macrophage functions involved in host defense and inflammation. But in some inflammatory responses, may negatively regulate NF- kappa-B-induced genes, through IL1A-dependent induction of NF- kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O- tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which modulates EIF4G1 binding to MKNK1 and may be involved in the regulation of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of KIT activity. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. {ECO:0000269|PubMed:10848585, ECO:0000269|PubMed:11909826, ECO:0000269|PubMed:12724315, ECO:0000269|PubMed:12832403, ECO:0000269|PubMed:15016832, ECO:0000269|PubMed:15504744, ECO:0000269|PubMed:15526160, ECO:0000269|PubMed:18056764, ECO:0000269|PubMed:19176525, ECO:0000269|PubMed:21576361, ECO:0000269|PubMed:23990668, ECO:0000269|PubMed:9738012, ECO:0000269|PubMed:9830023, ECO:0000269|PubMed:9873035, ECO:0000269|PubMed:9927633}. | Protein kinase C alpha type ligand: Ingenol Mebutate Protein kinase C alpha type unknown: Phosphatidylserine, Tamoxifen, Vitamin E | 15.1 | |||
| kccKPCB | Protein kinase C beta type | 18 | 353 | 98.73 | ND | 99.82 | 0.70 | ND | 0.7 | Mammalian | Kinase | B-lineage malignancies
Diabetes mellitus Diabetic retinopathy Macular edema | Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosome, oxidative stress-induced apoptosis, androgen receptor-dependent transcription regulation, insulin signaling and endothelial cells proliferation. Plays a key role in B-cell activation by regulating BCR-induced NF-kappa-B activation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11/CARMA1 at 'Ser-559', 'Ser-644' and 'Ser-652'. Phosphorylation induces CARD11/CARMA1 association with lipid rafts and recruitment of the BCL10-MALT1 complex as well as MAP3K7/TAK1, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. Plays a direct role in the negative feedback regulation of the BCR signaling, by down-modulating BTK function via direct phosphorylation of BTK at 'Ser-180', which results in the alteration of BTK plasma membrane localization and in turn inhibition of BTK activity. Involved in apoptosis following oxidative damage: in case of oxidative conditions, specifically phosphorylates 'Ser-36' of isoform p66Shc of SHC1, leading to mitochondrial accumulation of p66Shc, where p66Shc acts as a reactive oxygen species producer. Acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag for epigenetic transcriptional activation that prevents demethylation of histone H3 'Lys-4' (H3K4me) by LSD1/KDM1A. In insulin signaling, may function downstream of IRS1 in muscle cells and mediate insulin-dependent DNA synthesis through the RAF1- MAPK/ERK signaling cascade. May participate in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. Under high glucose in pancreatic beta-cells, is probably involved in the inhibition of the insulin gene transcription, via regulation of MYC expression. In endothelial cells, activation of PRKCB induces increased phosphorylation of RB1, increased VEGFA-induced cell proliferation, and inhibits PI3K/AKT-dependent nitric oxide synthase (NOS3/eNOS) regulation by insulin, which causes endothelial dysfunction. Also involved in triglyceride homeostasis (By similarity). Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. {ECO:0000250, ECO:0000269|PubMed:11598012, ECO:0000269|PubMed:19176525, ECO:0000269|PubMed:20228790}. | Protein kinase C beta type unknown: Tamoxifen, Vitamin E | 15.1 | |||
| kccKPCD | Protein kinase C delta type | 32 | 785 | 94.50 | ND | 95.59 | 0.52 | ND | 1.0 | Mammalian | Kinase | Autoimmune lymphoproliferative syndrome 3 (ALPS3) [MIM:615559]: A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. CVID9 patients have B-cell deficiency and severe autoimmunity. {ECO:0000269|PubMed:23319571}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor- initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Negatively regulates B cell proliferation and also has an important function in self- antigen induced B cell tolerance induction. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53. In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)- induced inhibition of cell cycle progression at G1/S phase by up- regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1. Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro- survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl- phenylalanine (fMLP)-treated cells, is required for NCF1 (p47- phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways. May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation. Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release. Phosphorylates MUC1 in the C- terminal and regulates the interaction between MUC1 and beta- catenin. The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (By similarity). {ECO:0000250}. | Protein kinase C delta type ligand: Ingenol Mebutate Protein kinase C delta type unknown: Tamoxifen | 15.1 | |||
| kccKPCD1 | Serine/threonine-protein kinase D1 | 7 | 154 | 98.37 | ND | 97.44 | 0.60 | ND | 1.3 | Mammalian | Kinase | Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and trafficking, cell survival through NF-kappa-B activation, cell migration, cell differentiation by mediating HDAC7 nuclear export, cell proliferation via MAPK1/3 (ERK1/2) signaling, and plays a role in cardiac hypertrophy, VEGFA-induced angiogenesis, genotoxic-induced apoptosis and flagellin-stimulated inflammatory response. Phosphorylates the epidermal growth factor receptor (EGFR) on dual threonine residues, which leads to the suppression of epidermal growth factor (EGF)-induced MAPK8/JNK1 activation and subsequent JUN phosphorylation. Phosphorylates RIN1, inducing RIN1 binding to 14-3-3 proteins YWHAB, YWHAE and YWHAZ and increased competition with RAF1 for binding to GTP-bound form of Ras proteins (NRAS, HRAS and KRAS). Acts downstream of the heterotrimeric G-protein beta/gamma-subunit complex to maintain the structural integrity of the Golgi membranes, and is required for protein transport along the secretory pathway. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane. May act by activating the lipid kinase phosphatidylinositol 4-kinase beta (PI4KB) at the TGN for the local synthesis of phosphorylated inositol lipids, which induces a sequential production of DAG, phosphatidic acid (PA) and lyso-PA (LPA) that are necessary for membrane fission and generation of specific transport carriers to the cell surface. Under oxidative stress, is phosphorylated at Tyr-463 via SRC-ABL1 and contributes to cell survival by activating IKK complex and subsequent nuclear translocation and activation of NFKB1. Involved in cell migration by regulating integrin alpha-5/beta-3 recycling and promoting its recruitment in newly forming focal adhesion. In osteoblast differentiation, mediates the bone morphogenic protein 2 (BMP2)- induced nuclear export of HDAC7, which results in the inhibition of HDAC7 transcriptional repression of RUNX2. In neurons, plays an important role in neuronal polarity by regulating the biogenesis of TGN-derived dendritic vesicles, and is involved in the maintenance of dendritic arborization and Golgi structure in hippocampal cells. May potentiate mitogenesis induced by the neuropeptide bombesin or vasopressin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. Plays an important role in the proliferative response induced by low calcium in keratinocytes, through sustained activation of MAPK1/3 (ERK1/2) pathway. Downstream of novel PKC signaling, plays a role in cardiac hypertrophy by phosphorylating HDAC5, which in turn triggers XPO1/CRM1-dependent nuclear export of HDAC5, MEF2A transcriptional activation and induction of downstream target genes that promote myocyte hypertrophy and pathological cardiac remodeling. Mediates cardiac troponin I (TNNI3) phosphorylation at the PKA sites, which results in reduced myofilament calcium sensitivity, and accelerated crossbridge cycling kinetics. The PRKD1-HDAC5 pathway is also involved in angiogenesis by mediating VEGFA-induced specific subset of gene expression, cell migration, and tube formation. In response to VEGFA, is necessary and required for HDAC7 phosphorylation which induces HDAC7 nuclear export and endothelial cell proliferation and migration. During apoptosis induced by cytarabine and other genotoxic agents, PRKD1 is cleaved by caspase-3 at Asp-378, resulting in activation of its kinase function and increased sensitivity of cells to the cytotoxic effects of genotoxic agents. In epithelial cells, is required for transducing flagellin-stimulated inflammatory responses by binding and phosphorylating TLR5, which contributes to MAPK14/p38 activation and production of inflammatory cytokines. May play a role in inflammatory response by mediating activation of NF-kappa- B. May be involved in pain transmission by directly modulating TRPV1 receptor. {ECO:0000269|PubMed:10523301, ECO:0000269|PubMed:10764790, ECO:0000269|PubMed:12505989, ECO:0000269|PubMed:12637538, ECO:0000269|PubMed:15471852, ECO:0000269|PubMed:17442957, ECO:0000269|PubMed:18332134, ECO:0000269|PubMed:18509061, ECO:0000269|PubMed:19135240, ECO:0000269|PubMed:19211839}. | 15.1 | |||||
| kccKPCD2 | Serine/threonine-protein kinase D2 | 24 | 344 | 93.76 | ND | 91.56 | 0.18 | ND | 1.1 | Mammalian | Widely expressed. | Kinase | Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of cell proliferation via MAPK1/3 (ERK1/2) signaling, oxidative stress- induced NF-kappa-B activation, inhibition of HDAC7 transcriptional repression, signaling downstream of T-cell antigen receptor (TCR) and cytokine production, and plays a role in Golgi membrane trafficking, angiogenesis, secretory granule release and cell adhesion. May potentiate mitogenesis induced by the neuropeptide bombesin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. In response to oxidative stress, is phosphorylated at Tyr-438 by ABL1, which leads to the activation of PRKD2 without increasing its catalytic activity, and mediates activation of NF-kappa-B. In response to the activation of the gastrin receptor CCKBR, is phosphorylated at Ser-244 by CSNK1D and CSNK1E, translocates to the nucleus, phosphorylates HDAC7, leading to nuclear export of HDAC7 and inhibition of HDAC7 transcriptional repression of NR4A1/NUR77. Upon TCR stimulation, is activated independently of ZAP70, translocates from the cytoplasm to the nucleus and is required for interleukin-2 (IL2) promoter up-regulation. During adaptive immune responses, is required in peripheral T-lymphocytes for the production of the effector cytokines IL2 and IFNG after TCR engagement and for optimal induction of antibody responses to antigens. In epithelial cells stimulated with lysophosphatidic acid (LPA), is activated through a PKC-dependent pathway and mediates LPA-stimulated interleukin-8 (IL8) secretion via a NF- kappa-B-dependent pathway. During TCR-induced T-cell activation, interacts with and is activated by the tyrosine kinase LCK, which results in the activation of the NFAT transcription factors. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane and in polarized cells is involved in the transport of proteins from the TGN to the basolateral membrane. Plays an important role in endothelial cell proliferation and migration prior to angiogenesis, partly through modulation of the expression of KDR/VEGFR2 and FGFR1, two key growth factor receptors involved in angiogenesis. In secretory pathway, is required for the release of chromogranin-A (CHGA)-containing secretory granules from the TGN. Downstream of PRKCA, plays important roles in angiotensin-2- induced monocyte adhesion to endothelial cells. Plays a regulatory role in angiogenesis and tumor growth by phosphorylating a downstream mediator CIB1 isoform 2, resulting in vascular endothelial growth factor A (VEGFA) secretion. {ECO:0000269|PubMed:14743217, ECO:0000269|PubMed:15604256, ECO:0000269|PubMed:16928771, ECO:0000269|PubMed:17077180, ECO:0000269|PubMed:17951978, ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:18262756, ECO:0000269|PubMed:19001381, ECO:0000269|PubMed:19192391, ECO:0000269|PubMed:23503467}. | 15.1 | ||||
| kccKPCD3 | Serine/threonine-protein kinase D3 | 26 | 412 | 94.01 | ND | 90.94 | 0.38 | ND | 1.1 | Mammalian | Ubiquitous. | Kinase | Converts transient diacylglycerol (DAG) signals into prolonged physiological effects, downstream of PKC. Involved in resistance to oxidative stress (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccKPCE | Protein kinase C epsilon type | 11 | 358 | 95.37 | ND | 94.42 | 0.45 | ND | 1.0 | Mammalian | Kinase | Not Available | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays essential roles in the regulation of multiple cellular processes linked to cytoskeletal proteins, such as cell adhesion, motility, migration and cell cycle, functions in neuron growth and ion channel regulation, and is involved in immune response, cancer cell invasion and regulation of apoptosis. Mediates cell adhesion to the extracellular matrix via integrin-dependent signaling, by mediating angiotensin-2-induced activation of integrin beta-1 (ITGB1) in cardiac fibroblasts. Phosphorylates MARCKS, which phosphorylates and activates PTK2/FAK, leading to the spread of cardiomyocytes. Involved in the control of the directional transport of ITGB1 in mesenchymal cells by phosphorylating vimentin (VIM), an intermediate filament (IF) protein. In epithelial cells, associates with and phosphorylates keratin-8 (KRT8), which induces targeting of desmoplakin at desmosomes and regulates cell-cell contact. Phosphorylates IQGAP1, which binds to CDC42, mediating epithelial cell-cell detachment prior to migration. In HeLa cells, contributes to hepatocyte growth factor (HGF)-induced cell migration, and in human corneal epithelial cells, plays a critical role in wound healing after activation by HGF. During cytokinesis, forms a complex with YWHAB, which is crucial for daughter cell separation, and facilitates abscission by a mechanism which may implicate the regulation of RHOA. In cardiac myocytes, regulates myofilament function and excitation coupling at the Z-lines, where it is indirectly associated with F- actin via interaction with COPB1. During endothelin-induced cardiomyocyte hypertrophy, mediates activation of PTK2/FAK, which is critical for cardiomyocyte survival and regulation of sarcomere length. Plays a role in the pathogenesis of dilated cardiomyopathy via persistent phosphorylation of troponin I (TNNI3). Involved in nerve growth factor (NFG)-induced neurite outgrowth and neuron morphological change independently of its kinase activity, by inhibition of RHOA pathway, activation of CDC42 and cytoskeletal rearrangement. May be involved in presynaptic facilitation by mediating phorbol ester-induced synaptic potentiation. Phosphorylates gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2), which reduces the response of GABA receptors to ethanol and benzodiazepines and may mediate acute tolerance to the intoxicating effects of ethanol. Upon PMA treatment, phosphorylates the capsaicin- and heat-activated cation channel TRPV1, which is required for bradykinin-induced sensitization of the heat response in nociceptive neurons. Is able to form a complex with PDLIM5 and N-type calcium channel, and may enhance channel activities and potentiates fast synaptic transmission by phosphorylating the pore-forming alpha subunit CACNA1B (CaV2.2). In prostate cancer cells, interacts with and phosphorylates STAT3, which increases DNA-binding and transcriptional activity of STAT3 and seems to be essential for prostate cancer cell invasion. Downstream of TLR4, plays an important role in the lipopolysaccharide (LPS)-induced immune response by phosphorylating and activating TICAM2/TRAM, which in turn activates the transcription factor IRF3 and subsequent cytokines production. In differentiating erythroid progenitors, is regulated by EPO and controls the protection against the TNFSF10/TRAIL- mediated apoptosis, via BCL2. May be involved in the regulation of the insulin-induced phosphorylation and activation of AKT1. {ECO:0000269|PubMed:11884385, ECO:0000269|PubMed:1374067, ECO:0000269|PubMed:15355962, ECO:0000269|PubMed:16757566, ECO:0000269|PubMed:17603037, ECO:0000269|PubMed:17875639, ECO:0000269|PubMed:17875724}. | Protein kinase C epsilon type unknown: Tamoxifen | 15.1 | |||
| kccKPCG | Protein kinase C gamma type | 13 | 379 | 91.43 | ND | 89.80 | 0.49 | ND | 0.8 | Mammalian | Expressed in Purkinje cells of the cerebellar cortex. {ECO:0000269|PubMed:12644968}. | Kinase | Spinocerebellar ataxia 14 (SCA14) [MIM:605361]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA14 is an autosomal dominant cerebellar ataxia (ADCA). {ECO:0000269|PubMed:12644968}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays diverse roles in neuronal cells and eye tissues, such as regulation of the neuronal receptors GRIA4/GLUR4 and GRIN1/NMDAR1, modulation of receptors and neuronal functions related to sensitivity to opiates, pain and alcohol, mediation of synaptic function and cell survival after ischemia, and inhibition of gap junction activity after oxidative stress. Binds and phosphorylates GRIA4/GLUR4 glutamate receptor and regulates its function by increasing plasma membrane-associated GRIA4 expression. In primary cerebellar neurons treated with the agonist 3,5-dihyidroxyphenylglycine, functions downstream of the metabotropic glutamate receptor GRM5/MGLUR5 and phosphorylates GRIN1/NMDAR1 receptor which plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. May be involved in the regulation of hippocampal long-term potentiation (LTP), but may be not necessary for the process of synaptic plasticity. May be involved in desensitization of mu-type opioid receptor-mediated G-protein activation in the spinal cord, and may be critical for the development and/or maintenance of morphine-induced reinforcing effects in the limbic forebrain. May modulate the functionality of mu-type-opioid receptors by participating in a signaling pathway which leads to the phosphorylation and degradation of opioid receptors. May also contributes to chronic morphine-induced changes in nociceptive processing. Plays a role in neuropathic pain mechanisms and contributes to the maintenance of the allodynia pain produced by peripheral inflammation. Plays an important role in initial sensitivity and tolerance to ethanol, by mediating the behavioral effects of ethanol as well as the effects of this drug on the GABA(A) receptors. During and after cerebral ischemia modulate neurotransmission and cell survival in synaptic membranes, and is involved in insulin-induced inhibition of necrosis, an important mechanism for minimizing ischemic injury. Required for the elimination of multiple climbing fibers during innervation of Purkinje cells in developing cerebellum. Is activated in lens epithelial cells upon hydrogen peroxide treatment, and phosphorylates connexin-43 (GJA1/CX43), resulting in disassembly of GJA1 gap junction plaques and inhibition of gap junction activity which could provide a protective effect against oxidative stress (By similarity). Phosphorylates p53/TP53 and promotes p53/TP53-dependent apoptosis in response to DNA damage. Involved in the phase resetting of the cerebral cortex circadian clock during temporally restricted feeding. Stabilizes the core clock component ARNTL/BMAL1 by interfering with its ubiquitination, thus suppressing its degradation, resulting in phase resetting of the cerebral cortex clock (By similarity). {ECO:0000250|UniProtKB:P63318, ECO:0000250|UniProtKB:P63319, ECO:0000269|PubMed:16377624}. | 15.1 | |||
| kccKPCI | Protein kinase C iota type | 4 | 107 | 89.72 | ND | 84.96 | 0.27 | ND | 1.5 | Mammalian | Predominantly expressed in lung and brain, but also expressed at lower levels in many tissues including pancreatic islets. Highly expressed in non-small cell lung cancers. {ECO:0000269|PubMed:15994303, ECO:0000269|PubMed:7607695, ECO:0000269|PubMed:8226978}. | Kinase | Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non- small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis. {ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10467349, ECO:0000269|PubMed:10906326, ECO:0000269|PubMed:11042363, ECO:0000269|PubMed:11724794, ECO:0000269|PubMed:12871960, ECO:0000269|PubMed:14684752, ECO:0000269|PubMed:15994303, ECO:0000269|PubMed:18270268, ECO:0000269|PubMed:19327373, ECO:0000269|PubMed:21189248, ECO:0000269|PubMed:21419810, ECO:0000269|PubMed:8226978, ECO:0000269|PubMed:9346882}. | Protein kinase C iota type unknown: Tamoxifen | 15.1 | |||
| kccKPCL | Protein kinase C eta type | 13 | 249 | 97.74 | ND | 96.02 | 0.32 | ND | 1.0 | Mammalian | Most abundant in lung, less in heart and skin. {ECO:0000269|PubMed:1986216}. | Kinase | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:17206144}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in the regulation of cell differentiation in keratinocytes and pre-B cell receptor, mediates regulation of epithelial tight junction integrity and foam cell formation, and is required for glioblastoma proliferation and apoptosis prevention in MCF-7 cells. In keratinocytes, binds and activates the tyrosine kinase FYN, which in turn blocks epidermal growth factor receptor (EGFR) signaling and leads to keratinocyte growth arrest and differentiation. Associates with the cyclin CCNE1-CDK2-CDKN1B complex and inhibits CDK2 kinase activity, leading to RB1 dephosphorylation and thereby G1 arrest in keratinocytes. In association with RALA activates actin depolymerization, which is necessary for keratinocyte differentiation. In the pre-B cell receptor signaling, functions downstream of BLNK by up-regulating IRF4, which in turn activates L chain gene rearrangement. Regulates epithelial tight junctions (TJs) by phosphorylating occludin (OCLN) on threonine residues, which is necessary for the assembly and maintenance of TJs. In association with PLD2 and via TLR4 signaling, is involved in lipopolysaccharide (LPS)-induced RGS2 down-regulation and foam cell formation. Upon PMA stimulation, mediates glioblastoma cell proliferation by activating the mTOR pathway, the PI3K/AKT pathway and the ERK1- dependent phosphorylation of ELK1. Involved in the protection of glioblastoma cells from irradiation-induced apoptosis by preventing caspase-9 activation. In camptothecin-treated MCF-7 cells, regulates NF-kappa-B upstream signaling by activating IKBKB, and confers protection against DNA damage-induced apoptosis. Promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Phosphorylates ATF2 which promotes its nuclear retention and transcriptional activity and negatively regulates its mitochondrial localization. {ECO:0000269|PubMed:10806212, ECO:0000269|PubMed:11112424, ECO:0000269|PubMed:11772428, ECO:0000269|PubMed:15489897, ECO:0000269|PubMed:17146445, ECO:0000269|PubMed:18780722, ECO:0000269|PubMed:19114660, ECO:0000269|PubMed:20558593, ECO:0000269|PubMed:21820409, ECO:0000269|PubMed:22304920}. | 15.1 | |||
| kccKPCT | Protein kinase C theta type | 18 | 577 | 94.67 | ND | 93.48 | 0.47 | ND | 1.1 | Mammalian | Expressed in skeletal muscle, T-cells, megakaryoblastic cells and platelets. {ECO:0000269|PubMed:7686153}. | Kinase | Not Available | Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non- redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non- canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. {ECO:0000269|PubMed:11342610, ECO:0000269|PubMed:14988727, ECO:0000269|PubMed:15364919, ECO:0000269|PubMed:16252004, ECO:0000269|PubMed:16356855, ECO:0000269|PubMed:16709830, ECO:0000269|PubMed:19549985, ECO:0000269|PubMed:8657160}. | Protein kinase C theta type unknown: Tamoxifen | 15.1 | ||
| kccKPCZ | Protein kinase C zeta type | 7 | 176 | 80.85 | ND | 83.93 | 0.36 | ND | 1.1 | Mammalian | Expressed in brain, and to a lesser extent in lung, kidney and testis. | Kinase | Not Available | Calcium- and diacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5-MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF-kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Necessary and sufficient for LTP maintenance in hippocampal CA1 pyramidal cells. In vein endothelial cells treated with the oxidant peroxynitrite, phosphorylates STK11 leading to nuclear export of STK11, subsequent inhibition of PI3K/Akt signaling, and increased apoptosis. {ECO:0000269|PubMed:11035106, ECO:0000269|PubMed:12162751, ECO:0000269|PubMed:15084291, ECO:0000269|PubMed:15324659, ECO:0000269|PubMed:18321849, ECO:0000269|PubMed:9447975}. | 15.1 | |||
| kccKPYM | Pyruvate kinase PKM | 22 | 1131 | 90.11 | ND | 89.26 | 0.42 | ND | 0.9 | Mammalian | Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. {ECO:0000269|PubMed:18191611}. | Enzyme | Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival. {ECO:0000269|PubMed:17308100, ECO:0000269|PubMed:18191611, ECO:0000269|PubMed:21620138}. | Pyruvate kinase PKM unknown: Pyruvic acid | 15.1 | |||
| kccKS6A1 | Ribosomal protein S6 kinase alpha-1 | 3 | 129 | 96.72 | ND | 95.69 | 0.13 | ND | 1.2 | Mammalian | Kinase | Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1, which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin- derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the pre-initiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro- apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Mediates induction of hepatocyte prolifration by TGFA through phosphorylation of CEBPB (By similarity). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. {ECO:0000250|UniProtKB:P18653, ECO:0000250|UniProtKB:Q63531, ECO:0000269|PubMed:10679322, ECO:0000269|PubMed:11684016, ECO:0000269|PubMed:12213813, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:15342917, ECO:0000269|PubMed:16213824, ECO:0000269|PubMed:16223362, ECO:0000269|PubMed:16763566, ECO:0000269|PubMed:17360704, ECO:0000269|PubMed:18722121, ECO:0000269|PubMed:9430688}. | Pyruvate kinase PKM unknown: Pyruvic acid | 15.1 | ||||
| kccKS6A3 | Ribosomal protein S6 kinase alpha-3 | 27 | 592 | 94.95 | ND | 91.54 | 0.15 | ND | 1.3 | Mammalian | Expressed in many tissues, highest levels in skeletal muscle. | Kinase | Coffin-Lowry syndrome (CLS) [MIM:303600]: A X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders. {ECO:0000269|PubMed:10094187, ECO:0000269|PubMed:10528858, ECO:0000269|PubMed:14986828, ECO:0000269|PubMed:15214012, ECO:0000269|PubMed:8955270, ECO:0000269|PubMed:9837815}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mental retardation, X-linked 19 (MRX19) [MIM:300844]: A non-syndromic form of mild to moderate mental retardation. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation. {ECO:0000269|PubMed:10319851, ECO:0000269|PubMed:17100996}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR- independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro- apoptotic proteins BAD and DAPK1 and suppressing their pro- apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Phosphorylates DAPK1. {ECO:0000269|PubMed:10436156, ECO:0000269|PubMed:16213824, ECO:0000269|PubMed:16223362, ECO:0000269|PubMed:17360704, ECO:0000269|PubMed:18722121, ECO:0000269|PubMed:8250835, ECO:0000269|PubMed:9770464}. | 15.1 | |||
| kccKS6A5 | Ribosomal protein S6 kinase alpha-5 | 11 | 252 | 91.29 | ND | 84.51 | 0.32 | ND | 1.1 | Mammalian | Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver. {ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9873047}. | Kinase | Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression. In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress. In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential. Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation. Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto- oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro- inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti- inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors. Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury. {ECO:0000269|PubMed:11909979, ECO:0000269|PubMed:12569367, ECO:0000269|PubMed:12628924, ECO:0000269|PubMed:12763138, ECO:0000269|PubMed:12773393, ECO:0000269|PubMed:15010469, ECO:0000269|PubMed:18511904, ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9873047}. | 15.1 | ||||
| kccKS6B1 | Ribosomal protein S6 kinase beta-1 | 28 | 448 | 93.94 | ND | 91.03 | 0.29 | ND | 1.2 | Mammalian | Widely expressed. {ECO:0000269|PubMed:9804755}. | Kinase | Cancer, unspecific
Solid tumors | Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the pre-initiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative feedback mechanism for the RPS6KB1 anti- apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1- 2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin. Phosphorylates and activates the pyrimidine biosynthesis enzyme CAD, downstream of MTOR. {ECO:0000269|PubMed:11500364, ECO:0000269|PubMed:12801526, ECO:0000269|PubMed:14673156, ECO:0000269|PubMed:15071500, ECO:0000269|PubMed:15341740, ECO:0000269|PubMed:16286006, ECO:0000269|PubMed:17052453, ECO:0000269|PubMed:17053147, ECO:0000269|PubMed:17936702, ECO:0000269|PubMed:18952604, ECO:0000269|PubMed:19085255, ECO:0000269|PubMed:19720745, ECO:0000269|PubMed:19935711, ECO:0000269|PubMed:19995915, ECO:0000269|PubMed:23429703}. | 15.1 | |||
| kccKSYK | Tyrosine-protein kinase SYK | 28 | 582 | 96.08 | ND | 94.46 | 0.55 | ND | 1.1 | Mammalian | Widely expressed in hematopoietic cells (at protein level). Within the B-cells compartment it is for instance expressed for pro-B-cells to plasma cells. {ECO:0000269|PubMed:8163536}. | Kinase | Allergic Reaction
Asthma Inflammatory diseases Lymphoma, Non-Hodgkin's Obstructive airway disease Rheumatoid arthritis Thrombocytopenia | Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine- phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T- cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. {ECO:0000269|PubMed:12387735, ECO:0000269|PubMed:12456653, ECO:0000269|PubMed:15388330, ECO:0000269|PubMed:19909739, ECO:0000269|PubMed:8657103, ECO:0000269|PubMed:9535867}. | Pyruvate kinase PKM unknown: Pyruvic acid | 15.1 | ||
| kccLCAP | Leucyl-cystinyl aminopeptidase | 4 | 88 | 99.64 | ND | 96.23 | 0.44 | ND | 0.7 | Mammalian | Highly expressed in placenta, heart, kidney and small intestine. Detected at lower levels in neuronal cells in the brain, in skeletal muscle, spleen, liver, testes and colon. {ECO:0000269|PubMed:11389728, ECO:0000269|PubMed:8550619, ECO:0000269|PubMed:9177475}. | Protease | Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain. {ECO:0000269|PubMed:11389728, ECO:0000269|PubMed:11707427, ECO:0000269|PubMed:1731608}. | 15.1 | ||||
| kccLCK | Tyrosine-protein kinase Lck | 72 | 1767 | 96.48 | ND | 95.14 | 0.51 | ND | 1.0 | Mammalian | Expressed specifically in lymphoid cells. | Kinase | Note=A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB. Immunodeficiency 22 (IMD22) [MIM:615758]: A primary immunodeficiency characterized by T-cell dysfunction. Affected individuals present with lymphopenia, recurrent infections, severe diarrhea, and failure to thrive. {ECO:0000269|PubMed:22985903}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T- cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. {ECO:0000269|PubMed:16339550, ECO:0000269|PubMed:16709819, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20851766, ECO:0000269|PubMed:21269457, ECO:0000269|PubMed:22080863}. | Tyrosine-protein kinase Lck Inhibitor: Nintedanib Tyrosine-protein kinase Lck inhibitor: Ponatinib Tyrosine-protein kinase Lck multitarget: Dasatinib | 15.1 | ||
| kccLDHA | L-lactate dehydrogenase A chain | 5 | 97 | 99.90 | ND | 99.96 | 0.39 | ND | 0.6 | Mammalian | Enzyme | Glycogen storage disease 11 (GSD11) [MIM:612933]: A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue. {ECO:0000269|PubMed:2334430}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase Lck Inhibitor: Nintedanib Tyrosine-protein kinase Lck inhibitor: Ponatinib Tyrosine-protein kinase Lck multitarget: Dasatinib | 15.1 | ||||
| kccLDHB | L-lactate dehydrogenase B chain | 3 | 48 | 99.90 | ND | 99.93 | 0.65 | ND | 0.4 | Mammalian | Enzyme | Lactate dehydrogenase B deficiency (LDHBD) [MIM:614128]: A condition with no deleterious effects on health. LDHBD is of interest to laboratory medicine mainly because it can cause misdiagnosis in those disorders in which elevation of serum LDH is expected. {ECO:0000269|PubMed:10211631, ECO:0000269|PubMed:11509017, ECO:0000269|PubMed:1587525, ECO:0000269|PubMed:2334429, ECO:0000269|PubMed:8314553, ECO:0000269|PubMed:8462975, ECO:0000269|PubMed:8611651, ECO:0000269|PubMed:9929983, ECO:0000269|Ref.19}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase Lck Inhibitor: Nintedanib Tyrosine-protein kinase Lck inhibitor: Ponatinib Tyrosine-protein kinase Lck multitarget: Dasatinib | 15.1 | ||||
| kccLGMN | Legumain | 3 | 41 | 99.96 | ND | 99.99 | 0.22 | ND | 0.2 | Mammalian | Ubiquitous. Particularly abundant in kidney, heart and placenta. | Protease | Has a strict specificity for hydrolysis of asparaginyl bonds. Can also cleave aspartyl bonds slowly, especially under acidic conditions. Required for normal lysosomal protein degradation in renal proximal tubules. Required for normal degradation of internalized EGFR. Plays a role in the regulation of cell proliferation via its role in EGFR degradation (By similarity). May be involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system. {ECO:0000250, ECO:0000269|PubMed:23776206}. | 15.1 | ||||
| kccLGUL | Lactoylglutathione lyase | 3 | 63 | 96.11 | ND | 94.23 | 0.75 | ND | 0.5 | Mammalian | Enzyme | Tumors | Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione. Involved in the regulation of TNF-induced transcriptional activity of NF- kappa-B. Required for normal osteoclastogenesis. {ECO:0000269|PubMed:19199007, ECO:0000269|PubMed:23122816, ECO:0000269|PubMed:9705294}. | Lactoylglutathione lyase inhibitor: Indomethacin Lactoylglutathione lyase unknown: Glutathione | 15.1 | |||
| kccLIMK1 | LIM domain kinase 1 | 12 | 437 | 95.34 | ND | 90.33 | 0.08 | ND | 1.1 | Mammalian | Highest expression in both adult and fetal nervous system. Detected ubiquitously throughout the different regions of adult brain, with highest levels in the cerebral cortex. Expressed to a lesser extent in heart and skeletal muscle. | Kinase | Note=LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. | Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin- 2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes. Required for atypical chemokine receptor ACKR2-induced phosphorylation of cofilin (CFL1). {ECO:0000269|PubMed:10196227, ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:11832213, ECO:0000269|PubMed:12807904, ECO:0000269|PubMed:15660133, ECO:0000269|PubMed:16230460, ECO:0000269|PubMed:18028908, ECO:0000269|PubMed:23633677}. | LIM domain kinase 1 inhibitor: Dabrafenib | 15.1 | ||
| kccLIMK2 | LIM domain kinase 2 | 2 | 120 | 98.82 | ND | 90.42 | 0.61 | ND | 1.2 | Mammalian | Highest expression in the placenta; moderate level in liver, lung, kidney, and pancreas. LIMK2a is found to be more abundant then LIMK2b in liver, colon, stomach, and spleen, while in brain, kidney, and placenta LIMK2b is the dominant form. In adult lung, both LIMK2a and LIMK2b is nearly equally observed. {ECO:0000269|PubMed:8954941}. | Kinase | Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro. {ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:11018042}. | 15.1 | ||||
| kccLIPE | Endothelial lipase | 4 | 64 | 95.12 | ND | 99.94 | 0.22 | ND | 0.7 | Mammalian | High level of expression in the liver, placenta, lung, thyroid, kidney, testis and in the corpus luteum of the ovary. Expressed also in coronary artery endothelial cells, umbilical vein endothelial cells and in hepatocytes and osteosarcoma cell lines. Not detected in heart, brain and muscle. | Enzyme | Has phospholipase and triglyceride lipase activities. Hydrolyzes high density lipoproteins (HDL) more efficiently than other lipoproteins. Binds heparin. | 15.1 | ||||
| kccLIPL | Lipoprotein lipase | 2 | 56 | 87.90 | ND | 99.98 | 0.73 | ND | 0.4 | Mammalian | Enzyme | Lipoprotein lipase deficiency (LPL deficiency) [MIM:238600]: Recessive disorder usually manifesting in childhood. On a normal diet, patients often present with abdominal pain, hepatosplenomegaly, lipemia retinalis, eruptive xanthomata, and massive hypertriglyceridemia, sometimes complicated with acute pancreatitis. {ECO:0000269|PubMed:10660334, ECO:0000269|PubMed:10787434, ECO:0000269|PubMed:11068186, ECO:0000269|PubMed:11099402, ECO:0000269|PubMed:11134145, ECO:0000269|PubMed:11441134, ECO:0000269|PubMed:12204001, ECO:0000269|PubMed:12641539, ECO:0000269|PubMed:12966036, ECO:0000269|PubMed:1400331, ECO:0000269|PubMed:1479292, ECO:0000269|PubMed:14984478, ECO:0000269|PubMed:15185149, ECO:0000269|PubMed:1521525, ECO:0000269|PubMed:15256764, ECO:0000269|PubMed:15877202, ECO:0000269|PubMed:1598907, ECO:0000269|PubMed:1619366, ECO:0000269|PubMed:1639392, ECO:0000269|PubMed:1674945, ECO:0000269|PubMed:1702428, ECO:0000269|PubMed:1730727, ECO:0000269|PubMed:1752947, ECO:0000269|PubMed:1907278, ECO:0000269|PubMed:1969408, ECO:0000269|PubMed:1975597, ECO:0000269|PubMed:2010533, ECO:0000269|PubMed:2038366, ECO:0000269|PubMed:2110364, ECO:0000269|PubMed:2121025, ECO:0000269|PubMed:7647785, ECO:0000269|PubMed:7806969, ECO:0000269|PubMed:7906986, ECO:0000269|PubMed:7912254, ECO:0000269|PubMed:7999071, ECO:0000269|PubMed:8077845, ECO:0000269|PubMed:8096693, ECO:0000269|PubMed:8135797, ECO:0000269|PubMed:8288243, ECO:0000269|PubMed:8301230, ECO:0000269|PubMed:8325986, ECO:0000269|PubMed:8486765, ECO:0000269|PubMed:8728326, ECO:0000269|PubMed:8778602, ECO:0000269|PubMed:8858123, ECO:0000269|PubMed:8872057, ECO:0000269|PubMed:8956048, ECO:0000269|PubMed:8956052, ECO:0000269|PubMed:9279761, ECO:0000269|PubMed:9298816, ECO:0000269|PubMed:9498099, ECO:0000269|PubMed:9662394, ECO:0000269|PubMed:9714430, ECO:0000269|PubMed:9719626}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The primary function of this lipase is the hydrolysis of triglycerides of circulating chylomicrons and very low density lipoproteins (VLDL). Binding to heparin sulfate proteogylcans at the cell surface is vital to the function. The apolipoprotein, APOC2, acts as a coactivator of LPL activity in the presence of lipids on the luminal surface of vascular endothelium (By similarity). {ECO:0000250}. | Lipoprotein lipase inhibitor: Tyloxapol | 15.1 | |||
| kccLIPS | Hormone-sensitive lipase | 5 | 159 | 94.90 | ND | 95.54 | 0.44 | ND | 0.7 | Mammalian | Enzyme | Lipodystrophy, familial partial, 6 (FPLD6) [MIM:615980]: A form of lipodystrophy characterized by abnormal subcutaneous fat distribution. Affected individuals have increased visceral fat, impaired lipolysis, dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. Some patients manifest muscular dystrophy. {ECO:0000269|PubMed:24848981}. Note=The disease is caused by mutations affecting the gene represented in this entry. | In adipose tissue and heart, it primarily hydrolyzes stored triglycerides to free fatty acids, while in steroidogenic tissues, it principally converts cholesteryl esters to free cholesterol for steroid hormone production. | 15.1 | ||||
| kccLKHA4 | Leukotriene A-4 hydrolase | 26 | 480 | 98.65 | ND | 97.05 | 0.69 | ND | 0.6 | Mammalian | Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts. | Protease | Inflammation
Leukemia, Myeloid Myocardial infarction Oesophageal cancer Solid tumors | Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity. {ECO:0000269|PubMed:11917124, ECO:0000269|PubMed:12207002, ECO:0000269|PubMed:15078870, ECO:0000269|PubMed:18804029, ECO:0000269|PubMed:1897988, ECO:0000269|PubMed:1975494, ECO:0000269|PubMed:2244921}. | Leukotriene A-4 hydrolase unknown: Captopril | 15.1 | ||
| kccLMBL3 | Lethal(3)malignant brain tumor-like protein 3 | 2 | 93 | 99.47 | ND | 97.20 | 0.76 | ND | 0.4 | Mammalian | Reader | Putative Polycomb group (PcG) protein. PcG proteins maintain the transcriptionally repressive state of genes, probably via a modification of chromatin, rendering it heritably changed in its expressibility. Required for normal maturation of myeloid progenitor cells (By similarity). {ECO:0000250}. | 15.1 | |||||
| kccLOX15 | Arachidonate 15-lipoxygenase | 21 | 1264 | 80.78 | ND | 83.19 | 0.47 | ND | 1.0 | Mammalian | Detected in monocytes and eosinophils (at protein level). Expressed in airway epithelial cells. {ECO:0000269|PubMed:21831839, ECO:0000269|PubMed:9414270}. | Enzyme | Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Met at position 560 may confer interindividual susceptibility to coronary artery disease (CAD) (PubMed:17959182). {ECO:0000269|PubMed:17959182}. | Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators. Converts arachidonic acid into 12- hydroperoxyeicosatetraenoic acid/12-HPETE and 15- hydroperoxyeicosatetraenoic acid/15-HPETE. Also converts linoleic acid to 13-hydroperoxyoctadecadienoic acid. May also act on (12S)- hydroperoxyeicosatetraenoic acid/(12S)-HPETE to produce hepoxilin A3. Probably plays an important role in the immune and inflammatory responses. Through the oxygenation of membrane-bound phosphatidylethanolamine in macrophages may favor clearance of apoptotic cells during inflammation by resident macrophages and prevent an autoimmune response associated with the clearance of apoptotic cells by inflammatory monocytes. In parallel, may regulate actin polymerization which is crucial for several biological processes, including macrophage function. May also regulate macrophage function through regulation of the peroxisome proliferator activated receptor signaling pathway. Finally, it is also involved in the cellular response to IL13/interleukin-13. In addition to its role in the immune and inflammatory responses, may play a role in epithelial wound healing in the cornea maybe through production of lipoxin A4. May also play a role in endoplasmic reticulum stress response and the regulation of bone mass. {ECO:0000269|PubMed:17052953, ECO:0000269|PubMed:21831839}. | Leukotriene A-4 hydrolase unknown: Captopril | 15.1 | ||
| kccLOX5 | Arachidonate 5-lipoxygenase | 94 | 2450 | 93.90 | ND | 96.37 | 0.46 | ND | 0.7 | Mammalian | Oxidoreductase | Not Available | Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes. {ECO:0000269|PubMed:21233389}. | Arachidonate 5-lipoxygenase inhibitor: Aminosalicylic Acid, Balsalazide, Diethylcarbamazine, Masoprocol, Meclofenamic acid, Mesalazine, Minocycline, Sulfasalazine, Zileuton Arachidonate 5-lipoxygenase other/unknown: Montelukast Arachidonate 5-lipoxygenase potentiator: Diclofenac Arachidonate 5-lipoxygenase unknown: Vitamin E | 15.1 | |||
| kccLPAR1 | Lysophosphatidic acid receptor 1 | 6 | 132 | 96.79 | ND | 97.75 | 0.75 | ND | 0.4 | Mammalian | Expressed in many adult organs, including brain, heart, colon, small intestine, placenta, prostate, ovary, pancreas, testes, spleen, skeletal muscle, and kidney. Little or no expression in liver, lung, thymus, or peripheral blood leukocytes (PubMed:9070858). Detected in lung fibroblasts from bronchoalveolar fluid from patients with idiopathic pulmonary fibrosis (PubMed:18066075). Detected in bone marrow-derived mesenchymal stem cells (PubMed:19733258). {ECO:0000269|PubMed:18066075, ECO:0000269|PubMed:19733258, ECO:0000269|PubMed:9070858}. | Family A G protein-coupled receptor | Multiple sclerosis | Receptor for lysophosphatidic acid (LPA) (PubMed:9070858, PubMed:19306925, PubMed:25025571, PubMed:26091040). Plays a role in the reorganization of the actin cytoskeleton, cell migration, differentiation and proliferation, and thereby contributes to the responses to tissue damage and infectious agents. Activates downstream signaling cascades via the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. Signaling inhibits adenylyl cyclase activity and decreases cellular cAMP levels (PubMed:26091040). Signaling triggers an increase of cytoplasmic Ca(2+) levels (PubMed:19656035, PubMed:19733258, PubMed:26091040). Activates RALA; this leads to the activation of phospholipase C (PLC) and the formation of inositol 1,4,5-trisphosphate (PubMed:19306925). Signaling mediates activation of down-stream MAP kinases (By similarity). Contributes to the regulation of cell shape. Promotes Rho-dependent reorganization of the actin cytoskeleton in neuronal cells and neurite retraction (PubMed:26091040). Promotes the activation of Rho and the formation of actin stress fibers (PubMed:26091040). Promotes formation of lamellipodia at the leading edge of migrating cells via activation of RAC1 (By similarity). Through its function as lysophosphatidic acid receptor, plays a role in chemotaxis and cell migration, including responses to injury and wounding (PubMed:18066075, PubMed:19656035, PubMed:19733258). Plays a role in triggering inflammation in response to bacterial lipopolysaccharide (LPS) via its interaction with CD14. Promotes cell proliferation in response to lysophosphatidic acid. Required for normal skeleton development. May play a role in osteoblast differentiation. Required for normal brain development. Required for normal proliferation, survival and maturation of newly formed neurons in the adult dentate gyrus. Plays a role in pain perception and in the initiation of neuropathic pain (By similarity). {ECO:0000250|UniProtKB:P61793, ECO:0000269|PubMed:18066075, ECO:0000269|PubMed:19306925, ECO:0000269|PubMed:19656035, ECO:0000269|PubMed:19733258, ECO:0000269|PubMed:25025571, ECO:0000269|PubMed:26091040, ECO:0000269|PubMed:9070858, ECO:0000305|PubMed:11093753, ECO:0000305|PubMed:9069262}. | 15.1 | |||
| kccLPAR2 | Lysophosphatidic acid receptor 2 | 3 | 84 | 82.34 | ND | 99.98 | 0.58 | ND | 0.4 | Mammalian | Expressed most abundantly in testes and peripheral blood leukocytes with less expression in pancreas, spleen, thymus and prostate. Little or no expression in heart, brain, placenta, lung, liver, skeletal muscle, kidney, ovary, small intestine, or colon. | Family A G protein-coupled receptor | Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. Seems to be coupled to the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. Plays a key role in phospholipase C-beta (PLC-beta) signaling pathway. Stimulates phospholipase C (PLC) activity in a manner that is independent of RALA activation. {ECO:0000269|PubMed:15143197, ECO:0000269|PubMed:19306925}. | 15.1 | ||||
| kccLPAR3 | Lysophosphatidic acid receptor 3 | 6 | 145 | 96.26 | ND | 93.79 | 0.55 | ND | 0.8 | Mammalian | Most abundantly expressed in prostate, testes, pancreas, and heart, with moderate levels in lung and ovary. No detectable expression in brain, placenta, liver, skeletal muscle, kidney, spleen, thymus, small intestine, colon, or peripheral blood leukocytes. | Family A G protein-coupled receptor | Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. May play a role in the development of ovarian cancer. Seems to be coupled to the G(i)/G(o) and G(q) families of heteromeric G proteins. | 15.1 | ||||
| kccLRRK2 | Leucine-rich repeat serine/threonine-protein kinase 2 | 17 | 368 | 94.94 | ND | 88.73 | 0.48 | ND | 1.3 | Mammalian | Expressed in the brain. Expressed in pyramidal neurons in all cortical laminae of the visual cortex, in neurons of the substantia nigra pars compacta and caudate putamen (at protein level). Expressed throughout the adult brain, but at a lower level than in heart and liver. Also expressed in placenta, lung, skeletal muscle, kidney and pancreas. In the brain, expressed in the cerebellum, cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, temporal lobe and putamen. Expression is particularly high in brain dopaminoceptive areas. {ECO:0000269|PubMed:15541308, ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:16532471, ECO:0000269|PubMed:17120249}. | Kinase | Parkinson disease 8 (PARK8) [MIM:607060]: A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients. {ECO:0000269|PubMed:15541308, ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:15680455, ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:15925109, ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16102999, ECO:0000269|PubMed:16157901, ECO:0000269|PubMed:16157908, ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:16240353, ECO:0000269|PubMed:16247070, ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, ECO:0000269|PubMed:16272164, ECO:0000269|PubMed:16272257, ECO:0000269|PubMed:16298482, ECO:0000269|PubMed:16333314, ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:18213618, ECO:0000269|PubMed:22956510}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Positively regulates autophagy through a calcium- dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose 6 phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner. Regulates neuronal process morphology in the intact central nervous system (CNS). Plays a role in synaptic vesicle trafficking. Phosphorylates PRDX3. Has GTPase activity. May play a role in the phosphorylation of proteins central to Parkinson disease. {ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:20949042, ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22012985, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:24687852}. | 15.1 | |||
| kccLSHR | Lutropin-choriogonadotropic hormone receptor | 5 | 72 | 99.95 | ND | 99.91 | 0.61 | ND | 0.8 | Mammalian | Gonadal and thyroid cells. | Family A G protein-coupled receptor | Familial male precocious puberty (FMPP) [MIM:176410]: In FMPP the receptor is constitutively activated. {ECO:0000269|PubMed:11134146, ECO:0000269|PubMed:11391350, ECO:0000269|PubMed:7629248, ECO:0000269|PubMed:7692306, ECO:0000269|PubMed:7714085, ECO:0000269|PubMed:7757065, ECO:0000269|PubMed:8281137, ECO:0000269|PubMed:8829636, ECO:0000269|PubMed:8929952, ECO:0000269|PubMed:9467560, ECO:0000269|PubMed:9661624}. Note=The disease is caused by mutations affecting the gene represented in this entry. Luteinizing hormone resistance (LHR) [MIM:238320]: An autosomal recessive disorder characterized by unresponsiveness to luteinizing hormone, defective sexual development in males, and defective follicular development and ovulation, amenorrhea and infertility in females. Two forms of the disorder have been defined in males. Type 1 is a severe form characterized by complete 46,XY male pseudohermaphroditism, low testosterone and high luteinizing hormone levels, total lack of responsiveness to luteinizing and chorionic gonadotropin hormones, lack of breast development, and absent development of secondary male sex characteristics. Type 2, a milder form, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias. {ECO:0000269|PubMed:12050206, ECO:0000269|PubMed:15372531, ECO:0000269|PubMed:15472221, ECO:0000269|PubMed:19551906, ECO:0000269|PubMed:7719343, ECO:0000269|PubMed:8559204, ECO:0000269|PubMed:9215288, ECO:0000269|PubMed:9514160, ECO:0000269|PubMed:9626144, ECO:0000269|PubMed:9626653}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for lutropin-choriogonadotropic hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. | Lutropin-choriogonadotropic hormone receptor agonist: Goserelin Lutropin-choriogonadotropic hormone receptor unknown: Cetrorelix | 15.1 | ||
| kccLT4R1 | Leukotriene B4 receptor 1 | 15 | 268 | 96.87 | ND | 96.67 | 0.50 | ND | 0.9 | Mammalian | Expressed at highest levels in heart, skeletal muscle and at lower levels in brain and liver. High level of expression in lymphoid tissues. | Family A G protein-coupled receptor | Adverse Effects, Chemotherapy
Asthma Cancer Chronic Obstructive Pulmonary Disease (COPD) Cystic Fibrosis Immunological disorders Inflammation Renal Cell Carcinoma Rheumatoid arthritis | Receptor for extracellular ATP > UTP and ADP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. May be the cardiac P2Y receptor involved in the regulation of cardiac muscle contraction through modulation of L-type calcium currents. Is a receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response. | 15.1 | |||
| kccLTK | Leukocyte tyrosine kinase receptor | 7 | 220 | 84.88 | ND | 82.65 | 0.11 | ND | 1.3 | Mammalian | Expressed in non-hematopoietic cell lines and T- and B-cell lines. {ECO:0000269|PubMed:2156206}. | Kinase | Note=Genetic variations in LTK that cause up-regulation of the PI3K pathway may possibly contribute to susceptibility to abnormal proliferation of self-reactive B-cells and, therefore, to systemic lupus erythematosus (SLE). SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue, thought to represent a failure of the regulatory mechanisms of the autoimmune system. | Orphan receptor with a tyrosine-protein kinase activity. The exact function of this protein is not known. Studies with chimeric proteins (replacing its extracellular region with that of several known growth factor receptors, such as EGFR and CSFIR) demonstrate its ability to promote growth and specifically neurite outgrowth, and cell survival. Signaling appears to involve the PI3 kinase pathway. Involved in regulation of the secretory pathway involving endoplasmic reticulum (ER) export sites (ERESs) and ER to Golgi transport. {ECO:0000269|PubMed:20548102}. | 15.1 | |||
| kccLYAM2 | E-selectin | 5 | 162 | 99.78 | ND | 99.81 | 0.37 | ND | 1.3 | Mammalian | Adhesion | Asthma
Atopic Dermatitis Chronic Obstructive Pulmonary Disease (COPD) Inflammatory skin disorder Ischemic stroke Psoriasis and Psoriatic Disorders | Cell-surface glycoprotein having a role in immunoadhesion. Mediates in the adhesion of blood neutrophils in cytokine-activated endothelium through interaction with PSGL1/SELPLG. May have a role in capillary morphogenesis. {ECO:0000269|PubMed:1689848}. | E-selectin inhibitor: Carvedilol | 15.1 | |||
| kccLYAM3 | P-selectin | 7 | 111 | 98.63 | ND | 99.82 | 0.32 | ND | 0.6 | Mammalian | Stored in the alpha-granules of platelets and Weibel-Palade bodies of endothelial cells. Upon cell activation by agonists, P-selectin is transported rapidly to the cell surface. | Adhesion | Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:14681304}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Ca(2+)-dependent receptor for myeloid cells that binds to carbohydrates on neutrophils and monocytes. Mediates the interaction of activated endothelial cells or platelets with leukocytes. The ligand recognized is sialyl-Lewis X. Mediates rapid rolling of leukocyte rolling over vascular surfaces during the initial steps in inflammation through interaction with PSGL1. {ECO:0000269|PubMed:7585950}. | P-selectin inhibitor: Heparin | 15.1 | ||
| kccLYN | Tyrosine-protein kinase Lyn | 21 | 458 | 98.06 | ND | 90.91 | 0.24 | ND | 1.2 | Mammalian | Detected in monocytes (at protein level). Detected in placenta, and in fetal brain, lung, liver and kidney. Widely expressed in a variety of organs, tissues, and cell types such as epidermoid, hematopoietic, and neuronal cells. Expressed in primary neuroblastoma tumors. {ECO:0000269|PubMed:3561390, ECO:0000269|PubMed:8064233}. | Kinase | Note=Constitutively phosphorylated and activated in cells from a number of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) patients. Mediates phosphorylation of the BCR-ABL fusion protein. Abnormally elevated expression levels or activation of LYN signaling may play a role in survival and proliferation of some types of cancer cells. | Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down- regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down- regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, PTK2B/PYK2, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3- kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr- 72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. {ECO:0000269|PubMed:10574931, ECO:0000269|PubMed:10748115, ECO:0000269|PubMed:10891478, ECO:0000269|PubMed:11435302, ECO:0000269|PubMed:11517336, ECO:0000269|PubMed:11825908, ECO:0000269|PubMed:14726379, ECO:0000269|PubMed:15795233, ECO:0000269|PubMed:16467205, ECO:0000269|PubMed:17640867, ECO:0000269|PubMed:17977829, ECO:0000269|PubMed:18056483, ECO:0000269|PubMed:18070987, ECO:0000269|PubMed:18235045, ECO:0000269|PubMed:18577747, ECO:0000269|PubMed:18802065, ECO:0000269|PubMed:19290919, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:7687428}. | Tyrosine-protein kinase Lyn Inhibitor: Nintedanib Tyrosine-protein kinase Lyn inhibitor: Ponatinib Tyrosine-protein kinase Lyn unknown: Bosutinib | 15.1 | ||
| kccM3K10 | Mitogen-activated protein kinase kinase kinase 10 | 1 | 87 | 84.00 | ND | 84.92 | 0.30 | ND | 1.4 | Mammalian | Expressed in brain and skeletal muscle. | Kinase | Cancer, unspecific | Activates the JUN N-terminal pathway. {ECO:0000250}. | 15.1 | |||
| kccM3K11 | Mitogen-activated protein kinase kinase kinase 11 | 3 | 111 | 92.77 | ND | 95.44 | 0.80 | ND | 0.8 | Mammalian | Expressed in a wide variety of normal and neoplastic tissues including fetal lung, liver, heart and kidney, and adult lung, liver, heart, kidney, placenta, skeletal muscle, pancreas and brain. {ECO:0000269|PubMed:8183572, ECO:0000269|PubMed:8195146}. | Kinase | Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle. {ECO:0000269|PubMed:12529434, ECO:0000269|PubMed:15258589, ECO:0000269|PubMed:8195146, ECO:0000269|PubMed:9003778}. | 15.1 | ||||
| kccM3K19 | Mitogen-activated protein kinase kinase kinase 19 | 1 | 61 | 83.93 | ND | 90.50 | 0.03 | ND | 1.2 | Mammalian | Kinase | 15.1 | ||||||
| kccM3K5 | Mitogen-activated protein kinase kinase kinase 5 | 2 | 130 | 95.38 | ND | 89.96 | 0.90 | ND | 0.4 | Mammalian | Abundantly expressed in heart and pancreas. | Kinase | Cardiac diseases
Malignant fibrous histiocytomas | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1). {ECO:0000269|PubMed:10411906, ECO:0000269|PubMed:10688666, ECO:0000269|PubMed:10849426, ECO:0000269|PubMed:11029458, ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11689443, ECO:0000269|PubMed:11920685, ECO:0000269|PubMed:12697749, ECO:0000269|PubMed:14688258, ECO:0000269|PubMed:14749717, ECO:0000269|PubMed:15023544, ECO:0000269|PubMed:16129676, ECO:0000269|PubMed:17220297, ECO:0000269|PubMed:23102700, ECO:0000269|PubMed:8940179, ECO:0000269|PubMed:8974401, ECO:0000269|PubMed:9564042, ECO:0000269|PubMed:9774977}. | 15.1 | |||
| kccM3K7 | Mitogen-activated protein kinase kinase kinase 7 | 1 | 107 | 97.00 | ND | 96.85 | 0.41 | ND | 1.0 | Mammalian | Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form. {ECO:0000269|PubMed:11118615}. | Kinase | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2- induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. {ECO:0000269|PubMed:10094049, ECO:0000269|PubMed:11460167, ECO:0000269|PubMed:12589052, ECO:0000269|PubMed:16845370, ECO:0000269|PubMed:16893890, ECO:0000269|PubMed:21512573, ECO:0000269|PubMed:8663074, ECO:0000269|PubMed:9079627}. | 15.1 | ||||
| kccM3K8 | Mitogen-activated protein kinase kinase kinase 8 | 7 | 224 | 99.88 | ND | 99.86 | 0.64 | ND | 0.7 | Mammalian | Expressed in several normal tissues and human tumor-derived cell lines. | Kinase | Not Available | Required for lipopolysaccharide (LPS)-induced, TLR4- mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF- alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B- cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant. {ECO:0000269|PubMed:11342626, ECO:0000269|PubMed:12667451, ECO:0000269|PubMed:15169888, ECO:0000269|PubMed:16371247, ECO:0000269|PubMed:1833717, ECO:0000269|PubMed:19001140, ECO:0000269|PubMed:19754427, ECO:0000269|PubMed:19808894}. | 15.1 | |||
| kccM3K9 | Mitogen-activated protein kinase kinase kinase 9 | 3 | 117 | 93.62 | ND | 81.56 | 0.47 | ND | 1.1 | Mammalian | Expressed in epithelial tumor cell lines of colonic, breast and esophageal origin. {ECO:0000269|PubMed:8477742}. | Kinase | Note=May play a role in esophageal cancer susceptibility and/or development. | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Plays also a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. {ECO:0000269|PubMed:11416147, ECO:0000269|PubMed:15610029}. | Mitogen-activated protein kinase kinase kinase 2 inhibitor: Bosutinib | 15.1 | ||
| kccM4K2 | Mitogen-activated protein kinase kinase kinase kinase 2 | 20 | 427 | 94.79 | ND | 89.82 | 0.24 | ND | 1.4 | Mammalian | Highly expressed in germinal center but not mantle zone B-cells. Also expressed in lung, brain and placenta and at lower levels in other tissues examined. {ECO:0000269|PubMed:7515885}. | Kinase | Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extend of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion. {ECO:0000269|PubMed:11784851, ECO:0000269|PubMed:15456887, ECO:0000269|PubMed:17584736, ECO:0000269|PubMed:7477268, ECO:0000269|PubMed:7515885, ECO:0000269|PubMed:9712898}. | 15.1 | ||||
| kccM4K4 | Mitogen-activated protein kinase kinase kinase kinase 4 | 38 | 596 | 95.89 | ND | 93.34 | 0.21 | ND | 1.2 | Mammalian | Appears to be ubiquitous. Expressed in all tissue types examined. Isoform 5 appears to be more abundant in the brain. Isoform 4 is predominant in the liver, skeletal muscle and placenta. {ECO:0000269|PubMed:9890973}. | Kinase | Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322. {ECO:0000269|PubMed:21690388, ECO:0000269|PubMed:9890973}. | 15.1 | ||||
| kccM4K5 | Mitogen-activated protein kinase kinase kinase kinase 5 | 20 | 357 | 96.53 | ND | 91.33 | 0.26 | ND | 1.5 | Mammalian | Ubiquitously expressed in all tissues examined, with high levels in the ovary, testis and prostate. {ECO:0000269|PubMed:9038372}. | Kinase | May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. {ECO:0000269|PubMed:9038372}. | 15.1 | ||||
| kccMAP11 | Methionine aminopeptidase 1 {ECO:0000255|HAMAP-Rule:MF_03174} | 5 | 187 | 93.38 | ND | 97.56 | 0.45 | ND | 0.7 | Mammalian | Protease | Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Required for normal progression through the cell cycle. {ECO:0000255|HAMAP- Rule:MF_03174, ECO:0000269|PubMed:16274222, ECO:0000269|PubMed:17114291}. | Mitogen-activated protein kinase kinase kinase 2 inhibitor: Bosutinib | 15.1 | ||||
| kccMAP2 | Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} | 10 | 392 | 91.15 | ND | 99.88 | 0.78 | ND | 0.6 | Mammalian | Protease | Bacterial infections
Cancer, unspecific Mesothelioma | Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N- terminal Met-Val and Met-Thr sequences in vivo. Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis. | Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} inhibitor: Nitroxoline Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} product of: L-Methionine | 15.1 | |||
| kccMAPK2 | MAP kinase-activated protein kinase 2 | 28 | 909 | 97.90 | ND | 96.23 | 0.70 | ND | 0.7 | Mammalian | Expressed in all tissues examined. | Kinase | Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, ELAVL1, HNRNPA0, HSF1, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat- shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilize GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:11844797, ECO:0000269|PubMed:12456657, ECO:0000269|PubMed:12565831, ECO:0000269|PubMed:14499342, ECO:0000269|PubMed:14517288, ECO:0000269|PubMed:15014438, ECO:0000269|PubMed:15629715, ECO:0000269|PubMed:16278218, ECO:0000269|PubMed:16456544, ECO:0000269|PubMed:17481585, ECO:0000269|PubMed:18021073, ECO:0000269|PubMed:20932473, ECO:0000269|PubMed:8093612, ECO:0000269|PubMed:8280084, ECO:0000269|PubMed:8774846}. | Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} inhibitor: Nitroxoline Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} product of: L-Methionine | 15.1 | |||
| kccMAPK3 | MAP kinase-activated protein kinase 3 | 4 | 48 | 83.37 | ND | 83.24 | 0.10 | ND | 1.3 | Mammalian | Widely expressed, with a higher expression level observed in heart and skeletal muscle. No expression in brain. {ECO:0000269|PubMed:8622688, ECO:0000269|PubMed:8626550}. | Kinase | Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38- alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression. {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:15563468, ECO:0000269|PubMed:18021073, ECO:0000269|PubMed:20599781, ECO:0000269|PubMed:8626550, ECO:0000269|PubMed:8774846}. | Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} inhibitor: Nitroxoline Methionine aminopeptidase 2 {ECO:0000255|HAMAP-Rule:MF_03175} product of: L-Methionine | 15.1 | |||
| kccMAPK5 | MAP kinase-activated protein kinase 5 | 6 | 141 | 92.65 | ND | 91.41 | 0.41 | ND | 1.2 | Mammalian | Expressed ubiquitously. {ECO:0000269|PubMed:9628874}. | Kinase | Tumor suppressor serine/threonine-protein kinase involved in mTORC1 signaling and post-transcriptional regulation. Phosphorylates FOXO3, ERK3/MAPK6, ERK4/MAPK4, HSP27/HSPB1, p53/TP53 and RHEB. Acts as a tumor suppressor by mediating Ras- induced senescence and phosphorylating p53/TP53. Involved in post- transcriptional regulation of MYC by mediating phosphorylation of FOXO3: phosphorylation of FOXO3 leads to promote nuclear localization of FOXO3, enabling expression of miR-34b and miR-34c, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent MYC translation. Acts as a negative regulator of mTORC1 signaling by mediating phosphorylation and inhibition of RHEB. Part of the atypical MAPK signaling via its interaction with ERK3/MAPK6 or ERK4/MAPK4: the precise role of the complex formed with ERK3/MAPK6 or ERK4/MAPK4 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPK (ERK3/MAPK6 or ERK4/MAPK4), ERK3/MAPK6 (or ERK4/MAPK4) is phosphorylated and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6 (or ERK4/MAPK4). Mediates phosphorylation of HSP27/HSPB1 in response to PKA/PRKACA stimulation, inducing F-actin rearrangement. {ECO:0000269|PubMed:17254968, ECO:0000269|PubMed:17728103, ECO:0000269|PubMed:19166925, ECO:0000269|PubMed:21329882, ECO:0000269|PubMed:9628874}. | 15.1 | ||||
| kccMARK1 | Serine/threonine-protein kinase MARK1 | 1 | 74 | 82.38 | ND | 97.52 | 0.08 | ND | 1.0 | Mammalian | Highly expressed in heart, skeletal muscle, brain, fetal brain and fetal kidney. {ECO:0000269|PubMed:9108484}. | Kinase | Note=Genetic variations in MARK1 may be associated with susceptibility to autism. MARK1 is overexpressed in the prefrontal cortex of patients with autism and causes changes in the function of cortical dendrites. | Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2, MAP4 and MAPT/TAU. Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). {ECO:0000269|PubMed:11433294, ECO:0000269|PubMed:17573348}. | 15.1 | |||
| kccMARK2 | Serine/threonine-protein kinase MARK2 | 17 | 282 | 89.93 | ND | 84.90 | 0.01 | ND | 1.1 | Mammalian | High levels of expression in heart, brain, skeletal muscle and pancreas, lower levels observed in lung, liver and kidney. {ECO:0000269|PubMed:9730619}. | Kinase | Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates CRTC2/TORC2, DCX, HDAC7, KIF13B, MAP2, MAP4, MAPT/TAU, and RAB11FIP2. Plays a key role in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Regulates epithelial cell polarity by phosphorylating RAB11FIP2. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Regulates axogenesis by phosphorylating KIF13B, promoting interaction between KIF13B and 14-3-3 and inhibiting microtubule- dependent accumulation of KIF13B. Also required for neurite outgrowth and establishment of neuronal polarity. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Modulates the developmental decision to build a columnar versus a hepatic epithelial cell apparently by promoting a switch from a direct to a transcytotic mode of apical protein delivery. Essential for the asymmetric development of membrane domains of polarized epithelial cells. {ECO:0000269|PubMed:11433294, ECO:0000269|PubMed:12429843, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15158914, ECO:0000269|PubMed:15324659, ECO:0000269|PubMed:15365179, ECO:0000269|PubMed:16775013, ECO:0000269|PubMed:16980613, ECO:0000269|PubMed:18626018, ECO:0000269|PubMed:20194617}. | 15.1 | ||||
| kccMARK3 | MAP/microtubule affinity-regulating kinase 3 | 21 | 306 | 95.03 | ND | 91.70 | 0.06 | ND | 1.3 | Mammalian | Ubiquitous. | Kinase | Leukaemia
RCC | Involved in the specific phosphorylation of microtubule- associated proteins for tau, MAP2 and MAP4. Phosphorylates CDC25C on 'Ser-216'. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. {ECO:0000269|PubMed:16980613}. | 15.1 | |||
| kccMATK | Megakaryocyte-associated tyrosine-protein kinase | 2 | 96 | 96.19 | ND | 89.97 | 0.20 | ND | 1.3 | Mammalian | Expressed in various myeloid cell lines, detected in brain and lung. | Kinase | Could play a significant role in the signal transduction of hematopoietic cells. May regulate tyrosine kinase activity of SRC-family members in brain by specifically phosphorylating their C-terminal regulatory tyrosine residue which acts as a negative regulatory site. It may play an inhibitory role in the control of T-cell proliferation. {ECO:0000269|PubMed:9171348}. | 15.1 | ||||
| kccMC3R | Melanocortin receptor 3 | 8 | 863 | 99.35 | ND | 99.56 | 0.68 | ND | 0.7 | Nature11159 | Mammalian | Brain, placental, and gut tissues. | Family A G protein-coupled receptor | Chronic inflammatory diseases
Gouty arthritis Obesity | Receptor for MSH (alpha, beta and gamma) and ACTH. This receptor is mediated by G proteins which activate adenylate cyclase. Required for expression of anticipatory patterns of activity and wakefulness during periods of limited nutrient availability and for the normal regulation of circadian clock activity in the brain. {ECO:0000250|UniProtKB:P33033}. | 15.1 | ||
| kccMC4R | Melanocortin receptor 4 | 24 | 2203 | 99.07 | ND | 99.26 | 0.64 | ND | 0.7 | Nature11159 | Mammalian | Brain, placental, and gut tissues. | Family A G protein-coupled receptor | Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:10199800, ECO:0000269|PubMed:11443223, ECO:0000269|PubMed:11487744, ECO:0000269|PubMed:12588803, ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:14671178, ECO:0000269|PubMed:14764818, ECO:0000269|PubMed:15486053}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP). {ECO:0000269|PubMed:12646665}. | 15.1 | ||
| kccMC5R | Melanocortin receptor 5 | 11 | 777 | 99.05 | ND | 98.46 | 0.68 | ND | 0.7 | Mammalian | Expressed in the brain but not in the melanoma cells. | Family A G protein-coupled receptor | Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. This receptor is a possible mediator of the immunomodulation properties of melanocortins. | 15.1 | ||||
| kccMCHR1 | Melanin-concentrating hormone receptor 1 | 78 | 2465 | 99.08 | ND | 98.82 | 0.52 | ND | 0.6 | Mammalian | Highest level in brain, particularly in the frontal cortex and hypothalamus, lower levels in the liver and heart. | Family A G protein-coupled receptor | Obesity
Social anxiety disorder Vitiligo | Receptor for melanin-concentrating hormone, coupled to both G proteins that inhibit adenylyl cyclase and G proteins that activate phosphoinositide hydrolysis. {ECO:0000269|PubMed:10421367}. | 15.1 | |||
| kccMCHR2 | Melanin-concentrating hormone receptor 2 | 3 | 125 | 98.01 | ND | 92.51 | 0.66 | ND | 0.9 | Mammalian | Specifically expressed in the brain, with highest levels in cerebral cortex, hippocampus and amygdala. No expression detected in the cerebellum, thalamus or hypothalamus. | Family A G protein-coupled receptor | Obesity
Social anxiety disorder | Receptor for melanin-concentrating hormone, coupled to G proteins that activate phosphoinositide hydrolysis. | 15.1 | |||
| kccMCL1 | Induced myeloid leukemia cell differentiation protein Mcl-1 | 53 | 1059 | 91.02 | ND | 89.06 | 0.12 | ND | 1.1 | Mammalian | Other cytosolic protein | Leukemia, Lymphoid
Lymphoma, Non-Hodgkin's Prostate cancer | Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis. {ECO:0000269|PubMed:10766760, ECO:0000269|PubMed:16543145}. | 15.1 | ||||
| kccMCLN3 | Mucolipin-3 | 4 | 123 | 84.28 | ND | 86.58 | 0.04 | ND | 1.2 | Mammalian | Voltage-gated ion channel | 15.1 | ||||||
| kccMCR | Mineralocorticoid receptor | 39 | 652 | 96.92 | ND | 96.62 | 0.45 | ND | 0.5 | VirtualToxLab | Mammalian | Ubiquitous. Highly expressed in distal tubules, convoluted tubules and cortical collecting duct in kidney, and in sweat glands. Detected at lower levels in cardiomyocytes, in epidermis and in colon enterocytes. {ECO:0000269|PubMed:11518808, ECO:0000269|PubMed:9141514}. | Acne Adrenal insufficiency Amenorrhoea Cushingoid Depression Embolism arterial Endocrine disorder Euphoric mood Hyperglycaemia Hypokalaemia Menstrual disorder Muscular weakness Oedema Osteoporosis Peptic ulcer | Nuclear receptor | Pseudohypoaldosteronism 1, autosomal dominant (PHA1A) [MIM:177735]: A salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1A is a mild form characterized by target organ defects confined to kidney. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. {ECO:0000269|PubMed:16972228}. Note=The disease is caused by mutations affecting the gene represented in this entry. Early-onset hypertension with severe exacerbation in pregnancy (EOHSEP) [MIM:605115]: Inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, and by suppression of aldosterone secretion. {ECO:0000269|PubMed:10884226}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels. {ECO:0000269|PubMed:3037703}. | Mineralocorticoid receptor agonist: Fludrocortisone Mineralocorticoid receptor antagonist: Drospirenone, Eplerenone, Felodipine, Fluticasone Propionate, Nimodipine, Progesterone, Spironolactone | 15.1 |
| kccMDM2 | E3 ubiquitin-protein ligase Mdm2 | 24 | 529 | 96.62 | ND | 95.96 | 0.87 | ND | 0.6 | Mammalian | Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues. | Other nuclear protein | Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. | E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation. {ECO:0000269|PubMed:12821780, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:15195100, ECO:0000269|PubMed:15632057, ECO:0000269|PubMed:16337594, ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:19098711, ECO:0000269|PubMed:19219073, ECO:0000269|PubMed:19837670, ECO:0000269|PubMed:19965871, ECO:0000269|PubMed:20173098, ECO:0000269|PubMed:20385133, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:22128911}. | Mineralocorticoid receptor agonist: Fludrocortisone Mineralocorticoid receptor antagonist: Drospirenone, Eplerenone, Felodipine, Fluticasone Propionate, Nimodipine, Progesterone, Spironolactone | 15.1 | ||
| kccMDM4 | Protein Mdm4 | 3 | 42 | 100.00 | ND | 100.00 | 0.68 | ND | 0.7 | Mammalian | Expressed in all tissues tested with high levels in thymus. | Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions. {ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:16511572}. | 15.1 | |||||
| kccMDR1 | Multidrug resistance protein 1 | 51 | 1274 | 91.52 | ND | 94.66 | 0.55 | ND | 0.6 | Mammalian | Expressed in liver, kidney, small intestine and brain. | Alopecia Angioedema Azoospermia Bone marrow failure Hyperlipidaemia Mucosal inflammation Oligomenorrhoea Stomatitis | Primary active transporter | Inflammatory bowel disease 13 (IBD13) [MIM:612244]: A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. | Multidrug resistance protein 1 inducer: Levothyroxine, Liothyronine, Liotrix, Nefazodone, Norethindrone, Streptozocin, Trazodone Multidrug resistance protein 1 inhibitor: Albendazole, Alfentanil, Amantadine, Aminohippurate, Amlodipine, Amsacrine, Astemizole, Atorvastatin, Azelastine, Azithromycin, Benzocaine, Bepridil, Biperiden, Buprenorphine, Buspirone, Candesartan, Captopril, Carvedilol, Caspofungin, Chloroquine, Chlorpropamide, Chlorprothixene, Cilazapril, Clofazimine, Clomipramine, Cyclophosphamide, Desipramine, Desloratadine, Dextromethorphan, Diclofenac, Dihydroergotamine, Doxazosin, Doxepin, Dronabinol, Dronedarone, Enalapril, Enzalutamide, Ergonovine, Ergotamine, Estramustine, Etravirine, Felodipine, Fentanyl, Fluconazole, Fluoxetine, Flupentixol, Fluphenazine, Flurazepam, Fluvoxamine, Glyburide, Itraconazole, Ivacaftor, Ketamine, Lapatinib, Lidocaine, Lisinopril, Lomitapide, Lopinavir, Loratadine, Lovastatin, Maprotiline, Mebendazole, Mefloquine, Megestrol acetate, Meprobamate, Methadone, Miconazole, Mitomycin, Naltrexone, Neostigmine, Nisoldipine, Nitrazepam, Nitrendipine, Omeprazole, Pantoprazole, Paroxetine, Perindopril, Pimozide, Posaconazole, Probenecid, Promethazine, Propafenone, Protriptyline, Quinacrine, Reboxetine, Regorafenib, Rilpivirine, Scopolamine, Selegiline, Sertraline, Simvastatin, Spironolactone, Sulfinpyrazone, Sumatriptan, Sunitinib, Telmisartan, Terazosin, Testosterone, Trifluoperazine, Triflupromazine, Trimipramine, Troleandomycin, Vinorelbine Multidrug resistance protein 1 inhibitor, competitive: Voacamine Multidrug resistance protein 1 inhibitor;inducer: Amiodarone, Amprenavir, Clotrimazole, Mifepristone, Sirolimus, Trimethoprim Multidrug resistance protein 1 substrate: Acebutolol, Acetylsalicylic acid, Alitretinoin, Apixaban, Arsenic trioxide, Betamethasone, Boceprevir, Carfilzomib, Ceritinib, Cisplatin, Clobazam, Clomifene, Clonidine, Clopidogrel, Clozapine, Conjugated Estrogens, Dabigatran etexilate, Dabrafenib, Dapagliflozin, Debrisoquin, Diazepam, Diethylstilbestrol, Digitoxin, Docetaxel, Domperidone, Edoxaban, Eletriptan, Epinastine, Erlotinib, Estradiol, Ethinyl Estradiol, Ezetimibe, Fesoterodine, Fluticasone furoate, Gemcitabine, Ibuprofen, Indacaterol, Irinotecan, Ketazolam, Lamivudine, Lamotrigine, Lenalidomide, Lenvatinib, Levetiracetam, Levomilnacipran, Linagliptin, Mannitol, Methotrexate, Methylprednisolone, Mirabegron, Mycophenolate mofetil, Nadolol, Naloxone, Nintedanib, Nizatidine, Olanzapine, Pazopanib, Phenytoin, Pitavastatin, Pomalidomide, Prednisolone, Quetiapine, Risperidone, Rivaroxaban, SOFOSBUVIR, Salicylic acid, Silodosin, Sitagliptin, Sparfloxacin, Telaprevir, Timolol, Topotecan, Toremifene, Umeclidinium, Vecuronium, Vismodegib, Zidovudine Multidrug resistance protein 1 substrate;inducer: Estriol, Estrone, Phenobarbital Multidrug resistance protein 1 substrate;inhibitor: Acetaminophen, Afatinib, Amitriptyline, Atazanavir, Atenolol, Bosutinib, Bromocriptine, Cabazitaxel, Caffeine, Canagliflozin, Chlorpromazine, Ciprofloxacin, Citalopram, Clarithromycin, Colchicine, Crizotinib, Dactinomycin, Dasatinib, Diltiazem, Dipyridamole, Etoposide, Fexofenadine, Fidaxomicin, Gefitinib, Haloperidol, Hydrocortisone, Idelalisib, Imatinib, Imipramine, Indomethacin, Ivermectin, Ketoconazole, Lansoprazole, Levofloxacin, Loperamide, Losartan, Metoprolol, Morphine, Nicardipine, Nilotinib, Paclitaxel, Ponatinib, Pravastatin, Prazosin, Prednisone, Propranolol, Quinidine, Quinine, Ranitidine, SIMEPREVIR, Sorafenib, Temsirolimus, Ticagrelor, Tolvaptan, Venlafaxine Multidrug resistance protein 1 substrate;inhibitor;inducer: Carbamazepine, Cimetidine, Cyclosporine, Daunorubicin, Dexamethasone, Digoxin, Doxorubicin, Erythromycin, Indinavir, Midazolam, Mitoxantrone, Nelfinavir, Nifedipine, Progesterone, Reserpine, Rifampicin, Ritonavir, Saquinavir, Tacrolimus, Tamoxifen, Verapamil, Vinblastine, Vincristine Multidrug resistance protein 1 unknown: Adenosine triphosphate, Clarithromycin, Clofazimine, Erythromycin, Roxithromycin | 15.1 | |
| kccMDR1A | Multidrug resistance protein 1A | 4 | 83 | 92.66 | ND | 82.29 | 0.47 | ND | 0.4 | Mammalian | Primary active transporter | Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. {ECO:0000269|PubMed:19325113}. | 15.1 | |||||
| kccMDR1B | Multidrug resistance protein 1B | 3 | 80 | 98.01 | ND | 94.44 | 0.41 | ND | 0.7 | Mammalian | Primary active transporter | Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. | 15.1 | |||||
| kccMELK | Maternal embryonic leucine zipper kinase | 12 | 218 | 95.03 | ND | 92.68 | 0.24 | ND | 1.5 | Mammalian | Expressed in placenta, kidney, thymus, testis, ovary and intestine. {ECO:0000269|PubMed:8724849}. | Kinase | Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation. | Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis. {ECO:0000269|PubMed:11802789, ECO:0000269|PubMed:12400006, ECO:0000269|PubMed:14699119, ECO:0000269|PubMed:15908796, ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:17280616}. | 15.1 | |||
| kccMEN1 | Menin | 2 | 49 | 99.96 | ND | 94.97 | 0.74 | ND | 0.4 | Mammalian | Ubiquitous. | Familial multiple endocrine neoplasia type I (MEN1) [MIM:131100]: Autosomal dominant disorder characterized by tumors of the parathyroid glands, gastro-intestinal endocrine tissue, the anterior pituitary and other tissues. Cutaneous lesions and nervous-tissue tumors can exist. Prognosis in MEN1 patients is related to hormonal hypersecretion by tumors, such as hypergastrinemia causing severe peptic ulcer disease (Zollinger- Ellison syndrome, ZES), primary hyperparathyroidism, and acute forms of hyperinsulinemia. {ECO:0000269|PubMed:10090472, ECO:0000269|PubMed:10229909, ECO:0000269|PubMed:10534569, ECO:0000269|PubMed:10576763, ECO:0000269|PubMed:10617276, ECO:0000269|PubMed:10660339, ECO:0000269|PubMed:10664520, ECO:0000269|PubMed:10849016, ECO:0000269|PubMed:10993647, ECO:0000269|PubMed:11102994, ECO:0000269|PubMed:11134142, ECO:0000269|PubMed:11241849, ECO:0000269|PubMed:12050235, ECO:0000269|PubMed:12112656, ECO:0000269|PubMed:12417605, ECO:0000269|PubMed:12652570, ECO:0000269|PubMed:12746426, ECO:0000269|PubMed:12791038, ECO:0000269|PubMed:14686752, ECO:0000269|PubMed:14992727, ECO:0000269|PubMed:15714081, ECO:0000269|PubMed:15730416, ECO:0000269|PubMed:17555499, ECO:0000269|PubMed:9103196, ECO:0000269|PubMed:9215689, ECO:0000269|PubMed:9215690, ECO:0000269|PubMed:9463336, ECO:0000269|PubMed:9506756, ECO:0000269|PubMed:9671267, ECO:0000269|PubMed:9683585, ECO:0000269|PubMed:9709921, ECO:0000269|PubMed:9709976, ECO:0000269|PubMed:9709985, ECO:0000269|PubMed:9740255, ECO:0000269|PubMed:9747036, ECO:0000269|PubMed:9820618, ECO:0000269|PubMed:9832038, ECO:0000269|PubMed:9888389, ECO:0000269|PubMed:9989505}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial isolated hyperparathyroidism (FIHP) [MIM:145000]: Autosomal dominant disorder characterized by hypercalcemia, elevated parathyroid hormone (PTH) levels, and uniglandular or multiglandular parathyroid tumors. {ECO:0000269|PubMed:10634381, ECO:0000269|PubMed:10664521, ECO:0000269|PubMed:12016470, ECO:0000269|PubMed:12699448, ECO:0000269|PubMed:9792884, ECO:0000269|PubMed:9843042, ECO:0000269|PubMed:9888389}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3 (H3K4). Functions as a transcriptional regulator. Binds to the TERT promoter and represses telomerase expression. Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity. Represses JUND-mediated transcriptional activation on AP1 sites, as well as that mediated by NFKB subunit RELA. Positively regulates HOXC8 and HOXC6 gene expression. May be involved in normal hematopoiesis through the activation of HOXA9 expression (By similarity). May be involved in DNA repair. {ECO:0000250, ECO:0000269|PubMed:11274402, ECO:0000269|PubMed:11526476, ECO:0000269|PubMed:12837246, ECO:0000269|PubMed:12874027, ECO:0000269|PubMed:14992727}. | 15.1 | ||||
| kccMERTK | Tyrosine-protein kinase Mer | 5 | 185 | 97.21 | ND | 96.30 | 0.49 | ND | 1.3 | Mammalian | Not expressed in normal B- and T-lymphocytes but is expressed in numerous neoplastic B- and T-cell lines. Highly expressed in testis, ovary, prostate, lung, and kidney, with lower expression in spleen, small intestine, colon, and liver. | Kinase | Retinitis pigmentosa 38 (RP38) [MIM:613862]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:11062461}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll- like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:17005688}. | Multidrug resistance protein 1 inducer: Levothyroxine, Liothyronine, Liotrix, Nefazodone, Norethindrone, Streptozocin, Trazodone Multidrug resistance protein 1 inhibitor: Albendazole, Alfentanil, Amantadine, Aminohippurate, Amlodipine, Amsacrine, Astemizole, Atorvastatin, Azelastine, Azithromycin, Benzocaine, Bepridil, Biperiden, Buprenorphine, Buspirone, Candesartan, Captopril, Carvedilol, Caspofungin, Chloroquine, Chlorpropamide, Chlorprothixene, Cilazapril, Clofazimine, Clomipramine, Cyclophosphamide, Desipramine, Desloratadine, Dextromethorphan, Diclofenac, Dihydroergotamine, Doxazosin, Doxepin, Dronabinol, Dronedarone, Enalapril, Enzalutamide, Ergonovine, Ergotamine, Estramustine, Etravirine, Felodipine, Fentanyl, Fluconazole, Fluoxetine, Flupentixol, Fluphenazine, Flurazepam, Fluvoxamine, Glyburide, Itraconazole, Ivacaftor, Ketamine, Lapatinib, Lidocaine, Lisinopril, Lomitapide, Lopinavir, Loratadine, Lovastatin, Maprotiline, Mebendazole, Mefloquine, Megestrol acetate, Meprobamate, Methadone, Miconazole, Mitomycin, Naltrexone, Neostigmine, Nisoldipine, Nitrazepam, Nitrendipine, Omeprazole, Pantoprazole, Paroxetine, Perindopril, Pimozide, Posaconazole, Probenecid, Promethazine, Propafenone, Protriptyline, Quinacrine, Reboxetine, Regorafenib, Rilpivirine, Scopolamine, Selegiline, Sertraline, Simvastatin, Spironolactone, Sulfinpyrazone, Sumatriptan, Sunitinib, Telmisartan, Terazosin, Testosterone, Trifluoperazine, Triflupromazine, Trimipramine, Troleandomycin, Vinorelbine Multidrug resistance protein 1 inhibitor, competitive: Voacamine Multidrug resistance protein 1 inhibitor;inducer: Amiodarone, Amprenavir, Clotrimazole, Mifepristone, Sirolimus, Trimethoprim Multidrug resistance protein 1 substrate: Acebutolol, Acetylsalicylic acid, Alitretinoin, Apixaban, Arsenic trioxide, Betamethasone, Boceprevir, Carfilzomib, Ceritinib, Cisplatin, Clobazam, Clomifene, Clonidine, Clopidogrel, Clozapine, Conjugated Estrogens, Dabigatran etexilate, Dabrafenib, Dapagliflozin, Debrisoquin, Diazepam, Diethylstilbestrol, Digitoxin, Docetaxel, Domperidone, Edoxaban, Eletriptan, Epinastine, Erlotinib, Estradiol, Ethinyl Estradiol, Ezetimibe, Fesoterodine, Fluticasone furoate, Gemcitabine, Ibuprofen, Indacaterol, Irinotecan, Ketazolam, Lamivudine, Lamotrigine, Lenalidomide, Lenvatinib, Levetiracetam, Levomilnacipran, Linagliptin, Mannitol, Methotrexate, Methylprednisolone, Mirabegron, Mycophenolate mofetil, Nadolol, Naloxone, Nintedanib, Nizatidine, Olanzapine, Pazopanib, Phenytoin, Pitavastatin, Pomalidomide, Prednisolone, Quetiapine, Risperidone, Rivaroxaban, SOFOSBUVIR, Salicylic acid, Silodosin, Sitagliptin, Sparfloxacin, Telaprevir, Timolol, Topotecan, Toremifene, Umeclidinium, Vecuronium, Vismodegib, Zidovudine Multidrug resistance protein 1 substrate;inducer: Estriol, Estrone, Phenobarbital Multidrug resistance protein 1 substrate;inhibitor: Acetaminophen, Afatinib, Amitriptyline, Atazanavir, Atenolol, Bosutinib, Bromocriptine, Cabazitaxel, Caffeine, Canagliflozin, Chlorpromazine, Ciprofloxacin, Citalopram, Clarithromycin, Colchicine, Crizotinib, Dactinomycin, Dasatinib, Diltiazem, Dipyridamole, Etoposide, Fexofenadine, Fidaxomicin, Gefitinib, Haloperidol, Hydrocortisone, Idelalisib, Imatinib, Imipramine, Indomethacin, Ivermectin, Ketoconazole, Lansoprazole, Levofloxacin, Loperamide, Losartan, Metoprolol, Morphine, Nicardipine, Nilotinib, Paclitaxel, Ponatinib, Pravastatin, Prazosin, Prednisone, Propranolol, Quinidine, Quinine, Ranitidine, SIMEPREVIR, Sorafenib, Temsirolimus, Ticagrelor, Tolvaptan, Venlafaxine Multidrug resistance protein 1 substrate;inhibitor;inducer: Carbamazepine, Cimetidine, Cyclosporine, Daunorubicin, Dexamethasone, Digoxin, Doxorubicin, Erythromycin, Indinavir, Midazolam, Mitoxantrone, Nelfinavir, Nifedipine, Progesterone, Reserpine, Rifampicin, Ritonavir, Saquinavir, Tacrolimus, Tamoxifen, Verapamil, Vinblastine, Vincristine Multidrug resistance protein 1 unknown: Adenosine triphosphate, Clarithromycin, Clofazimine, Erythromycin, Roxithromycin | 15.1 | ||
| kccMET | Hepatocyte growth factor receptor | 73 | 1770 | 98.27 | ND | 96.81 | 0.64 | ND | 0.8 | Mammalian | Expressed in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Found also in basal keratinocytes of esophagus and skin. High levels are found in liver, gastrointestinal tract, thyroid and kidney. Also present in the brain. {ECO:0000269|PubMed:1719465, ECO:0000269|PubMed:1917129}. | Kinase | Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. Note=Defects in MET may be associated with gastric cancer. Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:9927037}. Note=The disease is caused by mutations affecting the gene represented in this entry. Renal cell carcinoma papillary (RCCP) [MIM:605074]: A subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. {ECO:0000269|PubMed:10327054, ECO:0000269|PubMed:10417759, ECO:0000269|PubMed:10433944, ECO:0000269|PubMed:9140397, ECO:0000269|PubMed:9563489}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes. Note=MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies. | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells. | Hepatocyte growth factor receptor inhibitor: Crizotinib | 15.1 | ||
| kccMGA | Maltase-glucoamylase, intestinal | 3 | 87 | 99.25 | ND | 99.88 | 0.16 | ND | 1.2 | Mammalian | Expressed in small intestine, granulocyte, and kidney but not in salivary gland or pancreas. | Hydrolase | Diabetes mellitus | May serve as an alternate pathway for starch digestion when luminal alpha-amylase activity is reduced because of immaturity or malnutrition. May play a unique role in the digestion of malted dietary oligosaccharides used in food manufacturing. | Maltase-glucoamylase, intestinal antagonist;inhibitor: Miglitol Maltase-glucoamylase, intestinal inhibitor: Acarbose, Voglibose | 15.1 | ||
| kccMGLL | Monoglyceride lipase {ECO:0000312|HGNC:HGNC:17038} | 11 | 336 | 96.08 | ND | 97.92 | 0.68 | ND | 0.6 | Mammalian | Detected in adipose tissue, lung, liver, kidney, brain and heart. {ECO:0000269|PubMed:11470505}. | Enzyme | Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (By similarity). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth (PubMed:20079333). {ECO:0000250|UniProtKB:O35678, ECO:0000269|PubMed:20079333}. | 15.1 | ||||
| kccMGMT | Methylated-DNA--protein-cysteine methyltransferase | 6 | 52 | 99.98 | ND | 99.95 | 0.11 | ND | 1.0 | Mammalian | Enzyme | Cancer, unspecific | Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) in DNA. Repairs alkylated guanine in DNA by stoichiometrically transferring the alkyl group at the O-6 position to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated. | Methylated-DNA--protein-cysteine methyltransferase unknown: L-Cysteine | 15.1 | |||
| kccMIF | Macrophage migration inhibitory factor | 5 | 150 | 91.04 | ND | 89.29 | 0.30 | ND | 0.9 | Mammalian | Enzyme | Rheumatoid arthritis systemic juvenile (RASJ) [MIM:604302]: An inflammatory articular disorder with systemic- onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Pro-inflammatory cytokine. Involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. Counteracts the anti- inflammatory activity of glucocorticoids. Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known. It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity. {ECO:0000269|PubMed:15908412, ECO:0000269|PubMed:17443469, ECO:0000269|PubMed:23776208}. | Methylated-DNA--protein-cysteine methyltransferase unknown: L-Cysteine | 15.1 | |||
| kccMINK1 | Misshapen-like kinase 1 | 16 | 328 | 95.55 | ND | 89.14 | 0.34 | ND | 1.2 | Mammalian | Expressed in the brain, isoform 2 is more abundant than isoform 1. Isoform 3 is ubiquitously expressed. Isoform 1 is most abundant in the skeletal muscle. Isoform 4 is ubiquitously expressed with relative high levels in brain, skeletal muscle, pancreas and testis. {ECO:0000269|PubMed:15469942}. | Kinase | Serine/threonine kinase which acts as a negative regulator of Ras-related Rap2-mediated signal transduction to control neuronal structure and AMPA receptor trafficking. Required for normal synaptic density, dendrite complexity, as well as surface AMPA receptor expression in hippocampal neurons. Can activate the JNK and MAPK14/p38 pathways and mediates stimulation of the stress-activated protein kinase MAPK14/p38 MAPK downstream of the Raf/ERK pathway. Phosphorylates: TANC1 upon stimulation by RAP2A, MBP and SMAD1. Has an essential function in negative selection of thymocytes, perhaps by coupling NCK1 to activation of JNK1. Isoform 4 can activate the JNK pathway. Involved in the regulation of actin cytoskeleton reorganization, cell-matrix adhesion, cell-cell adhesion and cell migration. | 15.1 | ||||
| kccMITF | Microphthalmia-associated transcription factor | 22 | 673 | 85.78 | ND | 87.38 | 0.04 | ND | 1.0 | Mammalian | Isoform M is exclusively expressed in melanocytes and melanoma cells. Isoform A and isoform H are widely expressed in many cell types including melanocytes and retinal pigment epithelium (RPE). Isoform C is expressed in many cell types including RPE but not in melanocyte-lineage cells. Isoform Mdel is widely expressed in melanocytes, melanoma cell lines and tissues, but almost undetectable in non-melanoma cell lines. {ECO:0000269|PubMed:20163701}. | Waardenburg syndrome 2A (WS2A) [MIM:193510]: WS2 is a genetically heterogeneous, autosomal dominant disorder characterized by sensorineural deafness, pigmentary disturbances, and absence of dystopia canthorum. The frequency of deafness is higher in WS2 than in WS1. {ECO:0000269|PubMed:8589691}. Note=The disease is caused by mutations affecting the gene represented in this entry. Waardenburg syndrome 2, with ocular albinism, autosomal recessive (WS2-OA) [MIM:103470]: A disorder characterized by the association of features typical of Waardenburg syndrome type 2 with ocular albinism. Patients manifest reduced visual acuity, albinotic fundus, deafness, hypomelanosis. Note=The disease is caused by mutations affecting the gene represented in this entry. Tietz syndrome (TIETZS) [MIM:103500]: Autosomal dominant disorder characterized by generalized hypopigmentation and profound, congenital, bilateral deafness. Penetrance is complete. {ECO:0000269|PubMed:10851256}. Note=The disease is caused by mutations affecting the gene represented in this entry. Melanoma, cutaneous malignant 8 (CMM8) [MIM:614456]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:22012259, ECO:0000269|PubMed:22080950}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5'- CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest- derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium. {ECO:0000269|PubMed:10587587, ECO:0000269|PubMed:22647378}. | 15.1 | ||||
| kccMK01 | Mitogen-activated protein kinase 1 | 28 | 1575 | 85.54 | ND | 86.15 | 0.58 | ND | 0.8 | Mammalian | Kinase | Neurodegenerative diseases
Proliferative diseases | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in respons to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity. | Mitogen-activated protein kinase 1 inducer: Arsenic trioxide, Isoprenaline | 15.1 | |||
| kccMK03 | Mitogen-activated protein kinase 3 | 2 | 172 | 83.13 | ND | 83.04 | 0.56 | ND | 1.1 | Mammalian | Kinase | Neurodegenerative diseases
Proliferative diseases Traumatic brain injury | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. {ECO:0000269|PubMed:10393181, ECO:0000269|PubMed:10617468, ECO:0000269|PubMed:12110590, ECO:0000269|PubMed:12356731, ECO:0000269|PubMed:12974390, ECO:0000269|PubMed:15788397, ECO:0000269|PubMed:15952796, ECO:0000269|PubMed:16581800, ECO:0000269|PubMed:19265199, ECO:0000269|PubMed:8325880, ECO:0000269|PubMed:9155018, ECO:0000269|PubMed:9480836}. | Mitogen-activated protein kinase 3 inducer: Arsenic trioxide Mitogen-activated protein kinase 3 inhibitor: Sulindac | 15.1 | |||
| kccMK07 | Mitogen-activated protein kinase 7 | 1 | 86 | 93.74 | ND | 86.35 | 0.24 | ND | 1.3 | Mammalian | Expressed in many adult tissues. Abundant in heart, placenta, lung, kidney and skeletal muscle. Not detectable in liver. {ECO:0000269|PubMed:7759517}. | Kinase | Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras- independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction. {ECO:0000269|PubMed:11254654, ECO:0000269|PubMed:11278431, ECO:0000269|PubMed:22869143, ECO:0000269|PubMed:9384584, ECO:0000269|PubMed:9790194}. | 15.1 | ||||
| kccMK08 | Mitogen-activated protein kinase 8 | 52 | 1102 | 96.63 | ND | 93.54 | 0.46 | ND | 0.9 | Mammalian | Kinase | Cancer, unspecific
Crohn's disease, unspecified Hearing Loss Inflammatory Disorders, Unspecified Insulin resistance Obesity | Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:22441692}. JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta- 2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. | Mitogen-activated protein kinase 3 inducer: Arsenic trioxide Mitogen-activated protein kinase 3 inhibitor: Sulindac | 15.1 | |||
| kccMK09 | Mitogen-activated protein kinase 9 | 46 | 795 | 96.47 | ND | 93.18 | 0.44 | ND | 1.0 | Mammalian | Kinase | Not Available | Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:22441692}. MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it. | Mitogen-activated protein kinase 3 inducer: Arsenic trioxide Mitogen-activated protein kinase 3 inhibitor: Sulindac | 15.1 | |||
| kccMK10 | Mitogen-activated protein kinase 10 | 50 | 838 | 96.92 | ND | 93.56 | 0.50 | ND | 0.8 | Mammalian | Specific to a subset of neurons in the nervous system. Present in the hippocampus and areas, cerebellum, striatum, brain stem, and weakly in the spinal cord. Very weak expression in testis and kidney. | Kinase | Note=A chromosomal aberration involving MAPK10 has been found in a single patient with pharmacoresistant epileptic encephalopathy. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. {ECO:0000269|PubMed:16249883}. | Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress- activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the photic regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:11718727, ECO:0000269|PubMed:22441692}. | Mitogen-activated protein kinase 3 inducer: Arsenic trioxide Mitogen-activated protein kinase 3 inhibitor: Sulindac | 15.1 | ||
| kccMK11 | Mitogen-activated protein kinase 11 | 9 | 223 | 98.37 | ND | 91.63 | 0.16 | ND | 1.2 | Mammalian | Highest levels in the brain and heart. Also expressed in the placenta, lung, liver, skeletal muscle, kidney and pancreas. | Kinase | Inflammation
Psoriasis Rheumatoid arthritis, unspecified | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK11 functions are mostly redundant with those of MAPK14. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane- associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Additional examples of p38 MAPK substrates are the FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. {ECO:0000269|PubMed:10330143, ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:15356147, ECO:0000269|PubMed:9430721, ECO:0000269|PubMed:9687510}. | Mitogen-activated protein kinase 11 inhibitor: Regorafenib | 15.1 | ||
| kccMK12 | Mitogen-activated protein kinase 12 | 8 | 183 | 90.88 | ND | 83.80 | 0.23 | ND | 1.1 | Mammalian | Highly expressed in skeletal muscle and heart. {ECO:0000269|PubMed:11991731, ECO:0000269|PubMed:8633070}. | Kinase | Note=MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma- radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration. {ECO:0000269|PubMed:10848581, ECO:0000269|PubMed:14592936, ECO:0000269|PubMed:17724032, ECO:0000269|PubMed:20605917, ECO:0000269|PubMed:21172807, ECO:0000269|PubMed:8633070, ECO:0000269|PubMed:9430721}. | Mitogen-activated protein kinase 11 inhibitor: Regorafenib | 15.1 | ||
| kccMK13 | Mitogen-activated protein kinase 13 | 12 | 213 | 95.10 | ND | 88.59 | 0.60 | ND | 1.2 | Mammalian | Expressed in testes, pancreas, small intestine, lung and kidney. Abundant in macrophages, also present in neutrophils, CD4+ T-cells, and endothelial cells. {ECO:0000269|PubMed:10201954, ECO:0000269|PubMed:9374491}. | Kinase | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells. {ECO:0000269|PubMed:11500363, ECO:0000269|PubMed:11943212, ECO:0000269|PubMed:15632108, ECO:0000269|PubMed:17256148, ECO:0000269|PubMed:18006338, ECO:0000269|PubMed:18367666, ECO:0000269|PubMed:20478268, ECO:0000269|PubMed:9731215}. | 15.1 | ||||
| kccMK14 | Mitogen-activated protein kinase 14 | 125 | 3362 | 98.53 | ND | 96.81 | 0.66 | ND | 0.7 | Mammalian | Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney. | Abdominal pain upper | Kinase | Adult respiratory distress syndrome
Alzheimer's disease Crescentic glomerulonephritis Crohn's disease, unspecified Cytokine-mediated diseases Endotoxemia Inflammation Insulin resistance Multiple myeloma Psoriasis Rheumatoid arthritis, unspecified Skin diseases Thrombosis | Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF- induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14- mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF- kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'. {ECO:0000269|PubMed:10330143, ECO:0000269|PubMed:10747897, ECO:0000269|PubMed:10943842, ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:11333986, ECO:0000269|PubMed:15905572, ECO:0000269|PubMed:16932740, ECO:0000269|PubMed:17003045, ECO:0000269|PubMed:17724032, ECO:0000269|PubMed:19893488, ECO:0000269|PubMed:20188673, ECO:0000269|PubMed:20932473, ECO:0000269|PubMed:9430721, ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9792677, ECO:0000269|PubMed:9858528}. | Mitogen-activated protein kinase 11 inhibitor: Regorafenib | 15.1 | |
| kccMKNK1 | MAP kinase-interacting serine/threonine-protein kinase 1 | 5 | 100 | 90.10 | ND | 85.64 | 0.39 | ND | 1.1 | Mammalian | Ubiquitous. {ECO:0000269|PubMed:15350534}. | Kinase | May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7- methylguanosine-containing mRNA cap. {ECO:0000269|PubMed:11463832, ECO:0000269|PubMed:15350534, ECO:0000269|PubMed:9155018, ECO:0000269|PubMed:9878069}. | 15.1 | ||||
| kccMKNK2 | MAP kinase-interacting serine/threonine-protein kinase 2 | 17 | 332 | 94.29 | ND | 87.15 | 0.13 | ND | 1.2 | Mammalian | Ubiquitously expressed in all tissues examined. Isoform 2 is expressed at higher levels in the ovary than is isoform 1. {ECO:0000269|PubMed:11013076}. | Kinase | Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal. {ECO:0000269|PubMed:11154262, ECO:0000269|PubMed:11463832, ECO:0000269|PubMed:12897141, ECO:0000269|PubMed:16111636, ECO:0000269|PubMed:17965020, ECO:0000269|PubMed:18299328, ECO:0000269|PubMed:20823271, ECO:0000269|PubMed:20927323, ECO:0000269|PubMed:21149447}. | 15.1 | ||||
| kccMMP1 | Interstitial collagenase | 71 | 2818 | 97.32 | ND | 98.08 | 0.74 | ND | 0.6 | Mammalian | Protease | Cancer, unspecific
Chondrosarcoma Emphysema Hormone-refractory Prostate cancer Kaposi's Sarcoma Lung Cancer Myocardial infarction (MI) Non-small Cell Lung Cancer Osteoarthritis Pancreatic Cancer | Cleaves collagens of types I, II, and III at one site in the helical domain. Also cleaves collagens of types VII and X. In case of HIV infection, interacts and cleaves the secreted viral Tat protein, leading to a decrease in neuronal Tat's mediated neurotoxicity. {ECO:0000269|PubMed:1645757}. | Interstitial collagenase inhibitor: Marimastat | 15.1 | |||
| kccMMP12 | Macrophage metalloelastase | 25 | 418 | 95.39 | ND | 98.31 | 0.76 | ND | 0.8 | Mammalian | Found in alveolar macrophages but not in peripheral blood monocytes. | Protease | Atherosclerosis
Crohn's disease, unspecified Emphysema Gastro-intestinal ulcers Non-small Cell Lung Cancer (NSCLC) Prostate cancer Renal Cell Carcinoma Ulcerative colitis | May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3. | Macrophage metalloelastase inhibitor: Acetohydroxamic Acid, Marimastat | 15.1 | ||
| kccMMP13 | Collagenase 3 | 71 | 1971 | 98.85 | ND | 99.25 | 0.69 | ND | 0.7 | Mammalian | Detected in fetal cartilage and calvaria, in chondrocytes of hypertrophic cartilage in vertebrae and in the dorsal end of ribs undergoing ossification, as well as in osteoblasts and periosteal cells below the inner periosteal region of ossified ribs. Detected in chondrocytes from in joint cartilage that have been treated with TNF and IL1B, but not in untreated chondrocytes. Detected in T lymphocytes. Detected in breast carcinoma tissue. {ECO:0000269|PubMed:8207000, ECO:0000269|PubMed:8798568, ECO:0000269|PubMed:9056642, ECO:0000269|PubMed:9562863}. | Protease | Spondyloepimetaphyseal dysplasia Missouri type (SEMD-MO) [MIM:602111]: A bone disease characterized by moderate to severe metaphyseal changes, mild epiphyseal involvement, rhizomelic shortening of the lower limbs with bowing of the femora and/or tibiae, coxa vara, genu varum and pear-shaped vertebrae in childhood. Epimetaphyseal changes improve with age. {ECO:0000269|PubMed:16167086}. Note=The disease is caused by mutations affecting the gene represented in this entry. Metaphyseal anadysplasia 1 (MANDP1) [MIM:602111]: A bone development disorder characterized by skeletal anomalies that resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia. {ECO:0000269|PubMed:19615667}. Note=The disease is caused by mutations affecting the gene represented in this entry. Metaphyseal dysplasia, Spahr type (MDST) [MIM:250400]: An autosomal recessive, rare disease characterized by moderate short stature, mild genua vara, and radiographic signs of metaphyseal dysplasia, but no biochemical signs of rickets. {ECO:0000269|PubMed:24648384, ECO:0000269|PubMed:24781753}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a role in the degradation of extracellular matrix proteins including fibrillar collagen, fibronectin, TNC and ACAN. Cleaves triple helical collagens, including type I, type II and type III collagen, but has the highest activity with soluble type II collagen. Can also degrade collagen type IV, type XIV and type X. May also function by activating or degrading key regulatory proteins, such as TGFB1 and CTGF. Plays a role in wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization and ossification. Required for normal embryonic bone development and ossification. Plays a role in the healing of bone fractures via endochondral ossification. Plays a role in wound healing, probably by a mechanism that involves proteolytic activation of TGFB1 and degradation of CTGF. Plays a role in keratinocyte migration during wound healing. May play a role in cell migration and in tumor cell invasion. {ECO:0000269|PubMed:16167086, ECO:0000269|PubMed:17623656, ECO:0000269|PubMed:19422229, ECO:0000269|PubMed:19615667, ECO:0000269|PubMed:20726512, ECO:0000269|PubMed:22689580, ECO:0000269|PubMed:23810497, ECO:0000269|PubMed:8207000, ECO:0000269|PubMed:8576151, ECO:0000269|PubMed:8603731, ECO:0000269|PubMed:8663255, ECO:0000269|PubMed:9065415}. | Collagenase 3 inhibitor: Marimastat | 15.1 | ||
| kccMMP14 | Matrix metalloproteinase-14 | 29 | 628 | 98.23 | ND | 98.22 | 0.56 | ND | 0.8 | Mammalian | Expressed in stromal cells of colon, breast, and head and neck. Expressed in lung tumors. {ECO:0000269|PubMed:18223680}. | Protease | Winchester syndrome (WNCHRS) [MIM:277950]: A disease characterized by severe osteolysis in the hands and feet, generalized osteoporosis, bone thinning, and absence of subcutaneous nodules. Various additional features include coarse face, corneal opacities, gum hypertrophy, and EKG changes. {ECO:0000269|PubMed:22922033}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Seems to specifically activate progelatinase A. May thus trigger invasion by tumor cells by activating progelatinase A on the tumor cell surface. May be involved in actin cytoskeleton reorganization by cleaving PTK7. Acts as a positive regulator of cell growth and migration via activation of MMP15. Involved in the formation of the fibrovascular tissues in association with pro- MMP2. {ECO:0000269|PubMed:12714657, ECO:0000269|PubMed:20837484, ECO:0000269|PubMed:22065321}. | Matrix metalloproteinase-14 inhibitor: Marimastat | 15.1 | ||
| kccMMP16 | Matrix metalloproteinase-16 | 3 | 53 | 98.89 | ND | 93.57 | 0.50 | ND | 1.0 | Mammalian | Expressed in heart, brain, placenta, ovary and small intestine. Isoform Short is found in the ovary. | Protease | Endopeptidase that degrades various components of the extracellular matrix, such as collagen type III and fibronectin. Activates progelatinase A. Involved in the matrix remodeling of blood vessels. Isoform short cleaves fibronectin and also collagen type III, but at lower rate. It has no effect on type I, II, IV and V collagen. However, upon interaction with CSPG4, it may be involved in degradation and invasion of type I collagen by melanoma cells. {ECO:0000269|PubMed:11278606}. | Matrix metalloproteinase-16 inhibitor: Marimastat | 15.1 | |||
| kccMMP2 | 72 kDa type IV collagenase | 88 | 2820 | 96.83 | ND | 97.86 | 0.73 | ND | 0.7 | Mammalian | Produced by normal skin fibroblasts. PEX is expressed in a number of tumors including gliomas, breast and prostate. {ECO:0000269|PubMed:11751392}. | Protease | Multicentric osteolysis, nodulosis, and arthropathy (MONA) [MIM:259600]: An autosomal recessive syndrome characterized by severe multicentric osteolysis with predominant involvement of the hands and feet. Additional features include coarse face, corneal opacities, patches of thickened, hyperpigmented skin, hypertrichosis and gum hypertrophy. {ECO:0000269|PubMed:11431697, ECO:0000269|PubMed:15691365, ECO:0000269|PubMed:16542393}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ubiquitinous metalloproteinase that is involved in diverse functions such as remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. As well as degrading extracellular matrix proteins, can also act on several nonmatrix proteins such as big endothelial 1 and beta-type CGRP promoting vasoconstriction. Also cleaves KISS at a Gly-|-Leu bond. Appears to have a role in myocardial cell death pathways. Contributes to myocardial oxidative stress by regulating the activity of GSK3beta. Cleaves GSK3beta in vitro. Involved in the formation of the fibrovascular tissues in association with MMP14. PEX, the C-terminal non-catalytic fragment of MMP2, posseses anti-angiogenic and anti-tumor properties and inhibits cell migration and cell adhesion to FGF2 and vitronectin. Ligand for integrinv/beta3 on the surface of blood vessels. Isoform 2: Mediates the proteolysis of CHUK/IKKA and initiates a primary innate immune response by inducing mitochondrial-nuclear stress signaling with activation of the pro- inflammatory NF-kappaB, NFAT and IRF transcriptional pathways. | 72 kDa type IV collagenase inhibitor: Captopril, Marimastat | 15.1 | ||
| kccMMP3 | Stromelysin-1 | 77 | 1594 | 98.17 | ND | 98.31 | 0.65 | ND | 0.7 | Mammalian | Protease | Coronary heart disease 6 (CHDS6) [MIM:614466]: A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. {ECO:0000269|PubMed:12477941, ECO:0000269|PubMed:8662692}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions. | Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase. | Stromelysin-1 antagonist: Marimastat | 15.1 | |||
| kccMMP7 | Matrilysin | 22 | 500 | 98.09 | ND | 97.23 | 0.73 | ND | 0.5 | Mammalian | Protease | Cancer, unspecific
Inflammation | Degrades casein, gelatins of types I, III, IV, and V, and fibronectin. Activates procollagenase. {ECO:0000269|PubMed:2550050}. | Matrilysin antagonist: Marimastat | 15.1 | |||
| kccMMP8 | Neutrophil collagenase | 47 | 845 | 99.11 | ND | 98.76 | 0.71 | ND | 0.8 | Mammalian | Neutrophils. | Protease | Inflammatory diseases
Osteoarthritis Osteoporosis, unspecified Rheumatoid arthritis, unspecified Tumors | Can degrade fibrillar type I, II, and III collagens. | Neutrophil collagenase inhibitor: Marimastat | 15.1 | ||
| kccMMP9 | Matrix metalloproteinase-9 | 78 | 2234 | 97.16 | ND | 97.93 | 0.70 | ND | 0.7 | Mammalian | Produced by normal alveolar macrophages and granulocytes. | Protease | Intervertebral disc disease (IDD) [MIM:603932]: A common musculo-skeletal disorder caused by degeneration of intervertebral disks of the lumbar spine. It results in low-back pain and unilateral leg pain. {ECO:0000269|PubMed:18455130}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Metaphyseal anadysplasia 2 (MANDP2) [MIM:613073]: A bone development disorder characterized by skeletal anomalies that resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia. Note=The disease is caused by mutations affecting the gene represented in this entry. | May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. Could play a role in bone osteoclastic resorption. Cleaves KiSS1 at a Gly-|-Leu bond. Cleaves type IV and type V collagen into large C-terminal three quarter fragments and shorter N-terminal one quarter fragments. Degrades fibronectin but not laminin or Pz-peptide. {ECO:0000269|PubMed:1480034}. | Matrix metalloproteinase-9 antagonist: Glucosamine Matrix metalloproteinase-9 inhibitor: Captopril, Marimastat, Minocycline | 15.1 | ||
| kccMOT1 | Monocarboxylate transporter 1 | 4 | 89 | 99.16 | ND | 100.00 | 0.28 | ND | 0.7 | Mammalian | Detected in heart and in blood lymphocytes and monocytes (at protein level). Widely expressed. {ECO:0000269|PubMed:15505343}. | Electrochemical transporter | Symptomatic deficiency in lactate transport (SDLT) [MIM:245340]: Deficiency of lactate transporter may result in an acidic intracellular environment created by muscle activity with consequent degeneration of muscle and release of myoglobin and creatine kinase. This defect might compromise extreme performance in otherwise healthy individuals. {ECO:0000269|PubMed:10590411}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial hyperinsulinemic hypoglycemia 7 (HHF7) [MIM:610021]: Dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load. {ECO:0000269|PubMed:17701893}. Note=The disease is caused by mutations affecting the gene represented in this entry. Monocarboxylate transporter 1 deficiency (MCT1D) [MIM:616095]: A metabolic disorder characterized by recurrent ketoacidosis, a pathologic state due to ketone formation exceeding ketone utilization. The clinical consequences of ketoacidosis are vomiting, osmotic diuresis, dehydration, and Kussmaul breathing. The condition may progress to decreased consciousness and, ultimately, death. {ECO:0000269|PubMed:25390740}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetate. Depending on the tissue and on cicumstances, mediates the import or export of lactic acid and ketone bodies. Required for normal nutrient assimilation, increase of white adipose tissue and body weight gain when on a high-fat diet. Plays a role in cellular responses to a high-fat diet by modulating the cellular levels of lactate and pyruvate, small molecules that contribute to the regulation of central metabolic pathways and insulin secretion, with concomitant effects on plasma insulin levels and blood glucose homeostasis. {ECO:0000269|PubMed:17701893}. | Monocarboxylate transporter 1 inhibitor: Gamma Hydroxybutyric Acid, Niflumic Acid, Probenecid Monocarboxylate transporter 1 substrate: Acetic acid, Aminohippurate, Foscarnet, Methotrexate, Nateglinide, Niacin, Salicylic acid, Valproic Acid Monocarboxylate transporter 1 substrate;inhibitor: Pyruvic acid Monocarboxylate transporter 1 unknown: Ampicillin, Pravastatin, Pyruvic acid | 15.1 | ||
| kccMP2K1 | Dual specificity mitogen-activated protein kinase kinase 1 | 22 | 695 | 93.79 | ND | 88.89 | 0.53 | ND | 1.0 | Mammalian | Widely expressed, with extremely low levels in brain. {ECO:0000269|PubMed:1281467}. | Kinase | Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator- activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis. {ECO:0000269|PubMed:14737111, ECO:0000269|PubMed:17101779}. | Dual specificity mitogen-activated protein kinase kinase 1 inhibitor: Bosutinib, Trametinib | 15.1 | ||
| kccMP2K2 | Dual specificity mitogen-activated protein kinase kinase 2 | 5 | 184 | 87.58 | ND | 86.38 | 0.09 | ND | 1.4 | Mammalian | Kinase | Cardiofaciocutaneous syndrome 4 (CFC4) [MIM:615280]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262, ECO:0000269|PubMed:20358587}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). {ECO:0000250}. | Dual specificity mitogen-activated protein kinase kinase 2 inhibitor: Bosutinib, Trametinib | 15.1 | |||
| kccMP2K5 | Dual specificity mitogen-activated protein kinase kinase 5 | 1 | 63 | 97.00 | ND | 93.59 | 0.31 | ND | 1.1 | Mammalian | Expressed in many adult tissues. Abundant in heart and skeletal muscle. | Kinase | Breast cancer | Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex. Activation of this pathway appears to play a critical role in protecting cells from stress-induced apoptosis, neuronal survival and cardiac development and angiogenesis. {ECO:0000269|PubMed:7759517, ECO:0000269|PubMed:9384584}. | 15.1 | |||
| kccMPI | Mannose-6-phosphate isomerase | 3 | 237 | 88.63 | ND | 83.60 | 0.05 | ND | 0.6 | Mammalian | Expressed in all tissues, but more abundant in heart, brain and skeletal muscle. | Enzyme | Congenital disorder of glycosylation 1B (CDG1B) [MIM:602579]: A multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N- glycoproteins during embryonic development, differentiation, and maintenance of cell functions. Congenital disorder of glycosylation type 1B is clinically characterized by protein- losing enteropathy. {ECO:0000269|PubMed:10980531, ECO:0000269|PubMed:11134235, ECO:0000269|PubMed:11350186, ECO:0000269|PubMed:12357336, ECO:0000269|PubMed:12414827, ECO:0000269|PubMed:9525984, ECO:0000269|PubMed:9585601}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions. | 15.1 | |||
| kccMPIP2 | M-phase inducer phosphatase 2 | 17 | 393 | 84.40 | ND | 95.36 | 0.41 | ND | 0.5 | Mammalian | Phosphatase | Cancer, unspecific | Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Directly dephosphorylates CDK1 and stimulates its kinase activity. The three isoforms seem to have a different level of activity. {ECO:0000269|PubMed:17332740}. | Dual specificity mitogen-activated protein kinase kinase 2 inhibitor: Bosutinib, Trametinib | 15.1 | |||
| kccMRCKA | Serine/threonine-protein kinase MRCK alpha | 14 | 266 | 94.13 | ND | 90.49 | 0.26 | ND | 1.2 | Mammalian | Abundant in the heart, brain, skeletal muscle, kidney, and pancreas, with little or no expression in the lung and liver. {ECO:0000269|PubMed:9092543}. | Kinase | Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates: PPP1R12A, LIMK1 and LIMK2. May play a role in TFRC-mediated iron uptake. {ECO:0000269|PubMed:11340065, ECO:0000269|PubMed:11399775, ECO:0000269|PubMed:15723050, ECO:0000269|PubMed:18854160, ECO:0000269|PubMed:20188707, ECO:0000269|PubMed:21457715, ECO:0000269|PubMed:9092543, ECO:0000269|PubMed:9418861}. | 15.1 | ||||
| kccMRGX1 | Mas-related G-protein coupled receptor member X1 | 3 | 42 | 98.80 | ND | 88.87 | 0.48 | ND | 0.4 | Mammalian | Uniquely localized in a subset of small dorsal root and trigeminal sensory neurons. {ECO:0000269|PubMed:11850634}. | Orphan receptor. Probably involved in the function of nociceptive neurons. May regulate nociceptor function and/or development, including the sensation or modulation of pain. Potently activated by enkephalins including BAM22 (bovine adrenal medulla peptide 22) and BAM (8-22). BAM22 is the most potent compound and evoked a large and dose-dependent release of intracellular calcium in stably transfected cells. G(alpha)q proteins are involved in the calcium-signaling pathway. Activated by the antimalarial drug, chloroquine. May mediate chloroquine- induced itch, in a histamine-independent manner. {ECO:0000269|PubMed:11850634, ECO:0000269|PubMed:20004959}. | 15.1 | |||||
| kccMRP1 | Multidrug resistance-associated protein 1 | 10 | 309 | 92.23 | ND | 97.97 | 0.80 | ND | 0.6 | Mammalian | Lung, testis and peripheral blood mononuclear cells. | Primary active transporter | Cystic fibrosis
Streptococcus pneumoniae infections | Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o- glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency. {ECO:0000269|PubMed:10064732, ECO:0000269|PubMed:11114332, ECO:0000269|PubMed:16230346}. | Multidrug resistance-associated protein 1 inducer: Phenobarbital Multidrug resistance-associated protein 1 inhibitor: Abiraterone, Amprenavir, Conjugated Estrogens, Cyclosporine, Diclofenac, Erythromycin, Glyburide, Ibuprofen, Idarubicin, Indinavir, Indomethacin, Ivermectin, Lamivudine, Mifepristone, Ofloxacin, Paclitaxel, Probenecid, Progesterone, Rifampicin, Sulfinpyrazone, Vandetanib, Verapamil Multidrug resistance-associated protein 1 inhibitor;inducer: Ritonavir Multidrug resistance-associated protein 1 substrate: Aminohippurate, Atorvastatin, Colchicine, Dactinomycin, Docetaxel, Epirubicin, Fluorescein, Irinotecan, Rosuvastatin, Saquinavir, Saxagliptin, Zoledronate Multidrug resistance-associated protein 1 substrate;inhibitor: Atazanavir, Daunorubicin, Doxorubicin, Etoposide, Glutathione, Methotrexate, Mitoxantrone, Vemurafenib, Vincristine Multidrug resistance-associated protein 1 substrate;inhibitor;inducer: Vinblastine | 15.1 | ||
| kccMSHR | Melanocyte-stimulating hormone receptor | 15 | 914 | 99.20 | ND | 99.15 | 0.58 | ND | 0.8 | Mammalian | Melanocytes and corticoadrenal tissue. | Family A G protein-coupled receptor | Melanoma, cutaneous malignant 5 (CMM5) [MIM:613099]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:17434924, ECO:0000269|PubMed:19338054}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. | Canalicular multispecific organic anion transporter 1 inducer: Arsenic trioxide, Cisplatin, Clotrimazole, Dexamethasone, Eprosartan, Ethinyl Estradiol, Nifedipine, Phenobarbital, Rifampicin, Spironolactone, Ursodeoxycholic acid Canalicular multispecific organic anion transporter 1 inhibitor: Cyclosporine, Daunorubicin, Furosemide, Fusidic Acid, Glyburide, Ivermectin, Lomefloxacin, Ofloxacin, Pranlukast, Quinidine, Reserpine, Sorafenib, Sparfloxacin, Sulfinpyrazone, Sunitinib, Telmisartan, Tetrahydrofolic acid, Verapamil Canalicular multispecific organic anion transporter 1 substrate: Atorvastatin, Canagliflozin, Carbamazepine, Carboplatin, Conjugated Estrogens, Docetaxel, Doxorubicin, Ezetimibe, Gadoxetate, Indinavir, Irinotecan, Levetiracetam, Lovastatin, Mycophenolate mofetil, Norgestimate, Oxaliplatin, Paclitaxel, Phenytoin, Pitavastatin, Saquinavir, Simvastatin, Sulfasalazine, Tamoxifen, Tenofovir Canalicular multispecific organic anion transporter 1 substrate;inducer: Olmesartan, Ritonavir Canalicular multispecific organic anion transporter 1 substrate;inhibitor: Aminohippurate, Etoposide, Glutathione, Indomethacin, Leucovorin, Methotrexate, Pravastatin, Probenecid, Sulfinpyrazone, Vincristine Canalicular multispecific organic anion transporter 1 substrate;inhibitor;inducer: Vinblastine Canalicular multispecific organic anion transporter 1 unknown: Adenosine triphosphate, Lamivudine | 15.1 | ||
| kccMTAP | S-methyl-5'-thioadenosine phosphorylase {ECO:0000255|HAMAP-Rule:MF_03155} | 1 | 68 | 99.99 | ND | 99.97 | 0.56 | ND | 0.8 | Mammalian | Ubiquitously expressed. | Enzyme | Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) [MIM:112250]: An autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. Some patients show a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. {ECO:0000269|PubMed:22464254}. Note=The disease is caused by mutations affecting the gene represented in this entry. DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254). {ECO:0000269|PubMed:22464254}. Note=Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer. | Catalyzes the reversible phosphorylation of S-methyl-5'- thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S- adenosylmethionine. Has broad substrate specificity with 6- aminopurine nucleosides as preferred substrates. {ECO:0000255|HAMAP-Rule:MF_03155, ECO:0000269|PubMed:3091600}. | S-methyl-5'-thioadenosine phosphorylase {ECO:0000255|HAMAP-Rule:MF_03155} unknown: Adenine | 15.1 | ||
| kccMTLR | Motilin receptor | 12 | 237 | 99.44 | ND | 99.94 | 0.66 | ND | 0.7 | Mammalian | Expressed only in thyroid, stomach, and bone marrow. | Family A G protein-coupled receptor | Eating disorders
Gastroesophageal Reflux Disease (GERD) Gastrointestinal Diseases and Disorders, miscellaneous Gastrointestinal reflux disorders Gastroparesis Irritable Bowel Syndrome (IBS) Obesity | Receptor for motilin. {ECO:0000269|PubMed:11322507}. | Motilin receptor unknown: Erythromycin | 15.1 | ||
| kccMTOR | Serine/threonine-protein kinase mTOR | 79 | 1832 | 95.69 | ND | 93.99 | 0.80 | ND | 0.7 | Mammalian | Expressed in numerous tissues, with highest levels in testis. {ECO:0000269|PubMed:12408816, ECO:0000269|PubMed:7809080}. | Enzyme | Cancer, unspecific
Immunosuppression | Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1- mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1- pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser- 758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. Regulates osteoclastogensis by adjusting the expression of CEBPB isoforms (By similarity). {ECO:0000250|UniProtKB:Q9JLN9, ECO:0000269|PubMed:12087098, ECO:0000269|PubMed:12150925, ECO:0000269|PubMed:12150926, ECO:0000269|PubMed:12231510, ECO:0000269|PubMed:12718876, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15268862, ECO:0000269|PubMed:15467718, ECO:0000269|PubMed:15545625, ECO:0000269|PubMed:15718470, ECO:0000269|PubMed:18497260, ECO:0000269|PubMed:18762023, ECO:0000269|PubMed:18925875, ECO:0000269|PubMed:20516213, ECO:0000269|PubMed:20537536, ECO:0000269|PubMed:21659604, ECO:0000269|PubMed:23429703, ECO:0000269|PubMed:23429704}. | Serine/threonine-protein kinase mTOR inhibitor: Everolimus, Sirolimus, Temsirolimus Serine/threonine-protein kinase mTOR potentiator: Pimecrolimus | 15.1 | ||
| kccMTP | Microsomal triglyceride transfer protein large subunit | 6 | 179 | 99.68 | ND | 99.92 | 0.67 | ND | 0.7 | Mammalian | Liver and small intestine. Also found in ovary, testis and kidney. {ECO:0000269|PubMed:7961826}. | Other cytosolic protein | Abetalipoproteinemia (ABL) [MIM:200100]: An autosomal recessive disorder of lipoprotein metabolism. Affected individuals produce virtually no circulating apolipoprotein B-containing lipoproteins (chylomicrons, VLDL, LDL, lipoprotein(A)). Malabsorption of the antioxidant vitamin E occurs, leading to spinocerebellar and retinal degeneration. {ECO:0000269|PubMed:10679949, ECO:0000269|PubMed:10946006, ECO:0000269|PubMed:8939939}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces. Required for the secretion of plasma lipoproteins that contain apolipoprotein B. | Microsomal triglyceride transfer protein large subunit antagonist: Hesperetin, Lomitapide | 15.1 | ||
| kccMTR1A | Melatonin receptor type 1A | 23 | 609 | 98.98 | ND | 99.03 | 0.56 | ND | 0.8 | Mammalian | Expressed in hypophyseal pars tuberalis and hypothalamic suprachiasmatic nuclei (SCN). Hippocampus. | Family A G protein-coupled receptor | Chronic Primary Insomnia
Insomnia Major Depressive Disorder | High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. | Melatonin receptor type 1A agonist: Agomelatine, Melatonin, Tasimelteon Melatonin receptor type 1A multitarget: Ramelteon | 15.1 | ||
| kccMTR1B | Melatonin receptor type 1B | 22 | 508 | 98.99 | ND | 99.02 | 0.53 | ND | 0.8 | Mammalian | Expressed in retina and less in brain and hippocampus. | Family A G protein-coupled receptor | Insomnia | High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. | Melatonin receptor type 1B agonist: Agomelatine, Melatonin, Tasimelteon Melatonin receptor type 1B multitarget: Ramelteon | 15.1 | ||
| kccMYLK | Myosin light chain kinase, smooth muscle | 2 | 102 | 90.47 | ND | 93.38 | 0.44 | ND | 1.1 | Mammalian | Smooth muscle and non-muscle isozymes are expressed in a wide variety of adult and fetal tissues and in cultured endothelium with qualitative expression appearing to be neither tissue- nor development-specific. Non-muscle isoform 2 is the dominant splice variant expressed in various tissues. Telokin has been found in a wide variety of adult and fetal tissues. Accumulates in well differentiated enterocytes of the intestinal epithelium in response to tumor necrosis factor (TNF). {ECO:0000269|PubMed:10536370, ECO:0000269|PubMed:16835238, ECO:0000269|PubMed:20053363, ECO:0000269|PubMed:8575746}. | Kinase | Aortic aneurysm, familial thoracic 7 (AAT7) [MIM:613780]: A disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance. {ECO:0000269|PubMed:21055718}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). Also regulates actin-myosin interaction through a non-kinase activity. Phosphorylates PTK2B/PYK2 and myosin light-chains. Involved in the inflammatory response (e.g. apoptosis, vascular permeability, leukocyte diapedesis), cell motility and morphology, airway hyperreactivity and other activities relevant to asthma. Required for tonic airway smooth muscle contraction that is necessary for physiological and asthmatic airway resistance. Necessary for gastrointestinal motility. Implicated in the regulation of endothelial as well as vascular permeability, probably via the regulation of cytoskeletal rearrangements. In the nervous system it has been shown to control the growth initiation of astrocytic processes in culture and to participate in transmitter release at synapses formed between cultured sympathetic ganglion cells. Critical participant in signaling sequences that result in fibroblast apoptosis. Plays a role in the regulation of epithelial cell survival. Required for epithelial wound healing, especially during actomyosin ring contraction during purse-string wound closure. Mediates RhoA- dependent membrane blebbing. Triggers TRPC5 channel activity in a calcium-dependent signaling, by inducing its subcellular localization at the plasma membrane. Promotes cell migration (including tumor cells) and tumor metastasis. PTK2B/PYK2 activation by phosphorylation mediates ITGB2 activation and is thus essential to trigger neutrophil transmigration during acute lung injury (ALI). May regulate optic nerve head astrocyte migration. Probably involved in mitotic cytoskeletal regulation. Regulates tight junction probably by modulating ZO-1 exchange in the perijunctional actomyosin ring. Mediates burn-induced microvascular barrier injury; triggers endothelial contraction in the development of microvascular hyperpermeability by phosphorylating MLC. Essential for intestinal barrier dysfunction. Mediates Giardia spp.-mediated reduced epithelial barrier function during giardiasis intestinal infection via reorganization of cytoskeletal F-actin and tight junctional ZO-1. Necessary for hypotonicity-induced Ca(2+) entry and subsequent activation of volume-sensitive organic osmolyte/anion channels (VSOAC) in cervical cancer cells. Responsible for high proliferative ability of breast cancer cells through anti-apoptosis. {ECO:0000269|PubMed:11113114, ECO:0000269|PubMed:11976941, ECO:0000269|PubMed:15020676, ECO:0000269|PubMed:15825080, ECO:0000269|PubMed:16284075, ECO:0000269|PubMed:16723733, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18710790, ECO:0000269|PubMed:19826488, ECO:0000269|PubMed:20139351, ECO:0000269|PubMed:20181817, ECO:0000269|PubMed:20375339, ECO:0000269|PubMed:20453870}. | 15.1 | |||
| kccNAAA | N-acylethanolamine-hydrolyzing acid amidase | 2 | 58 | 90.06 | ND | 94.96 | 0.58 | ND | 0.6 | Mammalian | Expressed in numerous tissues, with highest levels in liver and kidney, followed by pancreas. {ECO:0000269|PubMed:10610717}. | Enzyme | Degrades bioactive fatty acid amides to their corresponding acids, with the following preference: N- palmitoylethanolamine > N-myristoylethanolamine > N- lauroylethanolamine = N-stearoylethanolamine > N- arachidonoylethanolamine > N-oleoylethanolamine. Also exhibits weak hydrolytic activity against the ceramides N- lauroylsphingosine and N-palmitoylsphingosine. {ECO:0000269|PubMed:15655246}. | 15.1 | ||||
| kccNAMPT | Nicotinamide phosphoribosyltransferase | 14 | 317 | 99.72 | ND | 99.96 | 0.53 | ND | 0.9 | Mammalian | Expressed in large amounts in bone marrow, liver tissue, and muscle. Also present in heart, placenta, lung, and kidney tissues. | Enzyme | Catalyzes the condensation of nicotinamide with 5- phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway. The secreted form behaves both as a cytokine with immunomodulating properties and an adipokine with anti-diabetic properties, it has no enzymatic activity, partly because of lack of activation by ATP, which has a low level in extracellular space and plasma. Plays a role in the modulation of circadian clock function. NAMPT-dependent oscillatory production of NAD regulates oscillation of clock target gene expression by releasing the core clock component: CLOCK-ARNTL/BMAL1 heterodimer from NAD-dependent SIRT1-mediated suppression (By similarity). {ECO:0000250|UniProtKB:Q99KQ4, ECO:0000269|PubMed:24130902}. | Melatonin receptor type 1B agonist: Agomelatine, Melatonin, Tasimelteon Melatonin receptor type 1B multitarget: Ramelteon | 15.1 | |||
| kccNCEH1 | Neutral cholesterol ester hydrolase 1 | 2 | 108 | 99.92 | ND | 99.97 | 0.73 | ND | 0.5 | Mammalian | Expressed in monocyte-derived macrophages. Up- regulated in invasive melanoma and breast carcinoma cell lines. {ECO:0000269|PubMed:12149457, ECO:0000269|PubMed:18782767}. | Enzyme | Hydrolyzes 2-acetyl monoalkylglycerol ether, the penultimate precursor of the pathway for de novo synthesis of platelet-activating factor. May be responsible for cholesterol ester hydrolysis in macrophages, thereby contributing to the development of atherosclerosis. Also involved in organ detoxification by hydrolyzing exogenous organophosphorus compounds. May contribute to cancer pathogenesis by promoting tumor cell migration. {ECO:0000269|PubMed:17052608}. | 15.1 | ||||
| kccNEK2 | Serine/threonine-protein kinase Nek2 | 12 | 335 | 92.33 | ND | 88.91 | 0.11 | ND | 1.2 | Mammalian | Isoform 1 and isoform 2 are expressed in peripheral blood T-cells and a wide variety of transformed cell types. Isoform 1 and isoform 4 are expressed in the testis. Up- regulated in various cancer cell lines, as well as primary breast tumors. {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:15659832}. | Kinase | Retinitis pigmentosa 67 (RP67) [MIM:615565]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:24043777}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGOL1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Isoform 1 phosphorylates and activates NEK11 in G1/S- arrested cells. Isoform 2, which is not present in the nucleolus, does not. {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:12857871, ECO:0000269|PubMed:14978040, ECO:0000269|PubMed:15161910, ECO:0000269|PubMed:15358203, ECO:0000269|PubMed:15388344, ECO:0000269|PubMed:17283141, ECO:0000269|PubMed:17621308, ECO:0000269|PubMed:17626005, ECO:0000269|PubMed:18086858, ECO:0000269|PubMed:18297113, ECO:0000269|PubMed:20034488, ECO:0000269|PubMed:21076410}. | Melatonin receptor type 1B agonist: Agomelatine, Melatonin, Tasimelteon Melatonin receptor type 1B multitarget: Ramelteon | 15.1 | ||
| kccNEK4 | Serine/threonine-protein kinase Nek4 | 10 | 201 | 92.89 | ND | 92.15 | 0.15 | ND | 1.3 | Mammalian | Highest expression in adult heart, followed by pancreas, skeletal muscle, brain, testis, retina, liver, kidney, lung and placenta. Present in most primary carcinomas. {ECO:0000269|PubMed:21685204, ECO:0000269|PubMed:8208544}. | Kinase | Protein kinase that seems to act exclusively upon threonine residues (By similarity). Required for normal entry into proliferative arrest after a limited number of cell divisions, also called replicative senescence. Required for normal cell cycle arrest in response to double-stranded DNA damage. {ECO:0000250|UniProtKB:Q9Z1J2, ECO:0000269|PubMed:22851694}. | 15.1 | ||||
| kccNEP | Neprilysin | 35 | 898 | 98.33 | ND | 98.20 | 0.52 | ND | 0.8 | Mammalian | Protease | Congestive Heart Failure
Hypertension Prostate cancer (early stage hormone sensitive) | Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:17101991). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:15283675). Involved in the degradation of atrial natriuretic factor (ANF) (PubMed:2531377, PubMed:2972276). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers (PubMed:20876573). {ECO:0000269|PubMed:15283675, ECO:0000269|PubMed:17101991, ECO:0000269|PubMed:20876573, ECO:0000269|PubMed:2531377, ECO:0000269|PubMed:2972276}. | Neprilysin inhibitor: Candoxatril | 15.1 | |||
| kccNISCH | Nischarin | 5 | 135 | 98.08 | ND | 97.28 | 0.15 | ND | 1.3 | Mammalian | Isoform 1, isoform 3 and isoform 4 are expressed in brain. Isoform 1 is expressed in endocrine tissues. {ECO:0000269|PubMed:15028621, ECO:0000269|PubMed:9851558}. | Other cytosolic protein | Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-signaling cascades triggering to cell survival, growth and migration. Its activation by the agonist rilmenidine induces an increase in phosphorylation of mitogen-activated protein kinases MAPK1 and MAPK3 in rostral ventrolateral medulla (RVLM) neurons that exhibited rilmenidine-evoked hypotension (By similarity). Blocking its activation with efaroxan abolished rilmenidine-induced mitogen-activated protein kinase phosphorylation in RVLM neurons (By similarity). Acts as a modulator of Rac-regulated signal transduction pathways (By similarity). Suppresses Rac1-stimulated cell migration by interacting with PAK1 and inhibiting its kinase activity (By similarity). Also blocks Pak-independent Rac signaling by interacting with RAC1 and inhibiting Rac1-stimulated NF-kB response element and cyclin D1 promoter activation (By similarity). Inhibits also LIMK1 kinase activity by reducing LIMK1 'Tyr-508' phosphorylation (By similarity). Inhibits Rac-induced cell migration and invasion in breast and colon epithelial cells (By similarity). Inhibits lamellipodia formation, when overexpressed (By similarity). Plays a role in protection against apoptosis. Involved in association with IRS4 in the enhancement of insulin activation of MAPK1 and MAPK3. When overexpressed, induces a redistribution of cell surface ITGA5 integrin to intracellular endosomal structures. {ECO:0000250, ECO:0000269|PubMed:10882231, ECO:0000269|PubMed:12868002, ECO:0000269|PubMed:15028619, ECO:0000269|PubMed:15028621, ECO:0000269|PubMed:15475348}. | Nischarin agonist: Tizanidine | 15.1 | |||
| kccNK1R | Substance-P receptor | 78 | 2254 | 99.02 | ND | 99.47 | 0.70 | ND | 0.7 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Analgesics
Asthma Mood [affective] disorders Neuropathic pain Visceral pain | This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance P > substance K > neuromedin-K. | Substance-P receptor antagonist: Aprepitant, Ketamine, Netupitant, Vapreotide | 15.1 | ||
| kccNK2R | Substance-K receptor | 25 | 816 | 97.58 | ND | 97.12 | 0.78 | ND | 0.7 | Mammalian | Family A G protein-coupled receptor | Analgesics
Anxiety Disorders Asthma Depression Generalized Anxiety Disorders (GAD) Pain, Acute or Chronic Urinary incontinence | This is a receptor for the tachykinin neuropeptide substance K (neurokinin A). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance K > neuromedin-K > substance P. {ECO:0000269|PubMed:1659297}. | 15.1 | ||||
| kccNK3R | Neuromedin-K receptor | 16 | 589 | 99.05 | ND | 98.98 | 0.75 | ND | 0.7 | Mammalian | Family A G protein-coupled receptor | Hypogonadotropic hypogonadism 11 with or without anosmia (HH11) [MIM:614840]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:19079066, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in TACR3 as well as in other HH-associated genes including FGFR1, SPRY4 and KAL1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}. | This is a receptor for the tachykinin neuropeptide neuromedin-K (neurokinin B). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: neuromedin-K > substance K > substance P. | Substance-P receptor antagonist: Aprepitant, Ketamine, Netupitant, Vapreotide | 15.1 | |||
| kccNMBR | Neuromedin-B receptor | 3 | 142 | 99.84 | ND | 97.73 | 0.79 | ND | 0.6 | Mammalian | Expressed in epididymis (at protein level). {ECO:0000269|PubMed:20736409}. | Family A G protein-coupled receptor | Receptor for neuromedin-B. | 15.1 | ||||
| kccNMDE2 | Glutamate receptor ionotropic, NMDA 2B | 27 | 344 | 98.33 | ND | 98.13 | 0.52 | ND | 0.9 | Mammalian | Primarily found in the fronto-parieto-temporal cortex and hippocampus pyramidal cells, lower expression in the basal ganglia. {ECO:0000269|PubMed:9547169}. | Ligand-gated ion channel | Mental retardation, autosomal dominant 6 (MRD6) [MIM:613970]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:20890276, ECO:0000269|PubMed:23033978}. Note=The disease is caused by mutations affecting the gene represented in this entry. Epileptic encephalopathy, early infantile, 27 (EIEE27) [MIM:616139]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=A chromosomal aberrations involving GRIN2B has been found in patients with mental retardation. Translocations t(9;12)(p23;p13.1) and t(10;12)(q21.1;p13.1) with a common breakpoint in 12p13.1. | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. In concert with DAPK1 at extrasynaptic sites, acts as a central mediator for stroke damage. Its phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity inducing injurious Ca2+ influx through them, resulting in an irreversible neuronal death (By similarity). {ECO:0000250}. | Glutamate receptor ionotropic, NMDA 2B activator: Acetylcysteine Glutamate receptor ionotropic, NMDA 2B antagonist: Acamprosate, Felbamate, Haloperidol, Ifenprodil, Ketobemidone, Memantine, Pentobarbital, Pethidine, Phenobarbital, Secobarbital Glutamate receptor ionotropic, NMDA 2B blocker: Atomoxetine Glutamate receptor ionotropic, NMDA 2B inhibitor: Milnacipran Glutamate receptor ionotropic, NMDA 2B unknown: Gabapentin | 15.1 | ||
| kccNMDE3 | Glutamate receptor ionotropic, NMDA 2C | 7 | 182 | 97.63 | ND | 96.53 | 0.31 | ND | 0.8 | Mammalian | Mainly expressed in brain with predominant expression is in the cerebellum, also present in the hippocampus, amygdala, caudate nucleus, corpus callosum, subthalamic nuclei and thalamus. Detected in the heart, skeletal muscle and pancreas. | Ligand-gated ion channel | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. | Glutamate receptor ionotropic, NMDA 2C antagonist: Acamprosate, Ketobemidone, Pentobarbital, Pethidine, Phenobarbital, Secobarbital Glutamate receptor ionotropic, NMDA 2C blocker: Atomoxetine Glutamate receptor ionotropic, NMDA 2C inhibitor: Milnacipran Glutamate receptor ionotropic, NMDA 2C unknown: Gabapentin, Glycine | 15.1 | |||
| kccNMDE4 | Glutamate receptor ionotropic, NMDA 2D | 1 | 56 | 99.30 | ND | 93.60 | 0.65 | ND | 0.2 | Mammalian | Ligand-gated ion channel | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. | Glutamate receptor ionotropic, NMDA 2D activator: Acetylcysteine Glutamate receptor ionotropic, NMDA 2D antagonist: Acamprosate, Ketobemidone, Orphenadrine, Pentobarbital, Pethidine, Phenobarbital, Secobarbital Glutamate receptor ionotropic, NMDA 2D blocker: Atomoxetine Glutamate receptor ionotropic, NMDA 2D inhibitor: Milnacipran Glutamate receptor ionotropic, NMDA 2D unknown: Gabapentin | 15.1 | ||||
| kccNMDZ1 | Glutamate receptor ionotropic, NMDA 1 | 29 | 606 | 97.92 | ND | 98.34 | 0.60 | ND | 0.8 | Mammalian | Respiratory depression | Ligand-gated ion channel | Mental retardation, autosomal dominant 8 (MRD8) [MIM:614254]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21376300}. Note=The disease is caused by mutations affecting the gene represented in this entry. | NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity). {ECO:0000250}. | Glutamate receptor ionotropic, NMDA 1 activator: Acetylcysteine Glutamate receptor ionotropic, NMDA 1 antagonist: Acamprosate, Ifenprodil, Ketobemidone, Orphenadrine, Pentobarbital, Pethidine, Phenobarbital, Secobarbital Glutamate receptor ionotropic, NMDA 1 binder: Memantine Glutamate receptor ionotropic, NMDA 1 blocker: Atomoxetine Glutamate receptor ionotropic, NMDA 1 inhibitor: Milnacipran Glutamate receptor ionotropic, NMDA 1 unknown: Gabapentin | 15.1 | ||
| kccNMT1 | Glycylpeptide N-tetradecanoyltransferase 1 | 2 | 45 | 87.68 | ND | 100.00 | 0.84 | ND | 0.4 | Mammalian | Heart, gut, kidney, liver and placenta. | Enzyme | Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins. {ECO:0000269|PubMed:25255805, ECO:0000269|PubMed:9353336, ECO:0000269|PubMed:9506952}. | Glutamate receptor ionotropic, NMDA 1 activator: Acetylcysteine Glutamate receptor ionotropic, NMDA 1 antagonist: Acamprosate, Ifenprodil, Ketobemidone, Orphenadrine, Pentobarbital, Pethidine, Phenobarbital, Secobarbital Glutamate receptor ionotropic, NMDA 1 binder: Memantine Glutamate receptor ionotropic, NMDA 1 blocker: Atomoxetine Glutamate receptor ionotropic, NMDA 1 inhibitor: Milnacipran Glutamate receptor ionotropic, NMDA 1 unknown: Gabapentin | 15.1 | |||
| kccNOD1 | Nucleotide-binding oligomerization domain-containing protein 1 | 13 | 212 | 81.64 | ND | 84.98 | 0.50 | ND | 1.1 | Mammalian | Highly expressed in adult heart, skeletal muscle, pancreas, spleen and ovary. Also detected in placenta, lung, liver, kidney, thymus, testis, small intestine and colon. | Enhances caspase-9-mediated apoptosis. Induces NF-kappa- B activity via RIPK2 and IKK-gamma. Confers responsiveness to intracellular bacterial lipopolysaccharides (LPS). Forms an intracellular sensing system along with ARHGEF2 for the detection of microbial effectors during cell invasion by pathogens. Required for RHOA and RIPK2 dependent NF-kappa-B signaling pathway activation upon S.flexneri cell invasion. Involved not only in sensing peptidoglycan (PGN)-derived muropeptides but also in the activation of NF-kappa-B by Shigella effector proteins IpgB2 and OspB. Recruits NLRP10 to the cell membrane following bacterial infection. {ECO:0000269|PubMed:11058605, ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:19043560, ECO:0000269|PubMed:22672233}. | 15.1 | |||||
| kccNOS1 | Nitric oxide synthase, brain | 24 | 1035 | 90.57 | ND | 97.21 | 0.54 | ND | 0.6 | Mammalian | Isoform 1 is ubiquitously expressed: detected in skeletal muscle and brain, also in testis, lung and kidney, and at low levels in heart, adrenal gland and retina. Not detected in the platelets. Isoform 3 is expressed only in testis. Isoform 4 is detected in testis, skeletal muscle, lung, and kidney, at low levels in the brain, but not in the heart and adrenal gland. | Enzyme | Helminth infection
Migraine and Cluster Headaches Schizophrenia | Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. | Nitric oxide synthase, brain substrate: Doxorubicin Nitric oxide synthase, brain unknown: Flavin adenine dinucleotide, L-Citrulline | 15.1 | ||
| kccNOS2 | Nitric oxide synthase, inducible | 20 | 1117 | 84.40 | ND | 95.34 | 0.63 | ND | 0.7 | Mammalian | Expressed in the liver, retina, bone cells and airway epithelial cells of the lung. Not expressed in the platelets. | Enzyme | Ischemia reperfusion injuries | Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such COX2. As component of the iNOS- S100A8/9 transnitrosylase complex involved in the selective inflammatory stimulus-dependent S-nitrosylation of GAPDH on 'Cys- 247' implicated in regulation of the GAIT complex activity and probably multiple targets including ANXA5, EZR, MSN and VIM. {ECO:0000269|PubMed:25417112}. | Nitric oxide synthase, inducible inhibitor: Miconazole Nitric oxide synthase, inducible negative modulator: Dexamethasone Nitric oxide synthase, inducible substrate: Doxorubicin Nitric oxide synthase, inducible unknown: L-Arginine, L-Citrulline | 15.1 | ||
| kccNOS3 | Nitric oxide synthase, endothelial | 11 | 786 | 91.73 | ND | 96.40 | 0.47 | ND | 0.5 | Mammalian | Platelets, placenta, liver and kidney. {ECO:0000269|PubMed:7515611}. | Enzyme | Note=Variation in NOS3 seem to be associated with susceptibility to coronary spasm. {ECO:0000269|PubMed:11740345, ECO:0000269|PubMed:9737779}. | Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1. | Nitric oxide synthase, endothelial cofactor: Tetrahydrobiopterin Nitric oxide synthase, endothelial inhibitor: Miconazole Nitric oxide synthase, endothelial substrate: Doxorubicin Nitric oxide synthase, endothelial unknown: L-Arginine, L-Citrulline | 15.1 | ||
| kccNOX1 | NADPH oxidase 1 | 6 | 64 | 97.76 | ND | 96.55 | 0.08 | ND | 0.6 | Mammalian | NOH-1L is detected in colon, uterus, prostate, and colon carcinoma, but not in peripheral blood leukocytes. NOH- 1S is detected only in colon and colon carcinoma cells. | Transmembrane 1-electron transfer carriers | NOH-1S is a voltage-gated proton channel that mediates the H(+) currents of resting phagocytes and other tissues. It participates in the regulation of cellular pH and is blocked by zinc. NOH-1L is a pyridine nucleotide-dependent oxidoreductase that generates superoxide and might conduct H(+) ions as part of its electron transport mechanism, whereas NOH-1S does not contain an electron transport chain. | 15.1 | ||||
| kccNOX4 | NADPH oxidase 4 | 3 | 88 | 97.01 | ND | 87.45 | 0.64 | ND | 0.4 | Mammalian | Expressed by distal tubular cells in kidney cortex and in endothelial cells (at protein level). Widely expressed. Strongly expressed in kidney and to a lower extent in heart, adipocytes, hepatoma, endothelial cells, skeletal muscle, brain, several brain tumor cell lines and airway epithelial cells. {ECO:0000269|PubMed:11032835, ECO:0000269|PubMed:11376945, ECO:0000269|PubMed:15210697, ECO:0000269|PubMed:16324151}. | Enzyme | Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 5 and isoform 6 display reduced activity. Isoform 4: Involved in redox signaling in vascular cells. Constitutively and NADPH-dependently generates reactive oxygen species (ROS). Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Displays an increased activity relative to isoform 1. | 15.1 | ||||
| kccNPBW1 | Neuropeptides B/W receptor type 1 | 5 | 271 | 98.68 | ND | 98.34 | 0.70 | ND | 0.4 | Mammalian | Found in cerebellum and frontal cortex. Detected at high levels in hippocampus, amygdala and trachea; at moderate levels in fetal brain, pituitary gland and prostate. Not in caudate, accumbens, kidney or liver. Also detected at high levels in lung carcinoma. {ECO:0000269|PubMed:12401809}. | Family A G protein-coupled receptor | Interacts specifically with a number of opioid ligands. Receptor for neuropeptides B and W, which may be involved in neuroendocrine system regulation, food intake and the organization of other signals. Has a higher affinity for neuropeptide B. | 15.1 | ||||
| kccNPC1 | Niemann-Pick C1 protein | 140 | 6047 | 94.02 | ND | 94.22 | 0.06 | ND | 0.7 | Mammalian | Niemann-Pick disease C1 (NPC1) [MIM:257220]: A lysosomal storage disorder that affects the viscera and the central nervous system. It is due to defective intracellular processing and transport of low-density lipoprotein derived cholesterol. It causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Niemann-Pick disease type C1 has a highly variable clinical phenotype. Clinical features include variable hepatosplenomegaly and severe progressive neurological dysfunction such as ataxia, dystonia and dementia. The age of onset can vary from infancy to late adulthood. An allelic variant of Niemann-Pick disease type C1 is found in people with Nova Scotia ancestry. Patients with the Nova Scotian clinical variant are less severely affected. {ECO:0000269|PubMed:10480349, ECO:0000269|PubMed:10521290, ECO:0000269|PubMed:10521297, ECO:0000269|PubMed:11182931, ECO:0000269|PubMed:11333381, ECO:0000269|PubMed:11349231, ECO:0000269|PubMed:11479732, ECO:0000269|PubMed:11545687, ECO:0000269|PubMed:11754101, ECO:0000269|PubMed:12401890, ECO:0000269|PubMed:12408188, ECO:0000269|PubMed:12554680, ECO:0000269|PubMed:12955717, ECO:0000269|PubMed:15774455, ECO:0000269|PubMed:16098014, ECO:0000269|PubMed:16126423, ECO:0000269|PubMed:16802107, ECO:0000269|PubMed:9211849, ECO:0000269|PubMed:9634529}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. Both NPC1 and NPC2 function as the cellular 'tag team duo' (TTD) to catalyze the mobilization of cholesterol within the multivesicular environment of the late endosome (LE) to effect egress through the limiting bilayer of the LE. NPC2 binds unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes and transfers it to the cholesterol-binding pocket of the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket and is exported from the limiting membrane of late endosomes/ lysosomes to the ER and plasma membrane by an unknown mechanism. Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals. {ECO:0000269|PubMed:18772377, ECO:0000269|PubMed:19563754}. (Microbial infection) Acts as an endosomal entry receptor for ebolavirus. {ECO:0000269|PubMed:21866103, ECO:0000269|PubMed:25855742}. | 15.1 | |||||
| kccNPCL1 | Niemann-Pick C1-like protein 1 | 3 | 100 | 99.42 | ND | 96.26 | 0.12 | ND | 0.3 | Mammalian | Widely expressed. Expressed in liver. Also expressed in small intestine, pancreas, kidney, lung, pancreas, spleen, heart, gall bladder, brain, testis, stomach and muscle. {ECO:0000269|PubMed:10783261, ECO:0000269|PubMed:14976318, ECO:0000269|PubMed:15671032}. | Other membrane protein | Hypercholesterolemia
Sitosterolemia | Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism. Acts as a negative regulator of NPC2 and down- regulates its expression and secretion by inhibiting its maturation and accelerating its degradation. {ECO:0000269|PubMed:15928087, ECO:0000269|PubMed:22095670}. | Niemann-Pick C1-like protein 1 inhibitor: Ezetimibe | 15.1 | ||
| kccNPFF2 | Neuropeptide FF receptor 2 | 4 | 53 | 98.22 | ND | 96.05 | 0.64 | ND | 0.5 | Mammalian | Isoform 1 is abundant in placenta. Relatively highly expressed in thymus, testis, and small intestine. Expressed at low levels in several tissues including spleen, prostate, brain, heart, ovary, colon, kidney, lung, liver and pancreas and not expressed in skeletal muscle and leukocytes. Isoform 2 expression is highest in placenta (but at relatively low level compared to isoform 1). Very low level of expression in numerous tissues including adipose tissue and many brain regions. Isoform 3 is expressed in brain and heart and, at lower levels, in kidney, liver, lung and pancreas. {ECO:0000269|PubMed:10079187}. | Family A G protein-coupled receptor | Receptor for NPAF (A-18-F-amide) and NPFF (F-8-F-amide) neuropeptides, also known as morphine-modulating peptides. Can also be activated by a variety of naturally occurring or synthetic FMRF-amide like ligands. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system. | 15.1 | ||||
| kccNPY1R | Neuropeptide Y receptor type 1 | 20 | 720 | 93.01 | ND | 90.59 | 0.61 | ND | 0.7 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Analgesics
Anxiety disorder, unspecified Cardiovascular disease, unspecified Convulsions Drug dependence Metabolic disorder, unspecified Obesity Pain, unspecified Rhinitis | Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is NPY > [Pro-34] PYY, PYY and [Leu-31, Pro-34] NPY > NPY (2-36) > [Ile-31, Gln-34] PP and PYY (3-36) > PP > NPY free acid. | 15.1 | |||
| kccNPY2R | Neuropeptide Y receptor type 2 | 11 | 445 | 88.96 | ND | 88.82 | 0.81 | ND | 0.5 | Nature11159 | Mammalian | High levels in amygdala, corpus callosum, hippocampus and subthalamic nucleus. Also detectable in caudate nucleus, hypothalamus and substantia nigra. | Family A G protein-coupled receptor | Obesity | Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is PYY > NPY > PYY (3-36) > NPY (2-36) > [Ile-31, Gln-34] PP > [Leu- 31, Pro-34] NPY > PP, [Pro-34] PYY and NPY free acid. | Neuropeptide Y receptor type 2 other/unknown: Cysteamine | 15.1 | |
| kccNPY4R | Neuropeptide Y receptor type 4 | 2 | 92 | 99.89 | ND | 99.97 | 0.64 | ND | 0.8 | Mammalian | Highest levels found in brain, coronary artery and ileum. Low levels in pancreas and kidney. Detected in colon and small intestine. | Family A G protein-coupled receptor | Obesity
Schizophrenia and Schizoaffective Disorders | Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is PP, PP (2-36) and [Ile-31, Gln-34] PP > [Pro-34] PYY > PYY and [Leu-31, Pro-34] NPY > NPY > PYY (3-36) and NPY (2-36) > PP (13- 36) > PP (31-36) > NPY free acid. | 15.1 | |||
| kccNPY5R | Neuropeptide Y receptor type 5 | 60 | 1119 | 98.89 | ND | 98.86 | 0.45 | ND | 0.8 | Mammalian | Brain; hypothalamus. | Family A G protein-coupled receptor | Epilepsy
Obesity Opioid dependence Temporal lobe epilepsy | Receptor for neuropeptide Y and peptide YY. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity. Seems to be associated with food intake. Could be involved in feeding disorders. | 15.1 | |||
| kccNQO1 | NAD(P)H dehydrogenase [quinone] 1 | 1 | 98 | 94.39 | ND | 99.85 | 0.74 | ND | 0.9 | Mammalian | Enzyme | Cancer, unspecific
Nonsmall cell lung cancer | The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis. | NAD(P)H dehydrogenase [quinone] 1 inducer: Vitamin E NAD(P)H dehydrogenase [quinone] 1 inhibitor: Dicoumarol NAD(P)H dehydrogenase [quinone] 1 substrate: Carboplatin, Cisplatin, Doxorubicin, Oxaliplatin NAD(P)H dehydrogenase [quinone] 1 unknown: Flavin adenine dinucleotide, Menadione | 15.1 | |||
| kccNQO2 | Ribosyldihydronicotinamide dehydrogenase [quinone] | 9 | 223 | 94.21 | ND | 92.76 | 0.51 | ND | 0.7 | Mammalian | Enzyme | Cancer, unspecific
Malaria Tumors | The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis. {ECO:0000269|PubMed:18254726}. | Ribosyldihydronicotinamide dehydrogenase [quinone] inhibitor: Dabigatran etexilate, Primaquine Ribosyldihydronicotinamide dehydrogenase [quinone] unknown: Flavin adenine dinucleotide, Melatonin, Menadione | 15.1 | |||
| kccNR1D1 | Nuclear receptor subfamily 1 group D member 1 | 4 | 60 | 99.95 | ND | 99.96 | 0.10 | ND | 0.2 | Mammalian | Widely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Also expressed in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and macrophages. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues. Expression increases during the differentiation of pre-adipocytes into mature adipocytes. Expressed at high levels in some squamous carcinoma cell lines. {ECO:0000269|PubMed:2539258}. | Nuclear receptor | Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. {ECO:0000269|PubMed:12021280, ECO:0000269|PubMed:15761026, ECO:0000269|PubMed:16968709, ECO:0000269|PubMed:18006707, ECO:0000269|PubMed:19710360, ECO:0000269|PubMed:1971514, ECO:0000269|PubMed:21479263, ECO:0000269|PubMed:22184247, ECO:0000269|PubMed:23398316, ECO:0000269|PubMed:2539258}. | 15.1 | ||||
| kccNR1H2 | Oxysterols receptor LXR-beta | 22 | 584 | 99.36 | ND | 99.83 | 0.73 | ND | 0.6 | VirtualToxLab | Mammalian | Ubiquitous. | Nuclear receptor | Atherosclerosis
Dyslipidemia | Nuclear receptor. Binds preferentially to double- stranded oligonucleotide direct repeats having the consensus half- site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8; DLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Exhibits a ligand-dependent transcriptional activation activity (PubMed:25661920). {ECO:0000250|UniProtKB:Q60644, ECO:0000269|PubMed:25661920}. | Ribosyldihydronicotinamide dehydrogenase [quinone] inhibitor: Dabigatran etexilate, Primaquine Ribosyldihydronicotinamide dehydrogenase [quinone] unknown: Flavin adenine dinucleotide, Melatonin, Menadione | 15.1 | |
| kccNR1H3 | Oxysterols receptor LXR-alpha | 23 | 524 | 98.69 | ND | 98.55 | 0.54 | ND | 0.7 | VirtualToxLab | Mammalian | Visceral organs specific expression. Strong expression was found in liver, kidney and intestine followed by spleen and to a lesser extent the adrenals. | Nuclear receptor | Atherosclerosis
Cancer, unspecific | Nuclear receptor. Interaction with RXR shifts RXR from its role as a silent DNA-binding partner to an active ligand- binding subunit in mediating retinoid responses through target genes defined by LXRES. LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half- sites spaced by four nucleotides. Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). Exhibits a ligand-dependent transcriptional activation activity (PubMed:25661920). {ECO:0000250|UniProtKB:Q9Z0Y9, ECO:0000269|PubMed:25661920}. | Ribosyldihydronicotinamide dehydrogenase [quinone] inhibitor: Dabigatran etexilate, Primaquine Ribosyldihydronicotinamide dehydrogenase [quinone] unknown: Flavin adenine dinucleotide, Melatonin, Menadione | 15.1 | |
| kccNR1H4 | Bile acid receptor | 14 | 512 | 96.11 | ND | 97.04 | 0.76 | ND | 0.4 | Mammalian | Nuclear receptor | Cancer, unspecific
Hypercholesterolemia Intrahepatic cholestasis | Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus. {ECO:0000269|PubMed:10334992, ECO:0000269|PubMed:10334993, ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12815072, ECO:0000269|PubMed:15471871, ECO:0000269|PubMed:18621523, ECO:0000269|PubMed:19410460, ECO:0000269|PubMed:19586769}. | Bile acid receptor other: Chenodeoxycholic acid | 15.1 | |||
| kccNR2E3 | Photoreceptor-specific nuclear receptor | 8 | 268 | 86.08 | ND | 84.24 | 0.17 | ND | 1.2 | Mammalian | Eye specific; found solely in the outer nuclear layer of the adult neurosensory retina, where the nuclei of cone and rod photoreceptors reside. {ECO:0000269|PubMed:15689355}. | Nuclear receptor | Enhanced S cone syndrome (ESCS) [MIM:268100]: Autosomal recessive retinopathy in which patients have increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones. ESCS is also associated with visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration. {ECO:0000269|PubMed:10655056, ECO:0000269|PubMed:11071390, ECO:0000269|PubMed:12963616, ECO:0000269|PubMed:15459973, ECO:0000269|PubMed:16225923, ECO:0000269|PubMed:18294254, ECO:0000269|PubMed:19006237}. Note=The disease is caused by mutations affecting the gene represented in this entry. Retinitis pigmentosa 37 (RP37) [MIM:611131]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:17564971, ECO:0000269|PubMed:19006237}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Orphan nuclear receptor of retinal photoreceptor cells. Transcriptional factor that is an activator of rod development and repressor of cone development. Binds the promoter region of a number of rod- and cone-specific genes, including rhodopsin, M- and S-opsin and rod-specific phosphodiesterase beta subunit. Enhances rhodopsin expression. Represses M- and S-cone opsin expression. {ECO:0000269|PubMed:15689355, ECO:0000269|PubMed:24069298}. | 15.1 | |||
| kccNRP1 | Neuropilin-1 | 2 | 46 | 99.96 | ND | 99.97 | 0.51 | ND | 0.3 | Mammalian | The expression of isoforms 1 and 2 does not seem to overlap. Isoform 1 is expressed by the blood vessels of different tissues. In the developing embryo it is found predominantly in the nervous system. In adult tissues, it is highly expressed in heart and placenta; moderately in lung, liver, skeletal muscle, kidney and pancreas; and low in adult brain. Isoform 2 is found in liver hepatocytes, kidney distal and proximal tubules. | Secreted protein | Cancer, unspecific | The membrane-bound isoform 1 is a receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits and in organogenesis outside the nervous system. It mediates the chemorepulsant activity of semaphorins. It binds to semaphorin 3A, The PLGF-2 isoform of PGF, The VEGF-165 isoform of VEGF and VEGF-B. Coexpression with KDR results in increased VEGF-165 binding to KDR as well as increased chemotaxis. It may regulate VEGF-induced angiogenesis. The soluble isoform 2 binds VEGF-165 and appears to inhibit its binding to cells. It may also induce apoptosis by sequestering VEGF-165. May bind as well various members of the semaphorin family. Its expression has an averse effect on blood vessel number and integrity. | 15.1 | |||
| kccNTCP2 | Ileal sodium/bile acid cotransporter | 3 | 199 | 99.41 | ND | 99.91 | 0.59 | ND | 0.6 | Mammalian | Hypokalaemia Pancreatitis | Electrochemical transporter | Primary bile acid malabsorption (PBAM) [MIM:613291]: An intestinal disorder associated with chronic watery diarrhea, excess fecal bile acids, steatorrhea and interruption of the enterohepatic circulation of bile acids. {ECO:0000269|PubMed:9109432}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine. Plays a key role in cholesterol metabolism. | Ileal sodium/bile acid cotransporter inhibitor: Cyclosporine, Ursodeoxycholic acid Ileal sodium/bile acid cotransporter substrate: Aciclovir Ileal sodium/bile acid cotransporter unknown: Valaciclovir | 15.1 | ||
| kccNTR1 | Neurotensin receptor type 1 | 5 | 328 | 90.51 | ND | 93.16 | 0.67 | ND | 1.0 | Nature11159 | Mammalian | Expressed in prostate (at protein level). Detected in colon and peripheral blood mononuclear cells. Detected at very low levels in brain. {ECO:0000269|PubMed:20048080, ECO:0000269|PubMed:8381365}. | Family A G protein-coupled receptor | Analgesics
Colorectal Cancer Depression Lung Cancer NTR-positive tumors Pain, Acute or Chronic Pancreatic cancer Prostate cancer Psychosis Schizophrenia and Schizoaffective Disorders | G-protein coupled receptor for the tridecapeptide neurotensin (NTS). Signaling is effected via G proteins that activate a phosphatidylinositol-calcium second messenger system. Signaling leads to the activation of downstream MAP kinases and protects cells against apoptosis. {ECO:0000269|PubMed:21725197, ECO:0000269|PubMed:23140271, ECO:0000269|PubMed:8381365}. | 15.1 | ||
| kccNTR2 | Neurotensin receptor type 2 | 2 | 104 | 98.93 | ND | 99.98 | 0.77 | ND | 0.8 | Mammalian | Expressed in prostate (at protein level). {ECO:0000269|PubMed:20048080}. | Family A G protein-coupled receptor | Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol- calcium second messenger system. | Neurotensin receptor type 2 partial antagonist: Levocabastine | 15.1 | |||
| kccNTRK1 | High affinity nerve growth factor receptor | 22 | 501 | 95.73 | ND | 91.07 | 0.41 | ND | 1.4 | Mammalian | Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors. {ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:8325889}. | Kinase | Congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]: Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II. {ECO:0000269|PubMed:10090906, ECO:0000269|PubMed:10233776, ECO:0000269|PubMed:10330344, ECO:0000269|PubMed:10567924, ECO:0000269|PubMed:10861667, ECO:0000269|PubMed:10982191, ECO:0000269|PubMed:11310631, ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:8696348}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thyroid papillary carcinoma (TPC) [MIM:188550]: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving NTRK1 are found in thyroid papillary carcinomas. Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1; a rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1; an intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein. | Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand, it can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras- PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras- MAPK signaling cascade. Antagonizes the anti-proliferative NGF- NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed. | High affinity nerve growth factor receptor agonist: Amitriptyline High affinity nerve growth factor receptor antagonist: Imatinib High affinity nerve growth factor receptor inhibitor: Regorafenib | 15.1 | ||
| kccNTRK2 | BDNF/NT-3 growth factors receptor | 14 | 293 | 96.83 | ND | 92.08 | 0.11 | ND | 1.5 | Mammalian | Isoform TrkB is expressed in the central and peripheral nervous system. In the central nervous system (CNS), expression is observed in the cerebral cortex, hippocampus, thalamus, choroid plexus, granular layer of the cerebellum, brain stem, and spinal cord. In the peripheral nervous system, it is expressed in many cranial ganglia, the ophthalmic nerve, the vestibular system, multiple facial structures, the submaxillary glands, and dorsal root ganglia. Isoform TrkB-T1 is mainly expressed in the brain but also detected in other tissues including pancreas, kidney and heart. Isoform TrkB-T-Shc is predominantly expressed in the brain. {ECO:0000269|PubMed:11798182, ECO:0000269|PubMed:7936202}. | Kinase | Obesity, hyperphagia, and developmental delay (OBHD) [MIM:613886]: A disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language. {ECO:0000269|PubMed:15494731}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin- 4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin- dependent calcium signaling in glial cells and mediate communication between neurons and glia. {ECO:0000269|PubMed:15494731}. | BDNF/NT-3 growth factors receptor agonist: Amitriptyline | 15.1 | ||
| kccNTRK3 | NT-3 growth factor receptor | 12 | 269 | 93.73 | ND | 86.60 | 0.12 | ND | 1.6 | Mammalian | Widely expressed but mainly in nervous tissue. Isoform 2 is expressed at higher levels in adult brain than in fetal brain. | Kinase | Receptor for neurotrophin-3 (NT-3). This is a tyrosine- protein kinase receptor. Known substrates for the trk receptors are SHC1, PI-3 kinase, and PLCG1. The different isoforms do not have identical signaling properties. | 15.1 | ||||
| kccNU1M | NADH-ubiquinone oxidoreductase chain 1 | 3 | 72 | 95.92 | ND | 94.61 | 0.53 | ND | 1.1 | Mammalian | Oxidoreductase | Leber hereditary optic neuropathy (LHON) [MIM:535000]: A maternally inherited disease resulting in acute or subacute loss of central vision, due to optic nerve dysfunction. Cardiac conduction defects and neurological defects have also been described in some patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. {ECO:0000269|PubMed:1417830, ECO:0000269|PubMed:1674640, ECO:0000269|PubMed:1900003, ECO:0000269|PubMed:1928099, ECO:0000269|PubMed:2018041}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) [MIM:540000]: Genetically heterogeneous disorder, characterized by episodic vomiting, seizures, and recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia, or cortical blindness. {ECO:0000269|PubMed:8723687}. Note=The disease is caused by mutations affecting the gene represented in this entry. Alzheimer disease mitochondrial (AD-MT) [MIM:502500]: Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Note=Genetic variation in MT-ND1 might contribute to the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). {ECO:0000269|PubMed:15265369, ECO:0000269|PubMed:7733935}. Mitochondrial complex I deficiency (MT-C1D) [MIM:252010]: A disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. {ECO:0000269|PubMed:24105702}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed to belong to the minimal assembly required for catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (By similarity). {ECO:0000250}. | NADH-ubiquinone oxidoreductase chain 1 inhibitor: Halothane, Isoflurane NADH-ubiquinone oxidoreductase chain 1 unknown: Desflurane, Methoxyflurane, Sevoflurane | 15.1 | |||
| kccNUAK2 | NUAK family SNF1-like kinase 2 | 1 | 64 | 85.17 | ND | 87.97 | 0.01 | ND | 0.8 | Mammalian | Kinase | Stress-activated kinase involved in tolerance to glucose starvation. Induces cell-cell detachment by increasing F-actin conversion to G-actin. Expression is induced by CD95 or TNF-alpha, via NF-kappa-B. Protects cells from CD95-mediated apoptosis and is required for the increased motility and invasiveness of CD95- activated tumor cells. Able to phosphorylate 'Ser-464' of LATS1. {ECO:0000269|PubMed:14575707, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15345718, ECO:0000269|PubMed:19927127}. | 15.1 | |||||
| kccOPRD | Delta-type opioid receptor | 71 | 4697 | 96.23 | ND | 97.77 | 0.69 | ND | 0.8 | Nature11159 | Mammalian | Detected in oocytes (at protein level). Detected in brain cortex, hypothalamus, hippocampus and olfactory bulb. Detected in oocytes. {ECO:0000269|PubMed:22417668, ECO:0000269|PubMed:7808419}. | Biliary colic Bladder disorder Bradycardia Cerebrovascular disorder Constipation Death Dependence Dermatitis contact Drug tolerance Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Restlessness Shock Somnolence Ureteral spasm Urticaria Withdrawal syndrome | Family A G protein-coupled receptor | Analgesics
Cough Dyspnea Ischemia Pain, unspecified Parkinson's disease | G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine. {ECO:0000269|PubMed:22184124, ECO:0000269|PubMed:7808419, ECO:0000269|PubMed:8201839}. | Delta-type opioid receptor agonist: Amitriptyline, Butorphanol, Codeine, Dextromethorphan, Dextropropoxyphene, Diphenoxylate, Fentanyl, Heroin, Hydrocodone, Ketobemidone, Levorphanol, Loperamide, Methadone, Morphine, Oxycodone, Remifentanil, Sufentanil, Tramadol Delta-type opioid receptor antagonist: Alvimopan, Buprenorphine, Nalbuphine, Naloxone, Naltrexone, Oxymorphone Delta-type opioid receptor binder: Ketamine Delta-type opioid receptor partial agonist: Hydromorphone Delta-type opioid receptor unknown: Tapentadol | 15.1 |
| kccOPRK | Kappa-type opioid receptor | 98 | 4599 | 93.37 | ND | 96.30 | 0.70 | ND | 0.8 | Nature11159 | Mammalian | Detected in brain and placenta. {ECO:0000269|PubMed:7624359, ECO:0000269|PubMed:8060324}. | Biliary colic Bladder disorder Bradycardia Cerebrovascular disorder Coma Constipation Death Dependence Dermatitis contact Drug tolerance Dysphoria Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Respiratory disorder Restlessness Shock Somnolence Ureteral spasm Withdrawal syndrome | Family A G protein-coupled receptor | Alcohol dependence
Analgesics Behcet's disease Diarrhea Dyspnea Focal ischemia Immune disease Neurodegenerative diseases Pain, unspecified | G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions. {ECO:0000269|PubMed:12004055, ECO:0000269|PubMed:22437504, ECO:0000269|PubMed:7624359, ECO:0000269|PubMed:8060324}. | Kappa-type opioid receptor activator: Progesterone Kappa-type opioid receptor agonist: Amitriptyline, Butorphanol, Dextromethorphan, Fentanyl, Heroin, Hydromorphone, Ketamine, Ketobemidone, Levorphanol, Loperamide, Menthol, Mianserin, Mirtazapine, Morphine, Nalbuphine, Oxycodone, Pentazocine, Remifentanil, Tramadol Kappa-type opioid receptor antagonist: Alvimopan, Buprenorphine, Dextropropoxyphene, Dezocine, Methylnaltrexone, Naloxone, Naltrexone Kappa-type opioid receptor other: Sufentanil Kappa-type opioid receptor partial agonist: Codeine Kappa-type opioid receptor unknown: Pethidine, Tapentadol | 15.1 |
| kccOPRM | Mu-type opioid receptor | 104 | 5816 | 96.36 | ND | 97.03 | 0.70 | ND | 0.7 | Nature11159 | Mammalian | Expressed in brain. Isoform 16 and isoform 17 are detected in brain. {ECO:0000269|PubMed:16580639}. | Biliary colic Biliary tract disorder Bladder disorder Bradycardia Cerebrovascular disorder Coma Constipation Death Dependence Dermatitis contact Disorientation Drug tolerance Dry mouth Dysphoria Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle rigidity Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Respiratory disorder Restlessness Shock Somnolence Ureteral spasm Urticaria Withdrawal syndrome | Family A G protein-coupled receptor | Analgesics
Cough Diarrhea Dyspnea Opioid-induced bowel dysfunction Pain, unspecified | Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta- gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist- specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling whereas morphine induces only low desensitization and endocytosis. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 12 couples to GNAS and is proposed to be involved in excitatory effects. Isoform 16 and isoform 17 do not bind agonists but may act through oligomerization with binding- competent OPRM1 isoforms and reduce their ligand binding activity. | Mu-type opioid receptor agonist: Alfentanil, Anileridine, Dextromethorphan, Dextropropoxyphene, Dezocine, Diphenoxylate, Ethylmorphine, Fentanyl, Heroin, Hydrocodone, Hydromorphone, Ketobemidone, Levomethadyl Acetate, Levorphanol, Loperamide, Methadone, Methadyl Acetate, Morphine, Oxycodone, Oxymorphone, Pethidine, Remifentanil, Sufentanil, Tapentadol, Tramadol Mu-type opioid receptor antagonist: Alvimopan, Methylnaltrexone, Nalbuphine, Naloxegol, Naloxone, Naltrexone, Pentazocine Mu-type opioid receptor binder: Amitriptyline, Ketamine Mu-type opioid receptor other/unknown: Ondansetron Mu-type opioid receptor partial agonist: Buprenorphine, Codeine, Levallorphan Mu-type opioid receptor partial antagonist: Butorphanol | 15.1 |
| kccOPRX | Nociceptin receptor | 35 | 1182 | 97.94 | ND | 98.92 | 0.47 | ND | 0.8 | Mammalian | Detected in blood leukocytes. {ECO:0000269|PubMed:7500847}. | Hyperhidrosis | Family A G protein-coupled receptor | Analgesics
Anorexia nervosa Anxiety disorder, unspecified Cerebral ischemia Depression Drug dependence Epilepsy Erectile dysfunction Hypertension Neurogenic bladder Neuropathic pain Pain, unspecified | G-protein coupled opioid receptor that functions as receptor for the endogenous neuropeptide nociceptin. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling via G proteins mediates inhibition of adenylate cyclase activity and calcium channel activity. Arrestins modulate signaling via G proteins and mediate the activation of alternative signaling pathways that lead to the activation of MAP kinases. Plays a role in modulating nociception and the perception of pain. Plays a role in the regulation of locomotor activity by the neuropeptide nociceptin. {ECO:0000269|PubMed:11238602, ECO:0000269|PubMed:12568343, ECO:0000269|PubMed:22596163, ECO:0000269|PubMed:23086955, ECO:0000269|PubMed:8137918}. | Mu-type opioid receptor agonist: Alfentanil, Anileridine, Dextromethorphan, Dextropropoxyphene, Dezocine, Diphenoxylate, Ethylmorphine, Fentanyl, Heroin, Hydrocodone, Hydromorphone, Ketobemidone, Levomethadyl Acetate, Levorphanol, Loperamide, Methadone, Methadyl Acetate, Morphine, Oxycodone, Oxymorphone, Pethidine, Remifentanil, Sufentanil, Tapentadol, Tramadol Mu-type opioid receptor antagonist: Alvimopan, Methylnaltrexone, Nalbuphine, Naloxegol, Naloxone, Naltrexone, Pentazocine Mu-type opioid receptor binder: Amitriptyline, Ketamine Mu-type opioid receptor other/unknown: Ondansetron Mu-type opioid receptor partial agonist: Buprenorphine, Codeine, Levallorphan Mu-type opioid receptor partial antagonist: Butorphanol | 15.1 | |
| kccOX1R | Orexin receptor type 1 | 21 | 650 | 90.35 | ND | 89.98 | 0.49 | ND | 1.0 | Mammalian | Family A G protein-coupled receptor | Gastrointestinal motility disorders
Insomnia Insulin disorders Nausea and vomiting Nutritional disorders Sleep Disorders Sleeping sickness | Moderately selective excitatory receptor for orexin-A and, with a lower affinity, for orexin-B neuropeptide. Seems to be exclusively coupled to the G(q) subclass of heteromeric G proteins, which activates the phospholipase C mediated signaling cascade (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccOX2R | Orexin receptor type 2 | 24 | 542 | 96.24 | ND | 95.35 | 0.58 | ND | 0.9 | Mammalian | Family A G protein-coupled receptor | Gastrointestinal motility disorders
Nausea and vomiting | Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides. | 15.1 | ||||
| kccOXDA | D-amino-acid oxidase | 7 | 141 | 99.10 | ND | 97.52 | 0.39 | ND | 1.0 | Mammalian | Enzyme | Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D- amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids. {ECO:0000269|PubMed:17303072}. | D-amino-acid oxidase unknown: Flavin adenine dinucleotide | 15.1 | ||||
| kccOXYR | Oxytocin receptor | 28 | 832 | 99.54 | ND | 99.04 | 0.74 | ND | 0.6 | Mammalian | Family A G protein-coupled receptor | Cancer, unspecific | Receptor for oxytocin. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol- calcium second messenger system. | Oxytocin receptor agonist: Carbetocin | 15.1 | |||
| kccP2RX1 | P2X purinoceptor 1 | 4 | 52 | 94.87 | ND | 89.87 | 0.51 | ND | 0.7 | Mammalian | Ligand-gated ion channel | Ligand-gated ion channel with relatively high calcium permeability. Binding to ATP mediates synaptic transmission between neurons and from neurons to smooth muscle. Seems to be linked to apoptosis, by increasing the intracellular concentration of calcium in the presence of ATP, leading to programmed cell death (By similarity). {ECO:0000250}. | 15.1 | |||||
| kccP2RX2 | P2X purinoceptor 2 | 3 | 133 | 98.75 | ND | 99.98 | 0.70 | ND | 0.4 | Mammalian | Ligand-gated ion channel | Deafness, autosomal dominant, 41 (DFNA41) [MIM:608224]: A form of non-syndromic deafness characterized by onset of progressive sensorineural hearing loss usually in the second decade. The hearing loss is severe and ultimately affects all frequencies. Exposure to noise exacerbates the hearing loss, particularly at high frequencies. {ECO:0000269|PubMed:23345450, ECO:0000269|PubMed:24211385}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ion channel gated by extracellular ATP involved in a variety of cellular responses, such as excitatory postsynaptic responses in sensory neurons, neuromuscular junctions (NMJ) formation, hearing, perception of taste and peristalsis. In the inner ear, regulates sound transduction and auditory neurotransmission, outer hair cell electromotility, inner ear gap junctions, and K(+) recycling. Mediates synaptic transmission between neurons and from neurons to smooth muscle. {ECO:0000269|PubMed:23345450}. | 15.1 | ||||
| kccP2RX3 | P2X purinoceptor 3 | 10 | 181 | 97.39 | ND | 99.85 | 0.46 | ND | 0.6 | Mammalian | Ligand-gated ion channel | Analgesics
Dysmotility Hypertonicity of bladder Inflammatory bowel disease Pain, unspecified | Receptor for ATP that acts as a ligand-gated ion channel. | 15.1 | ||||
| kccP2RX4 | P2X purinoceptor 4 | 2 | 141 | 96.14 | ND | 91.14 | 0.55 | ND | 0.3 | Mammalian | Ligand-gated ion channel | Analgesics
Pain, unspecific | Receptor for ATP that acts as a ligand-gated ion channel. This receptor is insensitive to the antagonists PPADS and suramin. {ECO:0000269|PubMed:10515189}. | 15.1 | ||||
| kccP2RX7 | P2X purinoceptor 7 | 34 | 1325 | 99.25 | ND | 99.58 | 0.54 | ND | 0.5 | Mammalian | Widely expressed with highest levels in brain and immune tissues. {ECO:0000269|PubMed:15896293}. | Ligand-gated ion channel | Analgesics
Diseases characterized by increased osteoclast number and excessive bone turnover Osteoporosis, unspecified Pain | Receptor for ATP that acts as a ligand-gated ion channel. Responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Could function in both fast synaptic transmission and the ATP-mediated lysis of antigen-presenting cells. | 15.1 | |||
| kccP2RY1 | P2Y purinoceptor 1 | 10 | 303 | 99.43 | ND | 99.08 | 0.57 | ND | 0.7 | Mammalian | Family A G protein-coupled receptor | Thrombosis | Receptor for extracellular adenine nucleotides such as ATP and ADP. In platelets binding to ADP leads to mobilization of intracellular calcium ions via activation of phospholipase C, a change in platelet shape, and probably to platelet aggregation. {ECO:0000269|PubMed:9442040}. | 15.1 | ||||
| kccP2RY2 | P2Y purinoceptor 2 | 3 | 245 | 96.76 | ND | 99.57 | 0.41 | ND | 0.6 | Mammalian | Spleen, testis, kidney, liver, lung, heart and brain. | Family A G protein-coupled receptor | Cystic fibrosis
Dry eye Glaucoma Oesophageal cancer | Receptor for ATP and UTP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. The affinity range is UTP = ATP > ATP-gamma-S >> 2-methylthio-ATP = ADP. | P2Y purinoceptor 2 antagonist: Suramin | 15.1 | ||
| kccP2RY4 | P2Y purinoceptor 4 | 2 | 143 | 99.90 | ND | 99.88 | 0.46 | ND | 0.6 | Mammalian | Pancreas. | Family A G protein-coupled receptor | Receptor for UTP and UDP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. Not activated by ATP or ADP. | 15.1 | ||||
| kccP2RY6 | P2Y purinoceptor 6 | 1 | 206 | 98.22 | ND | 99.79 | 0.45 | ND | 0.5 | Mammalian | Family A G protein-coupled receptor | Cystic fibrosis gallbladder disease | Receptor for extracellular UDP > UTP > ATP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. | 15.1 | ||||
| kccP2Y12 | P2Y purinoceptor 12 | 9 | 810 | 98.26 | ND | 99.23 | 0.78 | ND | 0.6 | Mammalian | Highly expressed in the platelets, lower levels in the brain. Lowest levels in the lung, appendix, pituitary and adrenal gland. Expressed in the spinal cord and in the fetal brain. {ECO:0000269|PubMed:11104774, ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:11502873}. | Family A G protein-coupled receptor | Bleeding disorder, platelet-type 8 (BDPLT8) [MIM:609821]: A condition characterized by mild to moderate mucocutaneous bleeding, and excessive bleeding after surgery or trauma. The defect is due to severe impairment of platelet response to ADP resulting in defective platelet aggregation. {ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:12578987, ECO:0000269|PubMed:25428217}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation. {ECO:0000269|PubMed:11104774, ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:11502873, ECO:0000269|PubMed:12578987, ECO:0000269|PubMed:24670650, ECO:0000269|PubMed:24784220}. | P2Y purinoceptor 12 agonist: Epoprostenol, Treprostinil P2Y purinoceptor 12 antagonist: Clopidogrel, Prasugrel, Ticlopidine P2Y purinoceptor 12 inhibitor: Ticagrelor | 15.1 | ||
| kccP2Y14 | P2Y purinoceptor 14 | 4 | 100 | 98.71 | ND | 99.97 | 0.25 | ND | 0.6 | Mammalian | Highest expression in the placenta, adipose tissue, stomach and intestine, intermediate levels in the brain, spleen, lung and heart, lowest levels in the kidney. | Family A G protein-coupled receptor | Receptor for UDP-glucose and other UDP-sugar coupled to G-proteins. Not activated by ATP, ADP, UTP or ATP. {ECO:0000269|PubMed:10753868}. | 15.1 | ||||
| kccP53 | Cellular tumor antigen p53 | 66 | 2283 | 86.40 | ND | 84.72 | 0.03 | ND | 0.8 | Mammalian | Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine. {ECO:0000269|PubMed:16131611}. | Transcription factor | Note=TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma. Esophageal cancer (ESCR) [MIM:133239]: A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage. Note=The disease is caused by mutations affecting the gene represented in this entry. Li-Fraumeni syndrome (LFS) [MIM:151623]: Autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers. {ECO:0000269|PubMed:10484981, ECO:0000269|PubMed:1565144, ECO:0000269|PubMed:1737852, ECO:0000269|PubMed:1933902, ECO:0000269|PubMed:1978757, ECO:0000269|PubMed:2259385, ECO:0000269|PubMed:7887414, ECO:0000269|PubMed:8825920, ECO:0000269|PubMed:9452042}. Note=The disease is caused by mutations affecting the gene represented in this entry. Squamous cell carcinoma of the head and neck (HNSCC) [MIM:275355]: A non-melanoma skin cancer affecting the head and neck. The hallmark of cutaneous SCC is malignant transformation of normal epidermal keratinocytes. Note=The gene represented in this entry is involved in disease pathogenesis. Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Note=The disease is caused by mutations affecting the gene represented in this entry. Papilloma of choroid plexus (CPP) [MIM:260500]: A benign tumor of neuroectodermal origin that generally occurs in childhood, but has also been reported in adults. Although generally found within the ventricular system, choroid plexus papillomas can arise ectopically in the brain parenchyma or disseminate throughout the neuraxis. Patients present with signs and symptoms of increased intracranial pressure including headache, hydrocephalus, papilledema, nausea, vomiting, cranial nerve deficits, gait impairment, and seizures. {ECO:0000269|PubMed:12085209}. Note=The disease is caused by mutations affecting the gene represented in this entry. Adrenocortical carcinoma (ADCC) [MIM:202300]: A malignant neoplasm of the adrenal cortex and a rare childhood tumor. It occurs with increased frequency in patients with Beckwith- Wiedemann syndrome and Li-Fraumeni syndrome. {ECO:0000269|PubMed:11481490}. Note=The disease is caused by mutations affecting the gene represented in this entry. Basal cell carcinoma 7 (BCC7) [MIM:614740]: A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter. {ECO:0000269|PubMed:21946351}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA- Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seem to have to effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1- mediated transcriptional activation of PER2 (PubMed:24051492). {ECO:0000269|PubMed:11025664, ECO:0000269|PubMed:12810724, ECO:0000269|PubMed:15186775, ECO:0000269|PubMed:15340061, ECO:0000269|PubMed:17317671, ECO:0000269|PubMed:17349958, ECO:0000269|PubMed:19556538, ECO:0000269|PubMed:20673990, ECO:0000269|PubMed:20959462, ECO:0000269|PubMed:22726440, ECO:0000269|PubMed:24051492, ECO:0000269|PubMed:9840937}. | Cellular tumor antigen p53 acetylation: Acetylsalicylic acid | 15.1 | ||
| kccPA24A | Cytosolic phospholipase A2 | 7 | 283 | 97.03 | ND | 96.05 | 0.54 | ND | 0.6 | Mammalian | Expressed in various tissues such as macrophages, platelets, neutrophils, fibroblasts and lung endothelium. | Enzyme | Note=PLA2G4A mutations resulting in phospholipase A2 deficiency have been found in a patient affected by recurrent episodes of multiple complicated ulcers of the small intestine, not due to cyclooxygenase inhibitors use. Disease features also include platelet dysfunction, and globally decreased eicosanoid synthesis (PubMed:18451993). {ECO:0000269|PubMed:18451993}. | Selectively hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid. Together with its lysophospholipid activity, it is implicated in the initiation of the inflammatory response. | Cytosolic phospholipase A2 inducer: Carbachol Cytosolic phospholipase A2 inhibitor: Carbenicillin, Epirubicin, Fluocinolone Acetonide, Fluticasone Propionate, Orlistat, Quinacrine, Suramin Cytosolic phospholipase A2 unknown: Niflumic Acid | 15.1 | ||
| kccPA2GA | Phospholipase A2, membrane associated | 11 | 351 | 98.36 | ND | 99.71 | 0.51 | ND | 0.7 | Mammalian | Enzyme | Atherosclerosis
Coronary Artery Disease | Thought to participate in the regulation of the phospholipid metabolism in biomembranes including eicosanoid biosynthesis. Catalyzes the calcium-dependent hydrolysis of the 2- acyl groups in 3-sn-phosphoglycerides. | Phospholipase A2, membrane associated inhibitor: Diclofenac, Indomethacin, Suramin | 15.1 | |||
| kccPA2GX | Group 10 secretory phospholipase A2 | 4 | 60 | 99.99 | ND | 99.93 | 0.85 | ND | 0.5 | Mammalian | Found in spleen, thymus, peripheral blood leukocytes, pancreas, lung, and colon. | Enzyme | PA2 catalyzes the calcium-dependent hydrolysis of the 2- acyl groups in 3-sn-phosphoglycerides. Has a powerful potency for releasing arachidonic acid from cell membrane phospholipids. Prefers phosphatidylethanolamine and phosphatidylcholine liposomes to those of phosphatidylserine. | 15.1 | ||||
| kccPAFA | Platelet-activating factor acetylhydrolase | 5 | 252 | 96.02 | ND | 99.13 | 0.78 | ND | 0.6 | Mammalian | Plasma. | Enzyme | Platelet-activating factor acetylhydrolase deficiency (PAFAD) [MIM:614278]: An enzymatic deficiency that results in exacerbated bodily response to inflammatory agents. It can be associated with several disease states including inflammatory gastrointestinal disorders, asthma and atopy. Asthmatic individuals with PAFAD may manifest aggravated respiratory symptoms. {ECO:0000269|PubMed:8675689, ECO:0000269|PubMed:9245731, ECO:0000269|PubMed:9412624, ECO:0000269|PubMed:9472966, ECO:0000269|PubMed:9759612}. Note=The disease is caused by mutations affecting the gene represented in this entry. Asthma (ASTHMA) [MIM:600807]: The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with wheezing due to spasmodic contraction of the bronchi. {ECO:0000269|PubMed:10733466}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Atopic hypersensitivity (ATOPY) [MIM:147050]: A condition characterized by predisposition to develop hypersensitivity reactions. Atopic individuals can develop eczema, allergic rhinitis and allergic asthma. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Modulates the action of platelet-activating factor (PAF) by hydrolyzing the sn-2 ester bond to yield the biologically inactive lyso-PAF. Has a specificity for substrates with a short residue at the sn-2 position. It is inactive against long-chain phospholipids. | Phospholipase A2, membrane associated inhibitor: Diclofenac, Indomethacin, Suramin | 15.1 | ||
| kccPAI1 | Plasminogen activator inhibitor 1 | 16 | 198 | 98.50 | ND | 98.24 | 0.47 | ND | 0.5 | Mammalian | Found in plasma and platelets and in endothelial, hepatoma and fibrosarcoma cells. | Secreted protein | Plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM:613329]: A hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of plasminogen activator inhibitor-1, which inhibits tissue and urinary activators of plasminogen. {ECO:0000269|PubMed:9207454}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=High concentrations of SERPINE1 seem to contribute to the development of venous but not arterial occlusions. | Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major control point in the regulation of fibrinolysis. {ECO:0000269|PubMed:15853774}. | Phospholipase A2, membrane associated inhibitor: Diclofenac, Indomethacin, Suramin | 15.1 | ||
| kccPAK1 | Serine/threonine-protein kinase PAK 1 | 7 | 196 | 95.38 | ND | 95.17 | 0.36 | ND | 1.1 | Mammalian | Overexpressed in gastric cancer cells and tissues (at protein level) (PubMed:25766321). {ECO:0000269|PubMed:25766321}. | Kinase | Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2- induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F- actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion (PubMed:25766321). {ECO:0000269|PubMed:10551809, ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:12624090, ECO:0000269|PubMed:12876277, ECO:0000269|PubMed:14585966, ECO:0000269|PubMed:15611088, ECO:0000269|PubMed:15831477, ECO:0000269|PubMed:15833848, ECO:0000269|PubMed:16278681, ECO:0000269|PubMed:17726028, ECO:0000269|PubMed:17989089, ECO:0000269|PubMed:22669945, ECO:0000269|PubMed:23633677, ECO:0000269|PubMed:25766321, ECO:0000269|PubMed:8805275, ECO:0000269|PubMed:9032240, ECO:0000269|PubMed:9395435, ECO:0000269|PubMed:9528787}. | 15.1 | ||||
| kccPAK4 | Serine/threonine-protein kinase PAK 4 | 13 | 352 | 95.35 | ND | 91.55 | 0.24 | ND | 1.3 | Mammalian | Highest expression in prostate, testis and colon. | Kinase | Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN. {ECO:0000269|PubMed:11278822, ECO:0000269|PubMed:11313478, ECO:0000269|PubMed:14560027, ECO:0000269|PubMed:15660133, ECO:0000269|PubMed:20507994, ECO:0000269|PubMed:20631255, ECO:0000269|PubMed:20805321}. | 15.1 | ||||
| kccPAR1 | Proteinase-activated receptor 1 | 11 | 560 | 99.49 | ND | 99.54 | 0.59 | ND | 0.5 | Mammalian | Platelets and vascular endothelial cells. | Family A G protein-coupled receptor | Acute Coronary Syndrome
Analgesics Cardiovascular Disorders Inflammation Ischemic Stroke Pain, unspecified Vascular disease | High affinity receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis. May play a role in platelets activation and in vascular development. {ECO:0000269|PubMed:10079109}. | Proteinase-activated receptor 1 antagonist: Vorapaxar | 15.1 | ||
| kccPAR2 | Proteinase-activated receptor 2 | 6 | 49 | 99.98 | ND | 99.96 | 0.57 | ND | 0.7 | Mammalian | Widely expressed in tissues with especially high levels in pancreas, liver, kidney, small intestine, and colon. Moderate expression is detected in many organs, but none in brain or skeletal muscle. | Family A G protein-coupled receptor | Coronary atherosclerotic lesions
Inflammation Inflammatory skin disorder Neurogenic inflammation Pruritus Rheumatoid arthritis, unspecified Tissue injury | Receptor for trypsin and trypsin-like enzymes coupled to G proteins. Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I- kappaB kinase/NF-kappaB and Rho. Can also be transactivated by cleaved F2R/PAR1. Involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and acts as a sensor for proteolytic enzymes generated during infection. Generally is promoting inflammation. Can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Has a protective role in establishing the endothelial barrier; the activity involves coagulation factor X. Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion. Involved in the regulation of vascular tone; activation results in hypotension presumably mediated by vasodilation. Associates with a subset of G proteins alpha subunits such as G alpha-q, G alpha-11, G alpha-14, G alpha- 12 and G alpha-13, but probably not with G(o) alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2. However, according to PubMed:21627585 can signal through G(i) subunit alpha. Believed to be a class B receptor which internalizes as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptor, for extended periods of time. Mediates inhibition of TNF-alpha stimulated JNK phosphorylation via coupling to G alpha-q/11; the function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536'; the function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal rearrangement and chemotaxis through beta-arrestin-promoted scaffolds; the function is independent of G alpha-q/11 and involves promotion of cofilin dephosphoryltaion and actin filament severing. Induces redistribution of COPS5 from the plasma membrane to the cytosol and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function such as proinflammatory cytokine secretion, superoxide production and degranulation. During inflammation promotes dendritic cell maturation, trafficking to the lymph nodes and subsequent T-cell activation. Involved in antimicrobial response of innate immnune cells; activation enhances phagocytosis of Gram- positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Implicated in a number of acute and chronic inflammatory diseases such as of the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, and in autoimmune disorders. {ECO:0000269|PubMed:10086357, ECO:0000269|PubMed:10725339, ECO:0000269|PubMed:11413129, ECO:0000269|PubMed:11441110, ECO:0000269|PubMed:11447194, ECO:0000269|PubMed:11714832, ECO:0000269|PubMed:12832443, ECO:0000269|PubMed:15155775, ECO:0000269|PubMed:16359518, ECO:0000269|PubMed:16410250, ECO:0000269|PubMed:16478888, ECO:0000269|PubMed:16714334, ECO:0000269|PubMed:17404307, ECO:0000269|PubMed:17500066, ECO:0000269|PubMed:18424071, ECO:0000269|PubMed:18453611, ECO:0000269|PubMed:18474671, ECO:0000269|PubMed:18622013, ECO:0000269|PubMed:19494303, ECO:0000269|PubMed:19781631, ECO:0000269|PubMed:19864598, ECO:0000269|PubMed:19865078, ECO:0000269|PubMed:20826780, ECO:0000269|PubMed:21501162}. | 15.1 | |||
| kccPARP1 | Poly [ADP-ribose] polymerase 1 | 61 | 1323 | 98.81 | ND | 98.86 | 0.63 | ND | 0.7 | Mammalian | Enzyme | Asthma
Cancer, unspecific Chronic obstructive pulmonary disease Diabetic cardiovascular dysfunction Diabetic endothelial dysfunction Multiple sclerosis Traumatic brain injury Tumors | Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP- ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Required for PARP9 and DTX3L recruitment to DNA damage sites. PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. {ECO:0000269|PubMed:17177976, ECO:0000269|PubMed:18172500, ECO:0000269|PubMed:19344625, ECO:0000269|PubMed:19661379, ECO:0000269|PubMed:23230272}. | Poly [ADP-ribose] polymerase 1 inhibitor: Olaparib | 15.1 | |||
| kccPARP2 | Poly [ADP-ribose] polymerase 2 | 3 | 81 | 91.45 | ND | 93.09 | 0.60 | ND | 1.1 | Mammalian | Widely expressed, mainly in actively dividing tissues. The highest levels are in the brain, heart, pancreas, skeletal muscle and testis; also detected in kidney, liver, lung, placenta, ovary and spleen; levels are low in leukocytes, colon, small intestine, prostate and thymus. | Enzyme | Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. | Poly [ADP-ribose] polymerase 2 Inhibitor: Olaparib | 15.1 | |||
| kccPAX8 | Paired box protein Pax-8 | 44 | 1323 | 83.24 | ND | 83.23 | 0.02 | ND | 0.7 | Mammalian | Expressed in the excretory system, thyroid gland and Wilms tumors. | Hypothyroidism, congenital, non-goitrous, 2 (CHNG2) [MIM:218700]: A disease characterized by thyroid dysgenesis, the most frequent cause of congenital hypothyroidism, accounting for 85% of case. The thyroid gland can be completely absent (athyreosis), ectopically located and/or severely hypoplastic. Ectopic thyroid gland is the most frequent malformation, with thyroid tissue being found most often at the base of the tongue. {ECO:0000269|PubMed:11232006, ECO:0000269|PubMed:11502839, ECO:0000269|PubMed:9590296}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transcription factor for the thyroid-specific expression of the genes exclusively expressed in the thyroid cell type, maintaining the functional differentiation of such cells. | 15.1 | ||||
| kccPCP | Lysosomal Pro-X carboxypeptidase | 16 | 280 | 99.82 | ND | 99.17 | 0.52 | ND | 0.7 | Mammalian | Highest levels in placenta, lung and liver. Also present in heart, brain, pancreas and kidney. | Protease | Cleaves C-terminal amino acids linked to proline in peptides such as angiotensin II, III and des-Arg9-bradykinin. This cleavage occurs at acidic pH, but enzymatic activity is retained with some substrates at neutral pH. | 15.1 | ||||
| kccPD2R | Prostaglandin D2 receptor | 15 | 547 | 99.64 | ND | 99.89 | 0.80 | ND | 0.6 | Mammalian | Expressed in retinal choroid, ciliary epithelium, longitudinal and circular ciliary muscles, iris, small intestine and platelet membranes. {ECO:0000269|PubMed:11082108, ECO:0000269|PubMed:6302737}. | Family A G protein-coupled receptor | Asthma-related traits 1 (ASRT1) [MIM:607277]: Asthma- related traits include clinical symptoms of asthma, such as coughing, wheezing, dyspnea, bronchial hyperresponsiveness as assessed by methacholine challenge test, serum IgE levels, atopy and atopic dermatitis. {ECO:0000269|PubMed:15496624}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for prostaglandin D2 (PGD2). The activity of this receptor is mainly mediated by G(s) proteins that stimulate adenylate cyclase, resulting in an elevation of intracellular cAMP. A mobilization of calcium is also observed, but without formation of inositol 1,4,5-trisphosphate (By similarity). {ECO:0000250}. | Prostaglandin D2 receptor unknown: Nedocromil | 15.1 | ||
| kccPD2R2 | Prostaglandin D2 receptor 2 | 35 | 1161 | 99.44 | ND | 99.63 | 0.52 | ND | 0.6 | Mammalian | Widespread expression. High expression in stomach, small intestine, heart and thymus. Intermediate expression in colon, spinal cord and peripheral blood and low expression in brain, skeletal muscle and spleen. Expressed also on Th2- and Tc2- type cells, eosinophils and basophils. {ECO:0000269|PubMed:11168006, ECO:0000269|PubMed:11208866, ECO:0000269|PubMed:12466225, ECO:0000269|PubMed:9973380}. | Family A G protein-coupled receptor | Asthma
Chronic obstructive pulmonary disease | Receptor for prostaglandin D2 (PGD2). Coupled to the G(i)-protein. Receptor activation may result in pertussis toxin- sensitive decreases in cAMP levels and Ca(2+) mobilization. PI3K signaling is also implicated in mediating PTGDR2 effects. PGD2 induced receptor internalization. CRTH2 internalization can be regulated by diverse kinases such as, PKC, PKA, ADRBK1/GRK2, GPRK5/GRK5 and GRK6. Receptor activation is responsible, at least in part, in immune regulation and allergic/inflammation responses. {ECO:0000269|PubMed:11208866, ECO:0000269|PubMed:11535533, ECO:0000269|PubMed:17196174}. | Prostaglandin D2 receptor 2 antagonist: Sulindac Prostaglandin D2 receptor 2 other/unknown: Indomethacin | 15.1 | ||
| kccPDE10 | cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A | 49 | 873 | 99.64 | ND | 98.22 | 0.61 | ND | 0.7 | Mammalian | Abundant in the putamen and caudate nucleus regions of brain and testis, moderately expressed in the thyroid gland, pituitary gland, thalamus and cerebellum. | Phosphodiesterase | Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate. {ECO:0000269|PubMed:17389385}. | cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A inhibitor: Dipyridamole, Papaverine, Tofisopam cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A inhibitor, competitive: Caffeine | 15.1 | |||
| kccPDE11 | Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A | 6 | 100 | 97.75 | ND | 97.08 | 0.62 | ND | 0.8 | Mammalian | Isoform 1 is present in prostate, pituitary, heart and liver. It is however not present in testis nor in penis, suggesting that weak inhibition by Tadalafil (Cialis) is not relevant (at protein level). Isoform 2 may be expressed in testis. Isoform 4 is expressed in adrenal cortex. {ECO:0000269|PubMed:10725373, ECO:0000269|PubMed:11121118, ECO:0000269|PubMed:15800651, ECO:0000269|PubMed:16079899, ECO:0000269|PubMed:16767104}. | Phosphodiesterase | Primary pigmented nodular adrenocortical disease 2 (PPNAD2) [MIM:610475]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:16767104}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP. Catalyzes the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'- GMP, respectively. {ECO:0000269|PubMed:10725373, ECO:0000269|PubMed:10906126, ECO:0000269|PubMed:11050148}. | Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A inhibitor: Tadalafil Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A inhibitor, competitive: Caffeine | 15.1 | ||
| kccPDE1A | Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A | 1 | 50 | 96.28 | ND | 100.00 | 0.66 | ND | 0.6 | Mammalian | Several tissues, including brain, kidney, testes and heart. | Flushing | Phosphodiesterase | Cardiovascular disease, unspecified
Erectile dysfunction | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a higher affinity for cGMP than for cAMP. | Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A inhibitor: Bepridil, Felodipine, Nicardipine Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A inhibitor, competitive: Caffeine | 15.1 | |
| kccPDE1C | Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C | 1 | 48 | 99.38 | ND | 99.95 | 0.03 | ND | 0.9 | Mammalian | Expressed in several tissues, including brain and heart. | Flushing | Phosphodiesterase | Cardiovascular disease, unspecified
Erectile dysfunction | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a high affinity for both cAMP and cGMP. | 15.1 | ||
| kccPDE2A | cGMP-dependent 3',5'-cyclic phosphodiesterase | 7 | 266 | 96.90 | ND | 95.34 | 0.89 | ND | 0.6 | Mammalian | Expressed in brain and to a lesser extent in heart, placenta, lung, skeletal muscle, kidney and pancreas. | Dyspepsia Flushing Headache | Phosphodiesterase | Colorectal cancer
Erectile dysfunction | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Isoform PDE2A2: Regulates Mitochondrial cAMP Levels and Respiration. | cGMP-dependent 3',5'-cyclic phosphodiesterase inhibitor: Tofisopam cGMP-dependent 3',5'-cyclic phosphodiesterase inhibitor, competitive: Caffeine | 15.1 | |
| kccPDE3A | cGMP-inhibited 3',5'-cyclic phosphodiesterase A | 11 | 262 | 97.20 | ND | 98.48 | 0.71 | ND | 0.8 | Nature11159 | Mammalian | Dyspepsia Palpitations | Phosphodiesterase | Hypertension and brachydactyly syndrome (HTNB) [MIM:112410]: A syndrome characterized by brachydactyly type E, severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, and altered baroreflex blood pressure regulation. It results in death from stroke before age 50 years when untreated. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. {ECO:0000269|PubMed:25961942}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. {ECO:0000250|UniProtKB:Q9Z0X4}. | cGMP-inhibited 3',5'-cyclic phosphodiesterase A inhibitor: Aminophylline, Amrinone, Anagrelide, Cilostazol, Enoximone, Ibudilast, Levosimendan, Milrinone, Oxtriphylline, Theophylline, Tofisopam cGMP-inhibited 3',5'-cyclic phosphodiesterase A inhibitor, competitive: Caffeine | 15.1 | |
| kccPDE3B | cGMP-inhibited 3',5'-cyclic phosphodiesterase B | 5 | 98 | 98.18 | ND | 94.99 | 0.90 | ND | 0.5 | Mammalian | Abundant in adipose tissues. | Phosphodiesterase | Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. May play a role in fat metabolism. Regulates cAMP binding of RAPGEF3. Through simultaneous binding to RAPGEF3 and PIK3R6 assembles a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis. {ECO:0000269|PubMed:15147193, ECO:0000269|PubMed:21393242}. | cGMP-inhibited 3',5'-cyclic phosphodiesterase B inhibitor, competitive: Caffeine | 15.1 | |||
| kccPDE4A | cAMP-specific 3',5'-cyclic phosphodiesterase 4A | 23 | 463 | 98.05 | ND | 98.30 | 0.62 | ND | 0.7 | Mammalian | Isoform 1 is widely expressed. Isoform 2 is abundant in liver, stomach, testis, thyroid and adrenal glands. It is also found in placenta, kidney, pancreas, ovary, uterus, skin, monocytes, mast cells, macrophages, as well as in bronchial smooth muscle. Isoform 6 is expressed at high levels in the heart and small intestine. It is also found in the brain, kidney, spleen, colon, salivary gland, ovary and peripheral blood lymphocytes. Isoform 7 is expressed predominantly in skeletal muscle and brain and at lower levels in the testis. Isoform 7 is expressed in the brain. Found in specific neuronal subpopulations in cortex, spinal cord and cerebellum (at protein level). {ECO:0000269|PubMed:11306681, ECO:0000269|PubMed:15738310, ECO:0000269|PubMed:18095939}. | Diarrhoea Dyspepsia Flushing Palpitations | Phosphodiesterase | Chronic lymphocytic leukemia | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:11566027, ECO:0000269|PubMed:17727341}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4A inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4A inhibitor: Dipyridamole, Drotaverine, Dyphylline, Enprofylline, Ibudilast, Ketotifen, Oxtriphylline, Pentoxifylline, Roflumilast, Theophylline, Tofisopam cAMP-specific 3',5'-cyclic phosphodiesterase 4A inhibitor, competitive: Caffeine | 15.1 | |
| kccPDE4B | cAMP-specific 3',5'-cyclic phosphodiesterase 4B | 40 | 743 | 98.80 | ND | 97.94 | 0.75 | ND | 0.8 | Mammalian | Expressed in brain, heart, lung and skeletal muscle. | Diarrhoea Dyspepsia Flushing Palpitations | Phosphodiesterase | Asthma
Chronic lymphocytic leukemia | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents. {ECO:0000269|PubMed:10846163, ECO:0000269|PubMed:15003452}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4B inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4B inhibitor: Amrinone, Caffeine, Dyphylline, Enprofylline, Ibudilast, Ketotifen, Papaverine, Pentoxifylline, Roflumilast, Theobromine, Theophylline cAMP-specific 3',5'-cyclic phosphodiesterase 4B product of: Adenosine monophosphate | 15.1 | |
| kccPDE4C | cAMP-specific 3',5'-cyclic phosphodiesterase 4C | 5 | 95 | 90.65 | ND | 88.54 | 0.30 | ND | 1.2 | Mammalian | Expressed in various tissues but not in cells of the immune system. | Phosphodiesterase | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:17727341}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4C inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4C inhibitor: Dyphylline, Ibudilast, Ketotifen, Roflumilast cAMP-specific 3',5'-cyclic phosphodiesterase 4C inhibitor, competitive: Caffeine | 15.1 | |||
| kccPDE4D | cAMP-specific 3',5'-cyclic phosphodiesterase 4D | 30 | 497 | 95.90 | ND | 98.14 | 0.81 | ND | 0.7 | Nature11159 | Mammalian | Expressed in colonic epithelial cells (at protein level). Widespread; most abundant in skeletal muscle. Isoform 6 is detected in brain. Isoform 8 is detected in brain, placenta, lung and kidney. Isoform 7 is detected in heart and skeletal muscle. {ECO:0000269|PubMed:12834813, ECO:0000269|PubMed:17244609}. | Dyspepsia Flushing | Phosphodiesterase | Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Acrodysostosis 2, with or without hormone resistance (ACRDYS2) [MIM:614613]: A pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems. {ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:23033274, ECO:0000269|PubMed:23043190}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036}. | cAMP-specific 3',5'-cyclic phosphodiesterase 4D inducer: Iloprost cAMP-specific 3',5'-cyclic phosphodiesterase 4D inhibitor: Dyphylline, Ibudilast, Ketotifen, Roflumilast cAMP-specific 3',5'-cyclic phosphodiesterase 4D inhibitor, competitive: Caffeine cAMP-specific 3',5'-cyclic phosphodiesterase 4D product of: Adenosine monophosphate | 15.1 |
| kccPDE5A | cGMP-specific 3',5'-cyclic phosphodiesterase | 41 | 1413 | 98.30 | ND | 98.40 | 0.81 | ND | 0.7 | Mammalian | Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung. | Diarrhoea Dyspepsia Flushing Palpitations | Phosphodiesterase | Erectile dysfunction
Injury to spine and spinal cord Pulmonary hypertension Vascular disease | Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'- GMP (PubMed:9714779, PubMed:15489334). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334). {ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9714779}. | cGMP-specific 3',5'-cyclic phosphodiesterase inhibitor: Avanafil, Dipyridamole, Pentoxifylline, Sildenafil, Tadalafil, Theophylline, Udenafil, Vardenafil cGMP-specific 3',5'-cyclic phosphodiesterase inhibitor, competitive: Caffeine | 15.1 | |
| kccPDE6A | Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha | 4 | 68 | 99.98 | ND | 99.96 | 0.43 | ND | 0.8 | Mammalian | Phosphodiesterase | Retinitis pigmentosa 43 (RP43) [MIM:613810]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:10393062, ECO:0000269|PubMed:7493036}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This protein participates in processes of transmission and amplification of the visual signal. | 15.1 | ||||
| kccPDE7A | High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A | 10 | 281 | 98.41 | ND | 99.92 | 0.72 | ND | 0.6 | Mammalian | PDE7A1 is found at high levels in skeletal muscle and at low levels in a variety of tissues including brain and heart. It is expressed as well in two T-cell lines. PDE7A2 is found abundantly in skeletal muscle and at low levels in heart. | Phosphodiesterase | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May have a role in muscle signal transduction. {ECO:0000269|PubMed:19350606}. | High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A inhibitor: Dyphylline, Ketotifen High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A inhibitor, competitive: Caffeine | 15.1 | |||
| kccPDE8B | High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B | 4 | 147 | 99.90 | ND | 99.96 | 0.54 | ND | 0.6 | Mammalian | Abundantly expressed in the thyroid. Also very weakly expressed in brain, spinal cord and placenta. In the thyroid isoform 1 predominates, and isoforms 2 and 6 are also highly expressed. In the placenta isoforms 1 and 2 are expressed equally. In the brain isoform 2 predominates. {ECO:0000269|PubMed:12372422, ECO:0000269|PubMed:12681444}. | Phosphodiesterase | Striatal degeneration autosomal dominant (ADSD) [MIM:609161]: A movement disorder affecting the striatal part of the basal ganglia and characterized by bradykinesia, dysarthria and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. {ECO:0000269|PubMed:20085714}. Note=The disease is caused by mutations affecting the gene represented in this entry. Primary pigmented nodular adrenocortical disease 3 (PPNAD3) [MIM:614190]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:18431404}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in specific signaling in the thyroid gland. | High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B inhibitor: Ketotifen High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B inhibitor, competitive: Caffeine | 15.1 | ||
| kccPDE9A | High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305} | 3 | 96 | 99.98 | ND | 99.98 | 0.84 | ND | 0.5 | Mammalian | Expressed in all tissues examined (testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary and prostate) except blood (PubMed:9624146). Highest levels in brain, heart, kidney, spleen, prostate and colon. Isoform PDE9A12 is found in prostate (PubMed:12565835). In brain, present in the cortex, cerebellum, and subiculum (at protein level) (PubMed:22328573). In heart, primarily localizes to myocytes (PubMed:25799991). {ECO:0000269|PubMed:12565835, ECO:0000269|PubMed:22328573, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146}. | Phosphodiesterase | Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP (PubMed:9624146, PubMed:18757755, PubMed:21483814). Specifically regulates natriuretic-peptide- dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart (PubMed:25799991). Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory (By similarity). {ECO:0000250|UniProtKB:Q8QZV1, ECO:0000269|PubMed:18757755, ECO:0000269|PubMed:21483814, ECO:0000269|PubMed:25799991, ECO:0000269|PubMed:9624146, ECO:0000305}. | High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A {ECO:0000305} inhibitor, competitive: Caffeine | 15.1 | |||
| kccPDPK1 | 3-phosphoinositide-dependent protein kinase 1 | 23 | 428 | 96.65 | ND | 92.85 | 0.69 | ND | 0.8 | Mammalian | Appears to be expressed ubiquitously. The Tyr- 9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast. {ECO:0000269|PubMed:18024423}. | Kinase | Cancer, unspecific
Diabetes mellitus | Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF- kappa-B activation in macrophages. Isoform 3 is catalytically inactive. {ECO:0000269|PubMed:10226025, ECO:0000269|PubMed:10480933, ECO:0000269|PubMed:10995762, ECO:0000269|PubMed:12167717, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:14604990, ECO:0000269|PubMed:16207722, ECO:0000269|PubMed:16251192, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:17371830, ECO:0000269|PubMed:18835241, ECO:0000269|PubMed:9094314, ECO:0000269|PubMed:9445476, ECO:0000269|PubMed:9707564, ECO:0000269|PubMed:9768361}. | 3-phosphoinositide-dependent protein kinase 1 inhibitor: Celecoxib | 15.1 | ||
| kccPE2R1 | Prostaglandin E2 receptor EP1 subtype | 23 | 831 | 98.92 | ND | 97.80 | 0.82 | ND | 0.6 | Mammalian | Abundant in kidney. Lower level expression in lung, skeletal muscle and spleen, lowest expression in testis and not detected in liver brain and heart. | Family A G protein-coupled receptor | Analgesics
Visceral pain | Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(q) proteins which activate a phosphatidylinositol-calcium second messenger system. May play a role as an important modulator of renal function. Implicated the smooth muscle contractile response to PGE2 in various tissues. | Prostaglandin E2 receptor EP1 subtype agonist: Alprostadil, Bimatoprost, Carboprost Tromethamine, Dinoprostone, Iloprost Prostaglandin E2 receptor EP1 subtype other/unknown: Bupivacaine | 15.1 | ||
| kccPE2R2 | Prostaglandin E2 receptor EP2 subtype | 20 | 496 | 96.59 | ND | 95.66 | 0.54 | ND | 0.7 | Mammalian | Placenta and lung. | Flushing | Family A G protein-coupled receptor | Cerebral oxidative damage | Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the relaxing effect of this receptor on smooth muscle. | Prostaglandin E2 receptor EP2 subtype agonist: Alprostadil, Dinoprostone, Misoprostol | 15.1 | |
| kccPE2R3 | Prostaglandin E2 receptor EP3 subtype | 28 | 814 | 98.86 | ND | 98.16 | 0.83 | ND | 0.7 | Mammalian | Expressed in small intestine, heart, pancreas, gastric fundic mucosa, mammary artery and pulmonary vessels. {ECO:0000269|PubMed:18023986}. | Diarrhoea | Family A G protein-coupled receptor | Peripheral Vascular Disease | Receptor for prostaglandin E2 (PGE2); the EP3 receptor may be involved in inhibition of gastric acid secretion, modulation of neurotransmitter release in central and peripheral neurons, inhibition of sodium and water reabsorption in kidney tubulus and contraction in uterine smooth muscle. The activity of this receptor can couple to both the inhibition of adenylate cyclase mediated by G-I proteins, and to an elevation of intracellular calcium. The various isoforms have identical ligand binding properties but can interact with different second messenger systems (By similarity). {ECO:0000250}. | Prostaglandin E2 receptor EP3 subtype agonist: Bimatoprost, Dinoprostone, Misoprostol | 15.1 | |
| kccPE2R4 | Prostaglandin E2 receptor EP4 subtype | 33 | 648 | 98.68 | ND | 98.85 | 0.78 | ND | 0.8 | Mammalian | High in intestine and in peripheral blood mononuclear cells; low in lung, kidney, thymus, uterus, vasculature and brain. Not found in liver, heart, retina oe skeletal muscle. | Diarrhoea | Family A G protein-coupled receptor | Dry eye
Osteoporosis, unspecified Renal failure Ulcerative colitis | Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role in regulating renal hemodynamics, intestinal epithelial transport, adrenal aldosterone secretion, and uterine function. | Prostaglandin E2 receptor EP4 subtype agonist: Dinoprostone, Misoprostol | 15.1 | |
| kccPEPA | Pepsin A-1 | 2 | 180 | 98.55 | ND | 96.22 | 0.70 | ND | 0.8 | Mammalian | Shows particularly broad specificity; although bonds involving phenylalanine and leucine are preferred, many others are also cleaved to some extent. | 15.1 | ||||||
| kccPERF | Perforin-1 | 6 | 164 | 99.84 | ND | 99.90 | 0.50 | ND | 0.3 | Mammalian | Other ion channel | Familial hemophagocytic lymphohistiocytosis 2 (FHL2) [MIM:603553]: A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia. {ECO:0000269|PubMed:10583959, ECO:0000269|PubMed:11179007}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays a key role in secretory granule-dependent cell death, and in defense against virus-infected or neoplastic cells. Plays an important role in killing other cells that are recognized as non-self by the immune system, e.g. in transplant rejection or some forms of autoimmune disease. Can insert into the membrane of target cells in its calcium-bound form, oligomerize and form large pores. Promotes cytolysis and apoptosis of target cells by facilitating the uptake of cytotoxic granzymes. {ECO:0000269|PubMed:20038786, ECO:0000269|PubMed:20225066, ECO:0000269|PubMed:20889983, ECO:0000269|PubMed:21037563, ECO:0000269|PubMed:9058810, ECO:0000269|PubMed:9164947}. | 15.1 | ||||
| kccPERM | Myeloperoxidase | 2 | 89 | 91.77 | ND | 91.24 | 0.64 | ND | 0.8 | Mammalian | Enzyme | Myeloperoxidase deficiency (MPOD) [MIM:254600]: A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis. {ECO:0000269|PubMed:7904599, ECO:0000269|PubMed:8142659, ECO:0000269|PubMed:9354683, ECO:0000269|PubMed:9637725}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity. | Myeloperoxidase inducer: Cefaclor, Cisplatin Myeloperoxidase inhibitor: Aminosalicylic Acid, Calcipotriol, Cefdinir, Melatonin, Nabumetone, Octreotide, Propylthiouracil, Tolmetin Myeloperoxidase substrate: Carboplatin, Cysteamine, Dapsone, Oxaliplatin, Ticlopidine Myeloperoxidase substrate;inhibitor: Melatonin Myeloperoxidase unknown: L-Carnitine, Mesalazine | 15.1 | |||
| kccPGES2 | Prostaglandin E synthase 2 | 2 | 40 | 96.86 | ND | 91.65 | 0.95 | ND | 0.3 | Mammalian | Widely expressed. Expressed in the heart, including apex, inter-ventricular septum, both atria and ventricles, but not in the aorta. Also expressed in fetal heart. Detected in various regions of the brain: cerebellum; occipital, frontal and parietal lobes. Also expressed in the lymph nodes, skeletal muscle, kidney and trachea, but not in the thymus or lung. Overexpressed in colorectal cancer. {ECO:0000269|PubMed:11866447}. | Enzyme | Isomerase that catalyzes the conversion of PGH2 into the more stable prostaglandin E2 (PGE2). {ECO:0000269|PubMed:12804604, ECO:0000269|PubMed:18198127}. | 15.1 | ||||
| kccPGFRA | Platelet-derived growth factor receptor alpha | 19 | 393 | 96.10 | ND | 93.20 | 0.26 | ND | 1.7 | Mammalian | Detected in platelets (at protein level). Widely expressed. Detected in brain, fibroblasts, smooth muscle, heart, and embryo. Expressed in primary and metastatic colon tumors and in normal colon tissue. {ECO:0000269|PubMed:2536956, ECO:0000269|PubMed:7896447, ECO:0000269|PubMed:8188664}. | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Note=A chromosomal aberration involving PDGFRA is found in some cases of hypereosinophilic syndrome. Interstitial chromosomal deletion del(4)(q12q12) causes the fusion of FIP1L1 and PDGFRA (FIP1L1-PDGFRA). Mutations that cause overexpression and/or constitutive activation of PDGFRA may be a cause of hypereosinophilic syndrome. {ECO:0000269|PubMed:12808148}. Gastrointestinal stromal tumor (GIST) [MIM:606764]: Common mesenchymal neoplasms arising in the gastrointestinal tract, most often in the stomach. They are histologically, immunohistochemically, and genetically different from typical leiomyomas, leiomyosarcomas, and schwannomas. Most GISTs are composed of a fairly uniform population of spindle-shaped cells. Some tumors are dominated by epithelioid cells or contain a mixture of spindle and epithelioid morphologies. Primary GISTs in the gastrointestinal tract commonly metastasize in the omentum and mesenteries, often as multiple nodules. However, primary tumors may also occur outside of the gastrointestinal tract, in other intra-abdominal locations, especially in the omentum and mesentery. {ECO:0000269|PubMed:12522257, ECO:0000269|PubMed:15928335}. Note=The gene represented in this entry may be involved in disease pathogenesis. Mutations causing PDGFRA constitutive activation have been found in gastrointestinal stromal tumors lacking KIT mutations (PubMed:12522257). {ECO:0000269|PubMed:12522257}. | Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:10734113, ECO:0000269|PubMed:10947961, ECO:0000269|PubMed:11297552, ECO:0000269|PubMed:12522257, ECO:0000269|PubMed:1646396, ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:17141222, ECO:0000269|PubMed:20972453, ECO:0000269|PubMed:21224473, ECO:0000269|PubMed:21596750, ECO:0000269|PubMed:2554309, ECO:0000269|PubMed:8188664, ECO:0000269|PubMed:8760137, ECO:0000269|PubMed:8943348}. | Platelet-derived growth factor receptor alpha antagonist: Imatinib, Sunitinib Platelet-derived growth factor receptor alpha inhibitor: Pazopanib, Ponatinib, Regorafenib | 15.1 | |
| kccPGFRB | Platelet-derived growth factor receptor beta | 47 | 1306 | 97.23 | ND | 94.98 | 0.54 | ND | 0.9 | Mammalian | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Note=A chromosomal aberration involving PDGFRB is found in a form of chronic myelomonocytic leukemia (CMML). Translocation t(5;12)(q33;p13) with EVT6/TEL. It is characterized by abnormal clonal myeloid proliferation and by progression to acute myelogenous leukemia (AML). Myeloproliferative disorder chronic with eosinophilia (MPE) [MIM:131440]: A hematologic disorder characterized by malignant eosinophils proliferation. Note=The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving PDGFRB have been found in many instances of chronic myeloproliferative disorder with eosinophilia. Translocation t(5;12) with ETV6 on chromosome 12 creating an PDGFRB-ETV6 fusion protein (PubMed:12181402). Translocation t(5;15)(q33;q22) with TP53BP1 creating a PDGFRB-TP53BP1 fusion protein (PubMed:15492236). Translocation t(1;5)(q23;q33) that forms a PDE4DIP-PDGFRB fusion protein (PubMed:12907457). Translocation t(5;6)(q33-34;q23) with CEP85L that fuses the 5'-end of CEP85L (isoform 4) to the 3'-end of PDGFRB (PubMed:21938754). {ECO:0000269|PubMed:12181402, ECO:0000269|PubMed:12907457, ECO:0000269|PubMed:15492236, ECO:0000269|PubMed:21938754}. Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving PDGFRB has been found in a patient with AML. Translocation t(5;14)(q33;q32) with TRIP11 (PubMed:9373237). {ECO:0000269|PubMed:9373237}. Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving PDGFRB has been found in a patient with JMML. Translocation t(5;17)(q33;p11.2) with SPECC1 (PubMed:15087372). {ECO:0000269|PubMed:15087372}. Basal ganglia calcification, idiopathic, 4 (IBGC4) [MIM:615007]: A form of basal ganglia calcification, an autosomal dominant condition characterized by symmetric calcification in the basal ganglia and other brain regions. Affected individuals can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, seizures, and chronic headache. Serum levels of calcium, phosphate, alkaline phosphatase and parathyroid hormone are normal. The neuropathological hallmark of the disease is vascular and pericapillary calcification, mainly of calcium phosphate, in the affected brain areas. {ECO:0000269|PubMed:23255827}. Note=The disease is caused by mutations affecting the gene represented in this entry. Myofibromatosis, infantile 1 (IMF1) [MIM:228550]: A rare mesenchymal disorder characterized by the development of benign tumors in the skin, striated muscles, bones, and, more rarely, visceral organs. Subcutaneous or soft tissue nodules commonly involve the skin of the head, neck, and trunk. Skeletal and muscular lesions occur in about half of the patients. Lesions may be solitary or multicentric, and they may be present at birth or become apparent in early infancy or occasionally in adult life. Visceral lesions are associated with high morbidity and mortality. {ECO:0000269|PubMed:23731537, ECO:0000269|PubMed:23731542}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5- trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:11297552, ECO:0000269|PubMed:11331881, ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1396585, ECO:0000269|PubMed:1653029, ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:1846866, ECO:0000269|PubMed:20494825, ECO:0000269|PubMed:20529858, ECO:0000269|PubMed:21098708, ECO:0000269|PubMed:21679854, ECO:0000269|PubMed:21733313, ECO:0000269|PubMed:2554309, ECO:0000269|PubMed:2835772, ECO:0000269|PubMed:2850496, ECO:0000269|PubMed:7685273, ECO:0000269|PubMed:7691811, ECO:0000269|PubMed:7692233, ECO:0000269|PubMed:8195171}. | Platelet-derived growth factor receptor beta antagonist: Dasatinib, Imatinib, Sorafenib, Sunitinib Platelet-derived growth factor receptor beta inhibitor: Pazopanib, Regorafenib | 15.1 | ||
| kccPGH1 | Prostaglandin G/H synthase 1 | 70 | 3078 | 91.10 | ND | 92.27 | 0.33 | ND | 0.6 | Nature11159 | Mammalian | Abdominal pain upper Aplastic anaemia Asthma Dyspepsia Erythema multiforme Gastrointestinal haemorrhage Haematuria Haemorrhagic diathesis Hepatitis Nephropathy Oedema Peptic ulcer Pruritus Rash Renal failure Renal tubular disorder Thrombocytopenia Tinnitus Toxic epidermal necrolysis | Oxidoreductase | Cardiovascular disease, unspecified
Chronic inflammatory diseases | Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells. | Prostaglandin G/H synthase 1 inducer: Desmopressin, Minoxidil Prostaglandin G/H synthase 1 inhibitor: Acetaminophen, Acetylsalicylic acid, Antipyrine, Antrafenine, Balsalazide, Bromfenac, Carprofen, Diclofenac, Diethylcarbamazine, Diflunisal, Dihomo-?-linolenic acid, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Icosapent, Indomethacin, Ketoprofen, Ketorolac, Lornoxicam, Lumiracoxib, Magnesium salicylate, Meclofenamic acid, Mefenamic acid, Meloxicam, Mesalazine, Nabumetone, Naproxen, Nepafenac, Oxaprozin, Phenylbutazone, Piroxicam, Salicylate-sodium, Salicylic acid, Salsalate, Sulfasalazine, Sulindac, Suprofen, Tenoxicam, Tiaprofenic acid, Tolmetin, Trisalicylate-choline Prostaglandin G/H synthase 1 substrate: Bortezomib, Candesartan, Carvedilol, Chlorpropamide, Dapsone, Diazepam, Diclofenac, Diphenhydramine, Dronabinol, Eletriptan, Eszopiclone, Etoposide, Hexobarbital, Hydromorphone, Ifosfamide, Imatinib, Irbesartan, Ketamine, Ketobemidone, Montelukast, Nateglinide, Nortriptyline, Pioglitazone, Rosiglitazone, Sulfamethoxazole, Terbinafine, Thalidomide, Torasemide, Trabectedin, Valproic Acid, Voriconazole, Zafirlukast, Zileuton, Zolpidem, Zopiclone Prostaglandin G/H synthase 1 unknown: Ibuprofen, Niflumic Acid | 15.1 | |
| kccPGH2 | Prostaglandin G/H synthase 2 | 105 | 3357 | 94.78 | ND | 96.05 | 0.55 | ND | 0.8 | Nature11159 | Mammalian | Abdominal pain upper Aplastic anaemia Dyspepsia Erythema multiforme Flatulence Gastrointestinal haemorrhage Haematuria Haemorrhagic diathesis Hepatitis Nephropathy Oedema Oliguria Peptic ulcer Pruritus Renal failure Thrombocytopenia Tinnitus | Oxidoreductase | Abdominal aortic aneurysm
Adenomatous polyposis Alzheimer's disease Analgesics Arthritis Bladder cancer Breast cancer Cancer, unspecific Carcinoma in situ, unspecified Carpal tunnel syndrome Colorectal cancer Dysmenorrhea, unspecified Endometriosis Genitourinary tumors Gestational hypertension Inflammation Inflammatory diseases Lung cancer Malignant mesothelioma Meningioma Myocardial infarction Oropharyngeal squamous cell carcinoma Osteoarthritis Pain, unspecified Pathological angiogenesis Peutz-Jeghers syndrome Prostate cancer Pyresis Renal cell carcinoma Rheumatoid arthritis, unspecified Stroke Vascular lesion regression | Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis. {ECO:0000269|PubMed:16373578}. | Prostaglandin G/H synthase 2 antagonist: Thalidomide Prostaglandin G/H synthase 2 inducer: Bumetanide, Desmopressin, Nonoxynol-9, Risedronate, Tafluprost, Tetrahydrobiopterin Prostaglandin G/H synthase 2 inhibitor: Acetaminophen, Acetylsalicylic acid, Aminosalicylic Acid, Antipyrine, Antrafenine, Balsalazide, Bromfenac, Carprofen, Celecoxib, Chlorphenesin, Cisplatin, Clodronate, Diclofenac, Diflunisal, Drospirenone, Etodolac, Etoricoxib, Fenoprofen, Flurbiprofen, Ibuprofen, Icosapent, Indomethacin, Ketoprofen, Ketorolac, Lornoxicam, Lumiracoxib, Magnesium salicylate, Meclofenamic acid, Mefenamic acid, Meloxicam, Mesalazine, Nabumetone, Naproxen, Nepafenac, Niflumic Acid, Oxaprozin, Phenylbutazone, Piroxicam, Pomalidomide, Salicylate-sodium, Salicylic acid, Salsalate, Sulfasalazine, Sulindac, Suprofen, Tenoxicam, Tiaprofenic acid, Tolmetin, Triamcinolone, Trisalicylate-choline Prostaglandin G/H synthase 2 negative modulator: Lenalidomide Prostaglandin G/H synthase 2 substrate: Dapsone, Etoposide, Thalidomide Prostaglandin G/H synthase 2 unknown: Dihomo-?-linolenic acid | 15.1 | |
| kccPGTB1 | Geranylgeranyl transferase type-1 subunit beta | 3 | 87 | 99.84 | ND | 99.94 | 0.59 | ND | 0.8 | Mammalian | Enzyme | Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. Known substrates include RAC1, RAC2, RAP1A and RAP1B. {ECO:0000269|PubMed:8106351}. | Prostaglandin G/H synthase 2 antagonist: Thalidomide Prostaglandin G/H synthase 2 inducer: Bumetanide, Desmopressin, Nonoxynol-9, Risedronate, Tafluprost, Tetrahydrobiopterin Prostaglandin G/H synthase 2 inhibitor: Acetaminophen, Acetylsalicylic acid, Aminosalicylic Acid, Antipyrine, Antrafenine, Balsalazide, Bromfenac, Carprofen, Celecoxib, Chlorphenesin, Cisplatin, Clodronate, Diclofenac, Diflunisal, Drospirenone, Etodolac, Etoricoxib, Fenoprofen, Flurbiprofen, Ibuprofen, Icosapent, Indomethacin, Ketoprofen, Ketorolac, Lornoxicam, Lumiracoxib, Magnesium salicylate, Meclofenamic acid, Mefenamic acid, Meloxicam, Mesalazine, Nabumetone, Naproxen, Nepafenac, Niflumic Acid, Oxaprozin, Phenylbutazone, Piroxicam, Pomalidomide, Salicylate-sodium, Salicylic acid, Salsalate, Sulfasalazine, Sulindac, Suprofen, Tenoxicam, Tiaprofenic acid, Tolmetin, Triamcinolone, Trisalicylate-choline Prostaglandin G/H synthase 2 negative modulator: Lenalidomide Prostaglandin G/H synthase 2 substrate: Dapsone, Etoposide, Thalidomide Prostaglandin G/H synthase 2 unknown: Dihomo-?-linolenic acid | 15.1 | ||||
| kccPHKG1 | Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform | 1 | 64 | 91.15 | ND | 86.90 | 0.61 | ND | 1.1 | Mammalian | Kinase | Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. In vitro, phosphorylates PYGM, TNNI3, MAPT/TAU, GAP43 and NRGN/RC3 (By similarity). {ECO:0000250}. | 15.1 | |||||
| kccPHKG2 | Phosphorylase b kinase gamma catalytic chain, liver/testis isoform | 7 | 165 | 87.44 | ND | 86.77 | 0.04 | ND | 1.4 | Mammalian | Kinase | Glycogen storage disease 9C (GSD9C) [MIM:613027]: A metabolic disorder manifesting in infancy with hepatomegaly, growth retardation, hypotonia, liver dysfunction, and elevated plasma aminotransferases and lipids. These symptoms improve with age in most cases; however, some patients may develop hepatic fibrosis or cirrhosis. {ECO:0000269|PubMed:12930917, ECO:0000269|PubMed:8896567, ECO:0000269|PubMed:9245685}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. May regulate glycogeneolysis in the testis. In vitro, phosphorylates PYGM (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccPI2R | Prostacyclin receptor | 11 | 288 | 95.60 | ND | 96.41 | 0.53 | ND | 0.6 | Mammalian | Family A G protein-coupled receptor | Analgesics
Diabetes mellitus Inflammatory pain | Receptor for prostacyclin (prostaglandin I2 or PGI2). The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase. | Prostacyclin receptor agonist: Epoprostenol, Iloprost, Treprostinil Prostacyclin receptor antagonist: Dinoprost Tromethamine | 15.1 | |||
| kccPI4KB | Phosphatidylinositol 4-kinase beta | 2 | 170 | 98.24 | ND | 89.54 | 0.15 | ND | 1.0 | Mammalian | Widely expressed with highest levels in heart, skeletal muscle, pancreas, testis and ovary. Weakly expressed in liver. {ECO:0000269|PubMed:9020160, ECO:0000269|PubMed:9405935, ECO:0000269|PubMed:9405938}. | Enzyme | Phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol- 1,4,5,-trisphosphate (PIP). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation. Involved in Golgi-to-plasma membrane trafficking (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccPI51A | Phosphatidylinositol 4-phosphate 5-kinase type-1 alpha | 1 | 64 | 84.61 | ND | 83.69 | 0.06 | ND | 1.3 | Mammalian | Highly expressed in heart, placenta, skeletal muscle, kidney and pancreas. Detected at lower levels in brain, lung and liver. | Kinase | Catalyzes the phosphorylation of phosphatidylinositol 4- phosphate (PtdIns4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). PtdIns(4,5)P2 is involved in a variety of cellular processes and is the substrate to form phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), another second messenger. The majority of PtdIns(4,5)P2 is thought to occur via type I phosphatidylinositol 4-phosphate 5-kinases given the abundance of PtdIns4P. Participates in a variety of cellular processes such as actin cytoskeleton organization, cell adhesion, migration and phagocytosis. Required for membrane ruffling formation, actin organization and focal adhesion formation during directional cell migration by controlling integrin-induced translocation of RAC1 to the plasma membrane. Together with PIP5K1C is required for phagocytosis, but they regulate different types of actin remodeling at sequential steps. Promotes particle ingestion by activating WAS that induces Arp2/3 dependent actin polymerization at the nascent phagocytic cup. Together with PIP5K1B is required after stimulation of G-protein coupled receptors for stable platelet adhesion. Plays a role during calcium-induced keratinocyte differentiation. Recruited to the plasma membrane by the E-cadherin/beta-catenin complex where it provides the substrate PtdIns(4,5)P2 for the production of PtdIns(3,4,5)P3, diacylglycerol and inositol 1,4,5-trisphosphate that mobilize internal calcium and drive keratinocyte differentiation. Together with PIP5K1C have a role during embryogenesis. Functions also in the nucleus where acts as an activator of TUT1 adenylyltransferase activity in nuclear speckles, thereby regulating mRNA polyadenylation of a select set of mRNAs. {ECO:0000269|PubMed:18288197, ECO:0000269|PubMed:19158393, ECO:0000269|PubMed:20660631}. | 15.1 | ||||
| kccPIM1 | Serine/threonine-protein kinase pim-1 | 66 | 1196 | 96.06 | ND | 94.72 | 0.61 | ND | 0.9 | Mammalian | Expressed primarily in cells of the hematopoietic and germline lineages. Isoform 1 and isoform 2 are both expressed in prostate cancer cell lines. {ECO:0000269|PubMed:16186805}. | Kinase | Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl- X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post- translational levels. Phosphorylation of CDKN1B,induces 14-3-3- proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis. {ECO:0000269|PubMed:10664448, ECO:0000269|PubMed:12431783, ECO:0000269|PubMed:15528381, ECO:0000269|PubMed:16356754, ECO:0000269|PubMed:1825810, ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:19749799}. | Serine/threonine-protein kinase pim-1 product of: Adenosine monophosphate | 15.1 | |||
| kccPIM2 | Serine/threonine-protein kinase pim-2 | 22 | 565 | 97.32 | ND | 95.37 | 0.53 | ND | 0.9 | Mammalian | Highly expressed in hematopoietic tissues, in leukemic and lymphoma cell lines, testis, small intestine, colon and colorectal adenocarcinoma cells. Weakly expressed in normal liver, but highly expressed in hepatocellular carcinoma tissues. {ECO:0000269|PubMed:18675992}. | Kinase | Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti- apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Isoform 1 is less active in this respect. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate. {ECO:0000269|PubMed:18593906, ECO:0000269|PubMed:18675992, ECO:0000269|PubMed:20307683}. | 15.1 | ||||
| kccPIM3 | Serine/threonine-protein kinase pim-3 | 29 | 421 | 94.93 | ND | 89.44 | 0.57 | ND | 1.3 | Mammalian | Detected in various tissues, including the heart, brain, lung, kidney, spleen, placenta, skeletal muscle, and peripheral blood leukocytes. Not found or barely expressed in the normal adult endoderm-derived organs such as colon, thymus, liver, or small intestine. However, expression is augmented in premalignant and malignant lesions of these organs. {ECO:0000269|PubMed:15540201, ECO:0000269|PubMed:16818649, ECO:0000269|PubMed:17270021}. | Kinase | Proto-oncogene with serine/threonine kinase activity that can prevent apoptosis, promote cell survival and protein translation. May contribute to tumorigenesis through: the delivery of survival signaling through phosphorylation of BAD which induces release of the anti-apoptotic protein Bcl-X(L), the regulation of cell cycle progression, protein synthesis and by regulation of MYC transcriptional activity. Additionally to this role on tumorigenesis, can also negatively regulate insulin secretion by inhibiting the activation of MAPK1/3 (ERK1/2), through SOCS6. Involved also in the control of energy metabolism and regulation of AMPK activity in modulating MYC and PPARGC1A protein levels and cell growth. {ECO:0000269|PubMed:15540201, ECO:0000269|PubMed:16818649, ECO:0000269|PubMed:17270021, ECO:0000269|PubMed:17876606, ECO:0000269|PubMed:18593906}. | 15.1 | ||||
| kccPIN1 | Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 | 7 | 189 | 84.32 | ND | 87.46 | 0.16 | ND | 1.0 | Mammalian | The phosphorylated form at Ser-71 is expressed in normal breast tissue cells but not in breast cancer cells. {ECO:0000269|PubMed:17828269, ECO:0000269|PubMed:21497122}. | Enzyme | Alzheimer's disease
Cancer, unspecific Hepatocellular carcinoma | Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr- Pro) motifs in a subset of proteins, resulting in conformational changes in the proteins (PubMed:21497122, PubMed:22033920). Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923). {ECO:0000269|PubMed:15664191, ECO:0000269|PubMed:16644721, ECO:0000269|PubMed:17828269, ECO:0000269|PubMed:21497122, ECO:0000269|PubMed:22033920, ECO:0000269|PubMed:22608923}. | Serine/threonine-protein kinase pim-1 product of: Adenosine monophosphate | 15.1 | ||
| kccPK3CA | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform | 72 | 2211 | 97.91 | ND | 99.05 | 0.68 | ND | 0.7 | Mammalian | Enzyme | Note=PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The gene represented in this entry may be involved in disease pathogenesis. Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:16353168}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:15608678}. Note=The gene represented in this entry may be involved in disease pathogenesis. Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:17673550}. Note=The disease is caused by mutations affecting the gene represented in this entry. Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) [MIM:602501]: A syndrome characterized by a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria. {ECO:0000269|PubMed:22729224}. Note=The disease is caused by mutations affecting the gene represented in this entry. Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:612918]: A sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth. {ECO:0000269|PubMed:22658544}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cowden syndrome 5 (CWS5) [MIM:615108]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. {ECO:0000269|PubMed:23246288}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1- AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. {ECO:0000269|PubMed:21708979}. | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform unknown: Caffeine | 15.1 | |||
| kccPK3CB | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform | 45 | 988 | 98.91 | ND | 97.54 | 0.62 | ND | 0.7 | Mammalian | Expressed ubiquitously. | Enzyme | Not Available | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors. {ECO:0000269|PubMed:18594509, ECO:0000269|PubMed:18755892, ECO:0000269|PubMed:21030680, ECO:0000269|PubMed:21383062}. | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform unknown: Caffeine | 15.1 | ||
| kccPK3CD | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform | 42 | 1049 | 99.22 | ND | 97.85 | 0.44 | ND | 0.8 | Mammalian | Isoform 2 is expressed in normal thymus, lung and spleen tissues, and is detected at low levels in normal lysates from colon and ovarian biopsies, at elevated levels in lysates from colorectal tumors and is abundantly expressed in some ovarian tumors (at protein level). Both isoform 1 and isoform 2 are widely expressed. Isoform 1 is expressed predominantly in leukocytes. {ECO:0000269|PubMed:22020336}. | Enzyme | Activated PI3K-delta syndrome (APDS) [MIM:615513]: A disorder characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, reduced immunoglobulin G2 levels in serum, and impaired vaccine responses. {ECO:0000269|PubMed:24136356}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity. {ECO:0000269|PubMed:20081091, ECO:0000269|PubMed:22020336}. | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform unknown: Caffeine | 15.1 | ||
| kccPK3CG | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform | 50 | 1181 | 98.03 | ND | 99.47 | 0.55 | ND | 0.8 | Mammalian | Pancreas, skeletal muscle, liver and heart. {ECO:0000269|PubMed:7624799}. | Enzyme | Angioedema
Cancer, unspecific Heart failure Myocardial infarction Solid tumors | Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin- based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B- lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis. {ECO:0000269|PubMed:12163475, ECO:0000269|PubMed:15294162, ECO:0000269|PubMed:16094730, ECO:0000269|PubMed:21393242, ECO:0000269|PubMed:7624799}. | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform unknown: Caffeine | 15.1 | ||
| kccPKN1 | Serine/threonine-protein kinase N1 | 1 | 85 | 94.75 | ND | 94.67 | 0.25 | ND | 0.5 | Mammalian | Found ubiquitously. Expressed in heart, brain, placenta, lung, skeletal muscle, kidney and pancreas. Expressed in numerous tumor cell lines, especially in breast tumor cells. {ECO:0000269|PubMed:21754995}. | Kinase | PKC-related serine/threonine-protein kinase involved in various processes such as regulation of the intermediate filaments of the actin cytoskeleton, cell migration, tumor cell invasion and transcription regulation. Regulates the cytoskeletal network by phosphorylating proteins such as VIM and neurofilament proteins NEFH, NEFL and NEFM, leading to inhibit their polymerization. Phosphorylates 'Ser-575', 'Ser-637' and 'Ser-669' of MAPT/Tau, lowering its ability to bind to microtubules, resulting in disruption of tubulin assembly. Acts as a key coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-11' of histone H3 (H3T11ph), a specific tag for epigenetic transcriptional activation that promotes demethylation of histone H3 'Lys-9' (H3K9me) by KDM4C/JMJD2C. Phosphorylates HDAC5, HDAC7 and HDAC9, leading to impair their import in the nucleus. Phosphorylates 'Thr-38' of PPP1R14A, 'Ser- 159', 'Ser-163' and 'Ser-170' of MARCKS, and GFAP. Able to phosphorylate RPS6 in vitro. {ECO:0000269|PubMed:11104762, ECO:0000269|PubMed:12514133, ECO:0000269|PubMed:17332740, ECO:0000269|PubMed:18066052, ECO:0000269|PubMed:20188095, ECO:0000269|PubMed:21754995, ECO:0000269|PubMed:24248594, ECO:0000269|PubMed:8557118, ECO:0000269|PubMed:8621664, ECO:0000269|PubMed:9175763}. | 15.1 | ||||
| kccPKN2 | Serine/threonine-protein kinase N2 | 18 | 309 | 95.47 | ND | 92.70 | 0.20 | ND | 1.4 | Mammalian | Ubiquitous. Expressed in numerous tumor cell lines, especially in bladder tumor cells. {ECO:0000269|PubMed:10026169, ECO:0000269|PubMed:21754995}. | Kinase | PKC-related serine/threonine-protein kinase and Rho/Rac effector protein that participates in specific signal transduction responses in the cell. Plays a role in the regulation of cell cycle progression, actin cytoskeleton assembly, cell migration, cell adhesion, tumor cell invasion and transcription activation signaling processes. Phosphorylates CTTN in hyaluronan-induced astrocytes and hence decreases CTTN ability to associate with filamentous actin. Phosphorylates HDAC5, therefore lead to impair HDAC5 import. Direct RhoA target required for the regulation of the maturation of primordial junctions into apical junction formation in bronchial epithelial cells. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Stimulates FYN kinase activity that is required for establishment of skin cell-cell adhesion during keratinocytes differentiation. Regulates epithelial bladder cells speed and direction of movement during cell migration and tumor cell invasion. Inhibits Akt pro-survival-induced kinase activity. Mediates Rho protein-induced transcriptional activation via the c- fos serum response factor (SRF). Phosphorylates HCV NS5B leading to stimulation of HCV RNA replication. {ECO:0000269|PubMed:10226025, ECO:0000269|PubMed:10926925, ECO:0000269|PubMed:11777936, ECO:0000269|PubMed:11781095, ECO:0000269|PubMed:15364941, ECO:0000269|PubMed:17332740, ECO:0000269|PubMed:20188095, ECO:0000269|PubMed:20974804, ECO:0000269|PubMed:21754995, ECO:0000269|PubMed:9121475}. | 15.1 | ||||
| kccPLCB | 1-acyl-sn-glycerol-3-phosphate acyltransferase beta | 3 | 99 | 99.82 | ND | 99.98 | 0.50 | ND | 0.5 | Mammalian | Expressed predominantly in adipose tissue, pancreas and liver. {ECO:0000269|PubMed:21873652}. | Enzyme | Congenital generalized lipodystrophy 1 (CGL1) [MIM:608594]: An autosomal recessive disorder characterized by a near complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. {ECO:0000269|PubMed:11967537}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts lysophosphatidic acid (LPA) into phosphatidic acid by incorporating an acyl moiety at the sn-2 position of the glycerol backbone. {ECO:0000269|PubMed:15629135, ECO:0000269|PubMed:21873652, ECO:0000269|PubMed:9242711}. | 15.1 | |||
| kccPLD1 | Phospholipase D1 | 2 | 150 | 98.65 | ND | 96.99 | 0.56 | ND | 0.6 | Mammalian | Expressed abundantly in the pancreas and heart and at high levels in brain, placenta, spleen, uterus and small intestine. {ECO:0000269|PubMed:9582313}. | Enzyme | Inflammation | Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear intravesicular membrane traffic (By similarity). {ECO:0000250}. | Phospholipase D1 product of: Choline Phospholipase D1 substrate: Miltefosine | 15.1 | ||
| kccPLD2 | Phospholipase D2 | 2 | 152 | 99.69 | ND | 96.71 | 0.23 | ND | 0.5 | Mammalian | Ubiquitous. | Enzyme | May have a role in signal-induced cytoskeletal regulation and/or endocytosis. {ECO:0000250}. | Phospholipase D2 product of: Choline | 15.1 | |||
| kccPLIN1 | Perilipin-1 | 6 | 156 | 81.44 | ND | 80.10 | 0.02 | ND | 0.5 | Mammalian | Adipocytes. {ECO:0000269|PubMed:9521880}. | perilipin | Lipodystrophy, familial partial, 4 (FPLD4) [MIM:613877]: A form of lipodystrophy characterized by loss of subcutaneous adipose tissue primarily affecting the lower limbs, insulin- resistant diabetes mellitus, hypertriglyceridemia, and hypertension. {ECO:0000269|PubMed:21345103}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Modulator of adipocyte lipid metabolism. Coats lipid storage droplets to protect them from breakdown by hormone- sensitive lipase (HSL). Its absence may result in leanness. Plays a role in unilocular lipid droplet formation by activating CIDEC. Their interaction promotes lipid droplet enlargement and directional net neutral lipid transfer. May modulate lipolysis and triglyceride levels. {ECO:0000269|PubMed:23399566}. | 15.1 | |||
| kccPLK1 | Serine/threonine-protein kinase PLK1 | 27 | 779 | 96.17 | ND | 95.11 | 0.73 | ND | 0.7 | Mammalian | Placenta and colon. | Kinase | Note=Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis. | Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, CENPU, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, CENPU, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, CENPU, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGOL1: required for spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis. Phosphorylates MISP, leading to stabilization of cortical and astral microtubule attachments required for proper spindle positioning (PubMed:8991084, PubMed:11202906, PubMed:12207013, PubMed:12447691, PubMed:12524548, PubMed:12738781, PubMed:12852856, PubMed:12939256, PubMed:14532005, PubMed:14734534, PubMed:15070733, PubMed:15148369, PubMed:15469984, PubMed:16198290, PubMed:16247472, PubMed:16980960, PubMed:17081991, PubMed:17351640, PubMed:17376779, PubMed:17617734, PubMed:18174154, PubMed:18331714, PubMed:18418051, PubMed:18477460, PubMed:18521620, PubMed:18615013, PubMed:19160488, PubMed:19351716, PubMed:19468300, PubMed:19468302, PubMed:19473992, PubMed:19509060, PubMed:19597481, PubMed:23455478, PubMed:23509069). Together with MEIKIN, acts as a regulator of kinetochore function during meiosis I: required both for mono- orientation of kinetochores on sister chromosomes and protection of centromeric cohesin from separase-mediated cleavage (By similarity). {ECO:0000250|UniProtKB:Q5F2C3, ECO:0000269|PubMed:11202906, ECO:0000269|PubMed:12207013, ECO:0000269|PubMed:12447691, ECO:0000269|PubMed:12524548, ECO:0000269|PubMed:12738781, ECO:0000269|PubMed:12852856, ECO:0000269|PubMed:12939256, ECO:0000269|PubMed:14532005, ECO:0000269|PubMed:14734534, ECO:0000269|PubMed:15070733, ECO:0000269|PubMed:15148369, ECO:0000269|PubMed:15469984, ECO:0000269|PubMed:16198290, ECO:0000269|PubMed:16247472, ECO:0000269|PubMed:16980960, ECO:0000269|PubMed:17081991, ECO:0000269|PubMed:17351640, ECO:0000269|PubMed:17376779, ECO:0000269|PubMed:17617734, ECO:0000269|PubMed:18174154, ECO:0000269|PubMed:18331714, ECO:0000269|PubMed:18418051, ECO:0000269|PubMed:18477460, ECO:0000269|PubMed:18521620, ECO:0000269|PubMed:18615013, ECO:0000269|PubMed:19160488, ECO:0000269|PubMed:19351716, ECO:0000269|PubMed:19468300, ECO:0000269|PubMed:19468302, ECO:0000269|PubMed:19473992, ECO:0000269|PubMed:19509060, ECO:0000269|PubMed:19597481, ECO:0000269|PubMed:23455478, ECO:0000269|PubMed:23509069, ECO:0000269|PubMed:8991084}. | Phospholipase D2 product of: Choline | 15.1 | ||
| kccPLK2 | Serine/threonine-protein kinase PLK2 | 4 | 160 | 99.45 | ND | 96.87 | 0.60 | ND | 0.7 | Mammalian | Expressed at higher level in the fetal lung, kidney, spleen and heart. {ECO:0000269|PubMed:11696980}. | Kinase | Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress. {ECO:0000269|PubMed:15242618, ECO:0000269|PubMed:19001868, ECO:0000269|PubMed:20352051, ECO:0000269|PubMed:20531387}. | 15.1 | ||||
| kccPLK3 | Serine/threonine-protein kinase PLK3 | 13 | 340 | 92.12 | ND | 86.62 | 0.44 | ND | 1.0 | Mammalian | Transcripts are highly detected in placenta, lung, followed by skeletal muscle, heart, pancreas, ovaries and kidney and weakly detected in liver and brain. May have a short half-live. In cells of hematopoietic origin, strongly and exclusively detected in terminally differentiated macrophages. Transcript expression appears to be down-regulated in primary lung tumor. | Kinase | Serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates ATF2, BCL2L1, CDC25A, CDC25C, CHEK2, HIF1A, JUN, p53/TP53, p73/TP73, PTEN, TOP2A and VRK1. Involved in cell cycle regulation: required for entry into S phase and cytokinesis. Phosphorylates BCL2L1, leading to regulate the G2 checkpoint and progression to cytokinesis during mitosis. Plays a key role in response to stress: rapidly activated upon stress stimulation, such as ionizing radiation, reactive oxygen species (ROS), hyperosmotic stress, UV irradiation and hypoxia. Involved in DNA damage response and G1/S transition checkpoint by phosphorylating CDC25A, p53/TP53 and p73/TP73. Phosphorylates p53/TP53 in response to reactive oxygen species (ROS), thereby promoting p53/TP53-mediated apoptosis. Phosphorylates CHEK2 in response to DNA damage, promoting the G2/M transition checkpoint. Phosphorylates the transcription factor p73/TP73 in response to DNA damage, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates HIF1A and JUN is response to hypoxia. Phosphorylates ATF2 following hyperosmotic stress in corneal epithelium. Also involved in Golgi disassembly during the cell cycle: part of a MEK1/MAP2K1-dependent pathway that induces Golgi fragmentation during mitosis by mediating phosphorylation of VRK1. May participate in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation, via its interaction with CIB1. {ECO:0000269|PubMed:10557092, ECO:0000269|PubMed:11156373, ECO:0000269|PubMed:11447225, ECO:0000269|PubMed:11551930, ECO:0000269|PubMed:11971976, ECO:0000269|PubMed:12242661, ECO:0000269|PubMed:14968113, ECO:0000269|PubMed:14980500, ECO:0000269|PubMed:15021912, ECO:0000269|PubMed:16478733, ECO:0000269|PubMed:16481012, ECO:0000269|PubMed:17264206, ECO:0000269|PubMed:17804415, ECO:0000269|PubMed:18062778, ECO:0000269|PubMed:18650425, ECO:0000269|PubMed:19103756, ECO:0000269|PubMed:19490146, ECO:0000269|PubMed:20889502, ECO:0000269|PubMed:20940307, ECO:0000269|PubMed:20951827, ECO:0000269|PubMed:21098032, ECO:0000269|PubMed:21264284, ECO:0000269|PubMed:21376736, ECO:0000269|PubMed:21840391, ECO:0000269|PubMed:9353331}. | 15.1 | ||||
| kccPLK4 | Serine/threonine-protein kinase PLK4 | 19 | 361 | 92.58 | ND | 87.40 | 0.31 | ND | 1.3 | Mammalian | Kinase | Microcephaly and chorioretinopathy, autosomal recessive, 2 (MCCRP2) [MIM:616171]: A severe disorder characterized by microcephaly, delayed psychomotor development, growth retardation with dwarfism, and ocular abnormalities. {ECO:0000269|PubMed:25344692}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2. {ECO:0000269|PubMed:16244668, ECO:0000269|PubMed:16326102, ECO:0000269|PubMed:17681131, ECO:0000269|PubMed:18239451, ECO:0000269|PubMed:19164942, ECO:0000269|PubMed:21725316}. | 15.1 | ||||
| kccPLMN | Plasminogen | 31 | 836 | 95.67 | ND | 95.58 | 0.57 | ND | 0.6 | Mammalian | Present in plasma and many other extracellular fluids. It is synthesized in the liver. | Protease | Plasminogen deficiency (PLGD) [MIM:217090]: A disorder characterized by decreased serum plasminogen activity. Two forms of the disorder are distinguished: type 1 deficiency is additionally characterized by decreased plasminogen antigen levels and clinical symptoms, whereas type 2 deficiency, also known as dysplasminogenemia, is characterized by normal, or slightly reduced antigen levels, and absence of clinical manifestations. Plasminogen deficiency type 1 results in markedly impaired extracellular fibrinolysis and chronic mucosal pseudomembranous lesions due to subepithelial fibrin deposition and inflammation. The most common clinical manifestation of type 1 deficiency is ligneous conjunctivitis in which pseudomembranes formation on the palpebral surfaces of the eye progresses to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa. {ECO:0000269|PubMed:10233898, ECO:0000269|PubMed:1427790, ECO:0000269|PubMed:1986355, ECO:0000269|PubMed:6216475, ECO:0000269|PubMed:6238949, ECO:0000269|PubMed:8392398, ECO:0000269|PubMed:9242524, ECO:0000269|PubMed:9858247}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells. {ECO:0000269|PubMed:14699093}. Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. {ECO:0000269|PubMed:14699093}. | Plasminogen inhibitor: Aminocaproic Acid, Tranexamic Acid | 15.1 | ||
| kccPNMT | Phenylethanolamine N-methyltransferase | 11 | 248 | 97.15 | ND | 99.79 | 0.58 | ND | 0.7 | Mammalian | Enzyme | Converts noradrenaline to adrenaline. | Plasminogen inhibitor: Aminocaproic Acid, Tranexamic Acid | 15.1 | ||||
| kccPNPH | Purine nucleoside phosphorylase | 11 | 252 | 99.05 | ND | 96.89 | 0.38 | ND | 1.2 | Mammalian | Expressed in red blood cells; overexpressed in red blood cells (cytoplasm) of patients with hereditary non- spherocytic hemolytic anemia of unknown etiology. {ECO:0000269|PubMed:22509282}. | Enzyme | Purine nucleoside phosphorylase deficiency (PNPD) [MIM:613179]: A disorder that interrupts both the catabolism of inosine into hypoxanthine and guanosine into guanine, and leads to the accumulation of guanosine, inosine, and their deoxified by- products. The main clinical presentation is recurrent infections due to severe T-cell immunodeficiency. Some patients also have neurologic impairment. {ECO:0000269|PubMed:1384322, ECO:0000269|PubMed:3029074, ECO:0000269|PubMed:8931706}. Note=The disease is caused by mutations affecting the gene represented in this entry. | The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta- (deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate. {ECO:0000269|PubMed:2104852}. | Purine nucleoside phosphorylase inducer: Cladribine Purine nucleoside phosphorylase unknown: Didanosine | 15.1 | ||
| kccPOLI | DNA polymerase iota | 20 | 3159 | 80.92 | ND | 83.38 | 0.12 | ND | 0.7 | Mammalian | Ubiquitous. Highly expressed in testis. {ECO:0000269|PubMed:10458907, ECO:0000269|PubMed:11387224}. | Enzyme | Error-prone DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Favors Hoogsteen base-pairing in the active site. Inserts the correct base with high-fidelity opposite an adenosine template. Exhibits low fidelity and efficiency opposite a thymidine template, where it will preferentially insert guanosine. May play a role in hypermutation of immunogobulin genes. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but may not have lyase activity. {ECO:0000269|PubMed:11013228, ECO:0000269|PubMed:11251121, ECO:0000269|PubMed:11387224, ECO:0000269|PubMed:12410315, ECO:0000269|PubMed:14630940, ECO:0000269|PubMed:15199127, ECO:0000269|PubMed:15254543}. | 15.1 | ||||
| kccPORCN | Protein-serine O-palmitoleoyltransferase porcupine {ECO:0000250|UniProtKB:Q9JJJ7} | 2 | 51 | 99.97 | ND | 100.00 | 0.22 | ND | 0.4 | Mammalian | Isoform 1 is expressed in fetal brain, brain, amygdala, caudate nucleus, cerebellum, hippocampus, pituitary, thalamus, heart, skeletal muscle and testis. Isoform 4 is expressed in amygdala, corpus callosum, hippocampus, spinal cord, kidney, liver, lung, spleen, uterus, testis. Isoform 2 and isoform 3 are expressed in substantia negra, spinal cord, heart and lung. {ECO:0000269|PubMed:12034504}. | Enzyme | Focal dermal hypoplasia (FODH) [MIM:305600]: A rare congenital ectomesodermal disorder characterized by a combination of skin defects, skeletal abnormalities, and ocular anomalies. Affected individuals have patchy dermal hypoplasia, often in a distribution pattern following the Blaschko lines, and areas of subcutaneous fat herniation or deposition of fat into the dermis. In addition, sparse and brittle hair, hypoplastic nails and papillomas have been described. Skeletal abnormalities usually comprise syndactyly, ectrodactyly, and brachydactyly, and in some cases osteopathia striata has been seen. Patients frequently have ocular anomalies, including microphthalmia/ anophthalmia, coloboma, pigmentary and vascularization defects of the retina. Dental abnormalities are often present. {ECO:0000269|PubMed:17546030, ECO:0000269|PubMed:17546031, ECO:0000269|PubMed:18325042, ECO:0000269|PubMed:19277062, ECO:0000269|PubMed:19309688, ECO:0000269|PubMed:19586929, ECO:0000269|PubMed:19863546, ECO:0000269|PubMed:21472892}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1), to Wnt proteins. Serine palmitoleylation of WNT proteins is required for efficient binding to frizzled receptors. {ECO:0000250|UniProtKB:Q9JJJ7, ECO:0000269|PubMed:12034504, ECO:0000269|PubMed:20826466, ECO:0000269|PubMed:24292069}. | 15.1 | |||
| kccPPAC | Low molecular weight phosphotyrosine protein phosphatase | 6 | 221 | 83.03 | ND | 85.63 | 0.03 | ND | 0.8 | Mammalian | T-lymphocytes express only isoform 2. {ECO:0000269|PubMed:9038134}. | Phosphatase | Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. Isoform 3 does not possess phosphatase activity. | Low molecular weight phosphotyrosine protein phosphatase unknown: Adenine | 15.1 | |||
| kccPPARA | Peroxisome proliferator-activated receptor alpha | 48 | 2163 | 97.43 | ND | 98.40 | 0.61 | ND | 0.6 | Mammalian | Skeletal muscle, liver, heart and kidney. {ECO:0000269|PubMed:7981125, ECO:0000269|PubMed:8993548}. | Myalgia | Nuclear receptor | Hyperglycemia
Hyperinsulinemia Insulin resistance Lipid metabolic disorders Obesity | Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl- 2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2. {ECO:0000269|PubMed:10195690, ECO:0000269|PubMed:24043310, ECO:0000269|PubMed:7629123, ECO:0000269|PubMed:7684926, ECO:0000269|PubMed:9556573}. | Peroxisome proliferator-activated receptor alpha agonist: Bezafibrate, Clofibrate, Fenofibrate, Gemfibrozil, Indomethacin | 15.1 | |
| kccPPARD | Peroxisome proliferator-activated receptor delta | 30 | 1253 | 99.09 | ND | 98.99 | 0.75 | ND | 0.6 | Mammalian | Ubiquitous with maximal levels in placenta and skeletal muscle. | Nuclear receptor | Atherosclerosis
Hyperlipidemia Inflammation Metabolic Disease Metabolic syndrome X Noninsulin-dependent diabetes mellitus Obesity Skin diseases | Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand. {ECO:0000269|PubMed:1333051, ECO:0000269|PubMed:15604518}. | Peroxisome proliferator-activated receptor delta agonist: Bezafibrate, Icosapent, Treprostinil Peroxisome proliferator-activated receptor delta negative modulator: Sulindac | 15.1 | ||
| kccPPARG | Peroxisome proliferator-activated receptor gamma | 65 | 2631 | 98.12 | ND | 98.63 | 0.63 | ND | 0.6 | VirtualToxLab | Mammalian | Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary. {ECO:0000269|PubMed:9065481}. | Dyspepsia | Nuclear receptor | Note=Defects in PPARG can lead to type 2 insulin- resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:9753710}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Lipodystrophy, familial partial, 3 (FPLD3) [MIM:604367]: A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. {ECO:0000269|PubMed:11788685, ECO:0000269|PubMed:12453919}. Note=The disease is caused by mutations affecting the gene represented in this entry. Glioma 1 (GLM1) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility. | Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity). {ECO:0000250|UniProtKB:P37238, ECO:0000269|PubMed:16150867, ECO:0000269|PubMed:20829347, ECO:0000269|PubMed:23525231, ECO:0000269|PubMed:9065481}. | Peroxisome proliferator-activated receptor gamma activator: Ibuprofen, Indomethacin Peroxisome proliferator-activated receptor gamma agonist: Balsalazide, Bezafibrate, Glipizide, Icosapent, Mesalazine, Mitiglinide, Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone, Sulfasalazine Peroxisome proliferator-activated receptor gamma partial agonist: Telmisartan | 15.1 |
| kccPPBI | Intestinal-type alkaline phosphatase | 6 | 376 | 81.49 | ND | 80.11 | 0.03 | ND | 1.0 | Mammalian | Enzyme | 15.1 | ||||||
| kccPPBT | Alkaline phosphatase, tissue-nonspecific isozyme | 9 | 545 | 93.71 | ND | 93.97 | 0.43 | ND | 0.7 | Mammalian | Enzyme | Hypophosphatasia (HOPS) [MIM:146300]: A metabolic bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Four forms are distinguished, depending on the age of onset: perinatal, infantile, childhood and adult type. The perinatal form is the most severe and is almost always fatal. The adult form is mild and characterized by recurrent fractures, osteomalacia, rickets, and loss of teeth. Some cases are asymptomatic, while some patients manifest dental features without skeletal manifestations (odontohypophosphatasia). {ECO:0000269|PubMed:10094560, ECO:0000269|PubMed:10332035, ECO:0000269|PubMed:10679946, ECO:0000269|PubMed:10690885, ECO:0000269|PubMed:10834525, ECO:0000269|PubMed:11438998, ECO:0000269|PubMed:11745997, ECO:0000269|PubMed:11760847, ECO:0000269|PubMed:11834095, ECO:0000269|PubMed:11855933, ECO:0000269|PubMed:11999978, ECO:0000269|PubMed:12815606, ECO:0000269|PubMed:12920074, ECO:0000269|PubMed:1409720, ECO:0000269|PubMed:15135428, ECO:0000269|PubMed:15694177, ECO:0000269|PubMed:3174660, ECO:0000269|PubMed:7833929, ECO:0000269|PubMed:8406453, ECO:0000269|PubMed:8954059, ECO:0000269|PubMed:9452105, ECO:0000269|PubMed:9747027, ECO:0000269|PubMed:9781036}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypophosphatasia childhood type (HOPSC) [MIM:241510]: A bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Note=The disease is caused by mutations affecting the gene represented in this entry. Hypophosphatasia infantile type (HOPSI) [MIM:241500]: A severe bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Three more or less distinct types of infantile hypophosphatasia can be identified: (1) type 1 with onset in utero or in early postnatal life, craniostenosis, severe skeletal abnormalities, hypercalcemia, and death in the first year or so of life; (2) type 2 with later, more gradual development of symptoms, moderately severe 'rachitic' skeletal changes and premature loss of teeth; (3) type 3 with no symptoms, the condition being determined on routine studies. Note=The disease is caused by mutations affecting the gene represented in this entry. | This isozyme may play a role in skeletal mineralization. | Alkaline phosphatase, tissue-nonspecific isozyme substrate: Fospropofol Alkaline phosphatase, tissue-nonspecific isozyme unknown: Amifostine | 15.1 | |||
| kccPPCE | Prolyl endopeptidase | 20 | 533 | 98.11 | ND | 99.09 | 0.66 | ND | 0.9 | Mammalian | Protease | Dementia
Neurological diseases | Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. | Alkaline phosphatase, tissue-nonspecific isozyme substrate: Fospropofol Alkaline phosphatase, tissue-nonspecific isozyme unknown: Amifostine | 15.1 | |||
| kccPPIA | Peptidyl-prolyl cis-trans isomerase A | 9 | 153 | 96.16 | ND | 95.37 | 0.52 | ND | 0.6 | Mammalian | Isomerase | Human immunodeficiency virus [HIV] disease | PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. | Peptidyl-prolyl cis-trans isomerase A binder: L-Proline Peptidyl-prolyl cis-trans isomerase A unknown: Cyclosporine | 15.1 | |||
| kccPPOX | Protoporphyrinogen oxidase | 2 | 72 | 99.92 | ND | 99.99 | 0.77 | ND | 0.3 | Mammalian | Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. | Enzyme | Variegate porphyria (VP) [MIM:176200]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Variegate porphyria is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. {ECO:0000269|PubMed:10486317, ECO:0000269|PubMed:10870850, ECO:0000269|PubMed:11074242, ECO:0000269|PubMed:11102990, ECO:0000269|PubMed:11286631, ECO:0000269|PubMed:11348478, ECO:0000269|PubMed:11350188, ECO:0000269|PubMed:11474578, ECO:0000269|PubMed:12380696, ECO:0000269|PubMed:12655566, ECO:0000269|PubMed:12859407, ECO:0000269|PubMed:14669009, ECO:0000269|PubMed:16433813, ECO:0000269|PubMed:16922948, ECO:0000269|PubMed:16947091, ECO:0000269|PubMed:18350656, ECO:0000269|PubMed:18570668, ECO:0000269|PubMed:19320019, ECO:0000269|PubMed:23430901, ECO:0000269|PubMed:24073655, ECO:0000269|PubMed:8673113, ECO:0000269|PubMed:8817334, ECO:0000269|PubMed:8852667, ECO:0000269|PubMed:9541112, ECO:0000269|PubMed:9763307, ECO:0000269|PubMed:9811936}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations leading to severe PPOX deficiency cause the rare homozygous variant form of VP. Missense mutations that preserve 10%-25% of wild-type activity may not cause clinically overt VP in heterozygotes (PubMed:9811936). Mutations with intermediate effect on catalytic activity may cause VP, but with a low clinical penetrance (PubMed:10486317). {ECO:0000269|PubMed:10486317, ECO:0000269|PubMed:9811936}. | Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX. {ECO:0000269|PubMed:21048046, ECO:0000269|PubMed:23467411, ECO:0000269|PubMed:7713909}. | 15.1 | |||
| kccPRGR | Progesterone receptor | 70 | 1530 | 96.67 | ND | 96.88 | 0.63 | ND | 0.8 | Nature11159 VirtualToxLab | Mammalian | Acne Amenorrhoea Biliary tract disorder Breast pain Depression Fibrocystic breast disease Gynaecomastia Hirsutism Jaundice cholestatic Libido disorder Menstrual disorder Metrorrhagia Migraine Oedema Urticaria Weight increased | Nuclear receptor | Breast cancer | The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation. Isoform A: inactive in stimulating c-Src/MAPK signaling on hormone stimulation. Isoform 4: Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone. | Progesterone receptor agonist: Allylestrenol, Danazol, Desogestrel, Drospirenone, Dydrogesterone, Ethynodiol, Etonogestrel, Fluticasone Propionate, Medroxyprogesterone Acetate, Megestrol acetate, Norelgestromin, Norethindrone, Norgestimate, Progesterone, Spironolactone Progesterone receptor antagonist: Mifepristone Progesterone receptor binder: Levonorgestrel | 15.1 | |
| kccPRKDC | DNA-dependent protein kinase catalytic subunit | 9 | 633 | 98.86 | ND | 97.45 | 0.66 | ND | 0.5 | Mammalian | Kinase | Immunodeficiency 26 with or without neurologic abnormalities (IMD26) [MIM:615966]: A form of severe combined immunodeficiency characterized by reduced or absent T and B cells, recurrent candidiasis, and lower respiratory tract infections. Some patients show dysmorphic features, severe growth failure, microcephaly, seizures, and impaired neurological functions. {ECO:0000269|PubMed:19075392, ECO:0000269|PubMed:23722905}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Required to protect and align broken ends of DNA. May also act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX, thereby regulating DNA damage response mechanism. Phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect machanism. Interacts with CRY1 and CRY2; negatively regulates CRY1 phosphorylation. {ECO:0000269|PubMed:12649176, ECO:0000269|PubMed:14734805, ECO:0000269|PubMed:15574326, ECO:0000269|PubMed:9679063}. | DNA-dependent protein kinase catalytic subunit unknown: Caffeine | 15.1 | |||
| kccPRKX | cAMP-dependent protein kinase catalytic subunit PRKX | 13 | 281 | 91.88 | ND | 85.99 | 0.36 | ND | 1.4 | Mammalian | Widely expressed (at protein level). Specifically expressed in blood by macrophages and granulocytes according to PubMed:9860982. {ECO:0000269|PubMed:15879576, ECO:0000269|PubMed:16236808, ECO:0000269|PubMed:7633447, ECO:0000269|PubMed:9860982}. | Kinase | Note=A chromosomal aberration involving PRKX is a cause of sex reversal disorder. Translocation t(X;Y)(p22;p11) with PRKY. Chromosomal translocations proximal to PRKY account for about 30% of the cases of sex reversal disorder in XX males and XY females. | Serine/threonine protein kinase regulated by and mediating cAMP signaling in cells. Acts through phosphorylation of downstream targets that may include CREB, SMAD6 and PKD1 and has multiple functions in cellular differentiation and epithelial morphogenesis. Regulates myeloid cell differentiation through SMAD6 phosphorylation. Involved in nephrogenesis by stimulating renal epithelial cell migration and tubulogenesis. Also involved in angiogenesis through stimulation of endothelial cell proliferation, migration and vascular-like structure formation. {ECO:0000269|PubMed:12082174, ECO:0000269|PubMed:16236808, ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:17980165, ECO:0000269|PubMed:19367327, ECO:0000269|PubMed:21684272, ECO:0000269|PubMed:9860982}. | 15.1 | |||
| kccPROC | Vitamin K-dependent protein C | 3 | 188 | 97.55 | ND | 96.36 | 0.36 | ND | 0.5 | Mammalian | Plasma; synthesized in the liver. | Protease | Thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency. {ECO:0000269|PubMed:1301959, ECO:0000269|PubMed:1347706, ECO:0000269|PubMed:1511989, ECO:0000269|PubMed:1868249, ECO:0000269|PubMed:2437584, ECO:0000269|PubMed:25618265, ECO:0000269|PubMed:2602169, ECO:0000269|PubMed:7792728, ECO:0000269|PubMed:7865674, ECO:0000269|PubMed:8292730, ECO:0000269|PubMed:8398832, ECO:0000269|PubMed:8499568, ECO:0000269|PubMed:8560401, ECO:0000269|PubMed:8829639, ECO:0000269|PubMed:9798967}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare. {ECO:0000269|PubMed:1511988, ECO:0000269|PubMed:1593215, ECO:0000269|PubMed:1611081, ECO:0000269|PubMed:25618265, ECO:0000269|PubMed:7841323, ECO:0000269|PubMed:7841324, ECO:0000269|PubMed:7878626}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids. {ECO:0000269|PubMed:25618265}. | Vitamin K-dependent protein C activator: Menadione Vitamin K-dependent protein C inhibitor: Sodium Tetradecyl Sulfate | 15.1 | ||
| kccPSB1 | Proteasome subunit beta type-1 | 4 | 92 | 98.98 | ND | 99.84 | 0.34 | ND | 0.5 | Mammalian | Protease | The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. | Proteasome subunit beta type-1 antagonist: Bortezomib Proteasome subunit beta type-1 inhibitor: Carfilzomib | 15.1 | ||||
| kccPSB2 | Proteasome subunit beta type-2 | 4 | 90 | 98.88 | ND | 99.64 | 0.50 | ND | 0.6 | Mammalian | Protease | The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit has a trypsin-like activity. | Proteasome subunit beta type-2 antagonist: Bortezomib Proteasome subunit beta type-2 inhibitor: Carfilzomib | 15.1 | ||||
| kccPSB5 | Proteasome subunit beta type-5 | 12 | 181 | 99.70 | ND | 99.80 | 0.19 | ND | 1.2 | Mammalian | Protease | The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This unit is responsible of the chymotrypsin-like activity of the proteasome and is one of the principal target of the proteasome inhibitor bortezomib. May catalyze basal processing of intracellular antigens. Plays a role in the protection against oxidative damage through the Nrf2-ARE pathway (By similarity). {ECO:0000250}. | Proteasome subunit beta type-5 antagonist: Bortezomib Proteasome subunit beta type-5 inhibitor: Carfilzomib | 15.1 | ||||
| kccPTAFR | Platelet-activating factor receptor | 37 | 1101 | 97.74 | ND | 99.05 | 0.65 | ND | 0.7 | Mammalian | Expressed in the placenta, lung, left and right heart ventricles, heart atrium, leukocytes and differentiated HL-60 granulocytes. {ECO:0000269|PubMed:1281995, ECO:0000269|PubMed:1656963, ECO:0000269|PubMed:1657923}. | Family A G protein-coupled receptor | Ocular allergy | Receptor for platelet activating factor, a chemotactic phospholipid mediator that possesses potent inflammatory, smooth- muscle contractile and hypotensive activity. Seems to mediate its action via a G protein that activates a phosphatidylinositol- calcium second messenger system. {ECO:0000269|PubMed:1281995, ECO:0000269|PubMed:1374385, ECO:0000269|PubMed:1656963, ECO:0000269|PubMed:1657923}. | 15.1 | |||
| kccPTGES | Prostaglandin E synthase | 22 | 451 | 92.11 | ND | 94.24 | 0.69 | ND | 0.6 | Mammalian | Enzyme | Inflammation
Rheumatoid arthritis, unspecified | Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2). {ECO:0000269|PubMed:18682561}. | 15.1 | ||||
| kccPTK6 | Protein-tyrosine kinase 6 | 5 | 198 | 95.56 | ND | 89.71 | 0.38 | ND | 1.5 | Mammalian | Epithelia-specific. Very high level in colon and high levels in small intestine and prostate, and low levels in some fetal tissues. Not expressed in breast or ovarian tissue but expressed in high percentage of breast and ovarian cancers. Also overexpressed in some metastatic melanomas, lymphomas, colon cancers, squamous cell carcinomas and prostate cancers. Also found in melanocytes. Not expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform 2 is present in prostate epithelial cell lines derived from normal prostate and prostate adenocarcinomas, as well as in a variety of cell lines. {ECO:0000269|PubMed:12833144, ECO:0000269|PubMed:15509496, ECO:0000269|PubMed:16651629, ECO:0000269|PubMed:9185712}. | Kinase | Breast cancer
Cancer, unspecific Pancreatic cancer Prostate tumor | Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage- independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways. Isoform 2 inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins. | Protein-tyrosine kinase 6 inhibitor: Vandetanib | 15.1 | ||
| kccPTN1 | Tyrosine-protein phosphatase non-receptor type 1 | 75 | 1963 | 91.14 | ND | 97.82 | 0.69 | ND | 0.5 | Mammalian | Phosphatase | Type 2 Diabetes | Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of MET. {ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:21135139, ECO:0000269|PubMed:22169477}. | Tyrosine-protein phosphatase non-receptor type 1 inhibitor: Tiludronate | 15.1 | |||
| kccPTN12 | Tyrosine-protein phosphatase non-receptor type 12 | 1 | 64 | 98.53 | ND | 93.63 | 0.32 | ND | 0.5 | Mammalian | Phosphatase | Dephosphorylates cellular tyrosine kinases, including PTK2B/PYK2, and thereby regulates signaling via PTK2B/PYK2. {ECO:0000269|PubMed:17329398}. | 15.1 | |||||
| kccPTN2 | Tyrosine-protein phosphatase non-receptor type 2 | 24 | 416 | 95.84 | ND | 95.46 | 0.86 | ND | 0.4 | Mammalian | Ubiquitously expressed. Isoform 2 is probably the major isoform. Isoform 1 is expressed in T-cells and in placenta. {ECO:0000269|PubMed:1731319, ECO:0000269|PubMed:2546150}. | Phosphatase | Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3, STAT5A, STAT5B and STAT6 either in the nucleus or the cytoplasm. Negatively regulates numerous signaling pathways and biological processes like hematopoiesis, inflammatory response, cell proliferation and differentiation, and glucose homeostasis. Plays a multifaceted and important role in the development of the immune system. Functions in T-cell receptor signaling through dephosphorylation of FYN and LCK to control T-cells differentiation and activation. Dephosphorylates CSF1R, negatively regulating its downstream signaling and macrophage differentiation. Negatively regulates cytokine (IL2/interleukin-2 and interferon)-mediated signaling through dephosphorylation of the cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that propagate signaling downstream of the cytokine receptors. Also regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine signaling through dephosphorylation of STAT3 and STAT6 respectively. In addition to the immune system, it is involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth. Activated by the integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates EGF signaling. Dephosphorylates PDGFRB and negatively regulates platelet-derived growth factor receptor-beta signaling pathway and therefore cell proliferation. Negatively regulates tumor necrosis factor-mediated signaling downstream via MAPK through SRC dephosphorylation. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of the hepatocyte growth factor receptor MET. Plays also an important role in glucose homeostasis. For instance, negatively regulates the insulin receptor signaling pathway through the dephosphorylation of INSR and control gluconeogenesis and liver glucose production through negative regulation of the IL6 signaling pathways. Finally, it negatively regulates prolactin-mediated signaling pathway through dephosphorylation of STAT5A and STAT5B. May also bind DNA. {ECO:0000269|PubMed:10734133, ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:12138178, ECO:0000269|PubMed:12612081, ECO:0000269|PubMed:14966296, ECO:0000269|PubMed:15592458, ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:22080863, ECO:0000269|PubMed:9488479}. | 15.1 | ||||
| kccPTN22 | Tyrosine-protein phosphatase non-receptor type 22 | 9 | 217 | 94.29 | ND | 91.18 | 0.40 | ND | 0.5 | Mammalian | Expressed in bone marrow, B and T-cells, PBMCs, natural killer cells, monocytes, dendritic cells and neutrophils (PubMed:15208781). Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells. {ECO:0000269|PubMed:15208781}. | Phosphatase | Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:15273934}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15004560}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269|PubMed:15208781}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Vitiligo (VTLG) [MIM:193200]: A pigmentary disorder of the skin and mucous membranes. It is characterized by circumscribed depigmented macules and patches, commonly on extensor aspects of extremities, on the face or neck and in skin folds. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. It is a multifactorial disorder with a complex etiology probably including autoimmune mechanisms, and is associated with an elevated risk of other autoimmune diseases. {ECO:0000269|PubMed:16015369}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr- 493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro- inflammatory cytokine secretion and autophagy (PubMed:23991106). {ECO:0000250|UniProtKB:P29352, ECO:0000269|PubMed:16461343, ECO:0000269|PubMed:18056643, ECO:0000269|PubMed:19167335, ECO:0000269|PubMed:21719704, ECO:0000269|PubMed:23871208, ECO:0000269|PubMed:23991106}. | 15.1 | |||
| kccPTN6 | Tyrosine-protein phosphatase non-receptor type 6 | 3 | 139 | 89.61 | ND | 94.81 | 0.65 | ND | 0.3 | Mammalian | Isoform 1 is expressed in hematopoietic cells. Isoform 2 is expressed in non-hematopoietic cells. | Phosphatase | Solid tumors | Modulates signaling by tyrosine phosphorylated cell surface receptors such as KIT and the EGF receptor/EGFR. The SH2 regions may interact with other cellular components to modulate its own phosphatase activity against interacting substrates. Together with MTUS1, induces UBE2V2 expression upon angiotensin II stimulation. Plays a key role in hematopoiesis. {ECO:0000269|PubMed:11266449}. | 15.1 | |||
| kccPTN7 | Tyrosine-protein phosphatase non-receptor type 7 | 15 | 288 | 87.26 | ND | 81.48 | 0.12 | ND | 0.9 | Mammalian | Expressed exclusively in thymus and spleen. {ECO:0000269|PubMed:1510684, ECO:0000269|PubMed:1530918}. | Phosphatase | Protein phosphatase that acts preferentially on tyrosine-phosphorylated MAPK1. Plays a role in the regulation of T and B-lymphocyte development and signal transduction. {ECO:0000269|PubMed:10206983, ECO:0000269|PubMed:10559944, ECO:0000269|PubMed:10702794, ECO:0000269|PubMed:1510684, ECO:0000269|PubMed:1530918, ECO:0000269|PubMed:9624114}. | 15.1 | ||||
| kccPTPRA | Receptor-type tyrosine-protein phosphatase alpha | 1 | 50 | 85.91 | ND | 85.53 | 0.24 | ND | 0.7 | Mammalian | Phosphatase | 15.1 | ||||||
| kccPTPRB | Receptor-type tyrosine-protein phosphatase beta | 2 | 57 | 92.63 | ND | 86.03 | 0.84 | ND | 0.5 | Mammalian | Phosphatase | Plays an important role in blood vessel remodeling and angiogenesis. Not necessary for the initial formation of blood vessels, but is essential for their maintenance and remodeling. Can induce dephosphorylation of TEK/TIE2, CDH5/VE-cadherin and KDR/VEGFR-2. Regulates angiopoietin-TIE2 signaling in endothelial cells. Acts as a negative regulator of TIE2, and controls TIE2 driven endothelial cell proliferation, which in turn affects blood vessel remodeling during embryonic development and determines blood vessel size during perinatal growth. Essential for the maintenance of endothelial cell contact integrity and for the adhesive function of VE-cadherin in endothelial cells and this requires the presence of plakoglobin (By similarity). {ECO:0000250}. | Tyrosine-protein phosphatase non-receptor type 1 inhibitor: Tiludronate | 15.1 | ||||
| kccPTPRC | Receptor-type tyrosine-protein phosphatase C | 9 | 215 | 96.55 | ND | 99.93 | 0.53 | ND | 0.7 | Mammalian | Enzyme | Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-positive/NK-cell-positive (T(-)B(+)NK(+) SCID) [MIM:608971]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:11145714}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple sclerosis (MS) [MIM:126200]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. {ECO:0000269|PubMed:11101853}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. | Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor. Acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. Upon T-cell activation, recruits and dephosphorylates SKAP1 and FYN. Dephosphorylates LYN, and thereby modulates LYN activity (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccPTPRF | Receptor-type tyrosine-protein phosphatase F | 2 | 123 | 94.87 | ND | 99.93 | 0.76 | ND | 0.4 | Mammalian | Phosphatase | Aplasia or hypoplasia of the breasts and/or nipples 2 (BNAH2) [MIM:616001]: A group of congenital deformities encompassing total absence of breasts and nipple (amastia), absence of the nipple (athelia), and absence of the mammary gland (amazia). {ECO:0000269|PubMed:24781087}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Possible cell adhesion receptor. It possesses an intrinsic protein tyrosine phosphatase activity (PTPase) and dephosphorylates EPHA2 regulating its activity. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. | 15.1 | ||||
| kccPUR2 | Trifunctional purine biosynthetic protein adenosine-3 | 3 | 101 | 98.26 | ND | 99.78 | 0.05 | ND | 1.3 | Mammalian | Ligase | Solid tumor | Trifunctional purine biosynthetic protein adenosine-3 inhibitor: Pemetrexed | 15.1 | ||||
| kccPUR9 | Bifunctional purine biosynthesis protein PURH | 2 | 57 | 87.51 | ND | 80.89 | 0.63 | ND | 0.5 | Mammalian | Enzyme | AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:608688]: A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA- riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness. {ECO:0000269|PubMed:15114530}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis. {ECO:0000269|PubMed:14966129}. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571). {ECO:0000269|PubMed:25687571}. | Bifunctional purine biosynthesis protein PURH cofactor: Tetrahydrofolic acid Bifunctional purine biosynthesis protein PURH inhibitor: Methotrexate, Pemetrexed | 15.1 | |||
| kccPYGL | Glycogen phosphorylase, liver form | 10 | 428 | 99.11 | ND | 99.30 | 0.54 | ND | 0.5 | Mammalian | Enzyme | Glycogen storage disease 6 (GSD6) [MIM:232700]: A metabolic disorder characterized by mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent hepatomegaly. Heart and skeletal muscle are not affected. {ECO:0000269|PubMed:9529348}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. | Glycogen phosphorylase, liver form activator: Adenosine monophosphate | 15.1 | |||
| kccPYGM | Glycogen phosphorylase, muscle form | 17 | 407 | 93.86 | ND | 95.94 | 0.66 | ND | 0.6 | Mammalian | Enzyme | Glycogen storage disease 5 (GSD5) [MIM:232600]: A metabolic disorder resulting in myopathy characterized by exercise intolerance, cramps, muscle weakness and recurrent myoglobinuria. {ECO:0000269|PubMed:10382911, ECO:0000269|PubMed:10382912, ECO:0000269|PubMed:10417800, ECO:0000269|PubMed:10590419, ECO:0000269|PubMed:10681080, ECO:0000269|PubMed:10714589, ECO:0000269|PubMed:10899452, ECO:0000269|PubMed:11706962, ECO:0000269|PubMed:12031624, ECO:0000269|PubMed:7603523, ECO:0000269|PubMed:8316268, ECO:0000269|PubMed:8535454, ECO:0000269|PubMed:9506549}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. | Glycogen phosphorylase, liver form activator: Adenosine monophosphate | 15.1 | |||
| kccPYRD | Dihydroorotate dehydrogenase (quinone), mitochondrial | 15 | 529 | 98.63 | ND | 97.65 | 0.75 | ND | 0.6 | Mammalian | Oxidoreductase | Postaxial acrofacial dysostosis (POADS) [MIM:263750]: POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases. {ECO:0000269|PubMed:19915526}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | Dihydroorotate dehydrogenase (quinone), mitochondrial inhibitor: Atovaquone, Leflunomide | 15.1 | |||
| kccQPCT | Glutaminyl-peptide cyclotransferase | 10 | 140 | 99.88 | ND | 96.74 | 0.52 | ND | 0.5 | Mammalian | Enzyme | Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides. {ECO:0000269|PubMed:15063747, ECO:0000269|PubMed:18486145, ECO:0000269|PubMed:21288892}. | Dihydroorotate dehydrogenase (quinone), mitochondrial inhibitor: Atovaquone, Leflunomide | 15.1 | ||||
| kccQRFPR | Pyroglutamylated RFamide peptide receptor | 3 | 67 | 99.94 | ND | 99.88 | 0.15 | ND | 0.7 | Mammalian | Expressed widely in the brain with high levels in the hypothalamus, trigeminal ganglia and vestibular neurons, and moderate levels in the amygdala, cortex, pituitary, hippocampus, thalamus, caudate nucleus and medulla oblongata. In peripheral tissues, expressed at high levels in the retina and at moderate levels in the heart, kidney, testis and thyroid. {ECO:0000269|PubMed:11574155, ECO:0000269|PubMed:12714592}. | Family A G protein-coupled receptor | Receptor for the orexigenic neuropeptide QRFP. The activity of this receptor is mediated by G proteins that modulate adenylate cyclase activity and intracellular calcium levels. {ECO:0000269|PubMed:12960173}. | 15.1 | ||||
| kccRAB9A | Ras-related protein Rab-9A | 146 | 7286 | 94.22 | ND | 95.26 | 0.05 | ND | 0.7 | Mammalian | Viral infection, unspecified | Involved in the transport of proteins between the endosomes and the trans Golgi network. | Dihydroorotate dehydrogenase (quinone), mitochondrial inhibitor: Atovaquone, Leflunomide | 15.1 | ||||
| kccRAD52 | DNA repair protein RAD52 homolog | 19 | 503 | 91.32 | ND | 90.41 | 0.09 | ND | 0.9 | Mammalian | Involved in double-stranded break repair. Plays a central role in genetic recombination and DNA repair by promoting the annealing of complementary single-stranded DNA and by stimulation of the RAD51 recombinase. {ECO:0000269|PubMed:12379650, ECO:0000269|PubMed:8702565}. | 15.1 | ||||||
| kccRAD54 | DNA repair and recombination protein RAD54-like | 5 | 316 | 90.76 | ND | 98.69 | 0.10 | ND | 0.7 | Mammalian | Enzyme | Involved in DNA repair and mitotic recombination. Functions in the recombinational DNA repair (RAD52) pathway. Dissociates RAD51 from nucleoprotein filaments formed on dsDNA. Could be involved in the turnover of RAD51 protein-dsDNA filaments (By similarity). May play also an essential role in telomere length maintenance and telomere capping in mammalian cells. {ECO:0000250, ECO:0000269|PubMed:11459989, ECO:0000269|PubMed:12205100, ECO:0000269|PubMed:9774452}. | 15.1 | |||||
| kccRAF1 | RAF proto-oncogene serine/threonine-protein kinase | 22 | 447 | 99.22 | ND | 95.64 | 0.48 | ND | 1.1 | Mammalian | In skeletal muscle, isoform 1 is more abundant than isoform 2. {ECO:0000269|PubMed:1886707}. | Kinase | Noonan syndrome 5 (NS5) [MIM:611553]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:17603482, ECO:0000269|PubMed:17603483, ECO:0000269|PubMed:20683980}. Note=The disease is caused by mutations affecting the gene represented in this entry. LEOPARD syndrome 2 (LPRD2) [MIM:611554]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:17603483}. Note=The disease is caused by mutations affecting the gene represented in this entry. Cardiomyopathy, dilated 1NN (CMD1NN) [MIM:615916]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:24777450}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2- antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation. {ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:16924233, ECO:0000269|PubMed:9360956}. | RAF proto-oncogene serine/threonine-protein kinase inhibitor: Dabrafenib, Regorafenib, Sorafenib | 15.1 | ||
| kccRARA | Retinoic acid receptor alpha | 13 | 240 | 99.48 | ND | 99.61 | 0.17 | ND | 0.9 | Mammalian | Nuclear receptor | Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled- coil domain functions in blocking RA-mediated transactivation and cell differentiation. | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Regulates expression of target genes in a ligand- dependent manner by recruiting chromatin complexes containing KMT2E/MLL5. Mediates retinoic acid-induced granulopoiesis. {ECO:0000250, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:19377461, ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:20215566}. | Retinoic acid receptor alpha agonist: Acitretin, Adapalene, Alitretinoin, Tamibarotene, Tazarotene Retinoic acid receptor alpha other/unknown: Isotretinoin | 15.1 | |||
| kccRARB | Retinoic acid receptor beta | 16 | 244 | 99.30 | ND | 99.82 | 0.33 | ND | 0.9 | Mammalian | Nuclear receptor | Microphthalmia, syndromic, 12 (MCOPS12) [MIM:615524]: A form of microphthalmia, a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS12 patients manifest variable features, including diaphragmatic hernia, pulmonary hypoplasia, and cardiac abnormalities. {ECO:0000269|PubMed:24075189}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. {ECO:0000269|PubMed:12554770}. | Retinoic acid receptor beta agonist: Acitretin, Adapalene, Alitretinoin, Tamibarotene, Tazarotene | 15.1 | |||
| kccRARG | Retinoic acid receptor gamma | 12 | 239 | 97.87 | ND | 96.36 | 0.40 | ND | 0.8 | Mammalian | Nuclear receptor | Acne
Emphysema Photoaging Psoriasis | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). {ECO:0000250}. | Retinoic acid receptor gamma agonist: Acitretin, Adapalene, Alitretinoin, Tazarotene, Tretinoin | 15.1 | |||
| kccRASH | GTPase HRas | 4 | 47 | 100.00 | ND | 99.89 | 0.69 | ND | 0.5 | Mammalian | Widely expressed. {ECO:0000269|PubMed:14500341}. | Other cytosolic protein | Costello syndrome (CSTLO) [MIM:218040]: A rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities. {ECO:0000269|PubMed:16170316, ECO:0000269|PubMed:16329078, ECO:0000269|PubMed:16443854, ECO:0000269|PubMed:17054105, ECO:0000269|PubMed:18039947, ECO:0000269|PubMed:18247425, ECO:0000269|PubMed:19995790}. Note=The disease is caused by mutations affecting the gene represented in this entry. Congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040]: Variant of Costello syndrome. {ECO:0000269|PubMed:17412879}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hurthle cell thyroid carcinoma (HCTC) [MIM:607464]: A rare type of thyroid cancer accounting for only about 3-10% of all differentiated thyroid cancers. These neoplasms are considered a variant of follicular carcinoma of the thyroid and are referred to as follicular carcinoma, oxyphilic type. {ECO:0000269|PubMed:12727991}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors. Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Schimmelpenning-Feuerstein-Mims syndrome (SFM) [MIM:163200]: A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis. {ECO:0000269|PubMed:22683711}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. {ECO:0000269|PubMed:12740440, ECO:0000269|PubMed:14500341, ECO:0000269|PubMed:9020151}. | Retinoic acid receptor gamma agonist: Acitretin, Adapalene, Alitretinoin, Tazarotene, Tretinoin | 15.1 | ||
| kccRB | Retinoblastoma-associated protein | 56 | 2170 | 97.06 | ND | 98.28 | 0.71 | ND | 0.7 | Mammalian | Expressed in the retina. | Childhood cancer retinoblastoma (RB) [MIM:180200]: Congenital malignant tumor that arises from the nuclear layers of the retina. It occurs in about 1:20'000 live births and represents about 2% of childhood malignancies. It is bilateral in about 30% of cases. Although most RB appear sporadically, about 20% are transmitted as an autosomal dominant trait with incomplete penetrance. The diagnosis is usually made before the age of 2 years when strabismus or a gray to yellow reflex from pupil ('cat eye') is investigated. {ECO:0000269|PubMed:10671068, ECO:0000269|PubMed:11524739, ECO:0000269|PubMed:1352883, ECO:0000269|PubMed:2594029, ECO:0000269|PubMed:7704558, ECO:0000269|PubMed:7795591, ECO:0000269|PubMed:7927327, ECO:0000269|PubMed:8346255, ECO:0000269|PubMed:8605116, ECO:0000269|PubMed:8776589, ECO:0000269|PubMed:9140452, ECO:0000269|PubMed:9311732, ECO:0000269|PubMed:9973307}. Note=The disease is caused by mutations affecting the gene represented in this entry. Bladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Osteogenic sarcoma (OSRC) [MIM:259500]: A sarcoma originating in bone-forming cells, affecting the ends of long bones. Note=The disease is caused by mutations affecting the gene represented in this entry. | Key regulator of entry into cell division that acts as a tumor suppressor. Promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C. Acts as a transcription repressor of E2F1 target genes. The underphosphorylated, active form of RB1 interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, SUV420H1 and SUV420H2, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex (By similarity). In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity. {ECO:0000250, ECO:0000269|PubMed:15084261}. | 15.1 | ||||
| kccRECQ1 | ATP-dependent DNA helicase Q1 | 5 | 1033 | 81.11 | ND | 81.23 | 0.01 | ND | 0.9 | Mammalian | High expression in heart, lung, skeletal muscle and kidney, low expression in brain. {ECO:0000269|PubMed:7961977}. | Enzyme | DNA helicase that may play a role in the repair of DNA that is damaged by ultraviolet light or other mutagens. Exhibits a magnesium-dependent ATP-dependent DNA-helicase activity that unwinds single- and double-stranded DNA in a 3'-5' direction. {ECO:0000269|PubMed:15886194, ECO:0000269|PubMed:7961977, ECO:0000269|PubMed:8056767}. | 15.1 | ||||
| kccRENI | Renin | 38 | 2127 | 98.99 | ND | 99.49 | 0.68 | ND | 0.7 | Mammalian | Protease | Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial juvenile hyperuricemic nephropathy 2 (HNFJ2) [MIM:613092]: A renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia. {ECO:0000269|PubMed:19664745}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney. | Renin inhibitor: Aliskiren, Remikiren | 15.1 | |||
| kccRET | Proto-oncogene tyrosine-protein kinase receptor Ret | 30 | 575 | 96.72 | ND | 92.42 | 0.13 | ND | 1.4 | Mammalian | Kinase | Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry. Hirschsprung disease 1 (HSCR1) [MIM:142623]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. {ECO:0000269|PubMed:10090908, ECO:0000269|PubMed:10484767, ECO:0000269|PubMed:10618407, ECO:0000269|PubMed:22174939, ECO:0000269|PubMed:7581377, ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:7704557, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8114938, ECO:0000269|PubMed:8114939, ECO:0000269|PubMed:9043870, ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9094028, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9384613, ECO:0000269|Ref.56}. Note=The disease is caused by mutations affecting the gene represented in this entry. Medullary thyroid carcinoma (MTC) [MIM:155240]: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. {ECO:0000269|PubMed:10323403, ECO:0000269|PubMed:10826520, ECO:0000269|PubMed:11692159, ECO:0000269|PubMed:7784092, ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:7849720, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8557249, ECO:0000269|PubMed:8625130, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9223675, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9398735, ECO:0000269|PubMed:9452077, ECO:0000269|PubMed:9506724, ECO:0000269|PubMed:9621513, ECO:0000269|PubMed:9677065}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple neoplasia 2B (MEN2B) [MIM:162300]: Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. {ECO:0000269|PubMed:7906417, ECO:0000269|PubMed:7906866, ECO:0000269|PubMed:7911697, ECO:0000269|PubMed:8595427, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9294615, ECO:0000269|PubMed:9360560}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pheochromocytoma (PCC) [MIM:171300]: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:12000816}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. {ECO:0000269|PubMed:10522989, ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8099202, ECO:0000269|PubMed:8626834, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9097963, ECO:0000269|PubMed:9384613, ECO:0000269|PubMed:9452064}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thyroid papillary carcinoma (TPC) [MIM:188550]: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving RET have been found in thyroid papillary carcinomas. Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene; inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene; translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene; translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion; translocation t(6;10)(p21.3;q11.2) with RFP generates the Delta RFP/RET oncogene; translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene; translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene. The PTC5 oncogene has been found in 2 cases of PACT in children exposed to radioactive fallout after Chernobyl. A chromosomal aberration involving TRIM27/RFP is found in thyroid papillary carcinomas. Translocation t(6;10)(p21.3;q11.2) with RET. The translocation generates TRIM27/RET and delta TRIM27/RET oncogenes. Note=Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis. Congenital central hypoventilation syndrome (CCHS) [MIM:209880]: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. {ECO:0000269|PubMed:12086152, ECO:0000269|PubMed:14566559, ECO:0000269|PubMed:9497256}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut- associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. {ECO:0000269|PubMed:20064382, ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698}. | Proto-oncogene tyrosine-protein kinase receptor Ret inhibitor: Ponatinib, Regorafenib, Sorafenib | 15.1 | |||
| kccRIOK3 | Serine/threonine-protein kinase RIO3 | 1 | 64 | 92.65 | ND | 99.59 | 0.05 | ND | 0.9 | Mammalian | Widely expressed. {ECO:0000269|PubMed:9602165}. | Kinase | 15.1 | |||||
| kccRIPK1 | Receptor-interacting serine/threonine-protein kinase 1 | 3 | 93 | 98.20 | ND | 95.18 | 0.65 | ND | 1.0 | Mammalian | Kinase | Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex. {ECO:0000269|PubMed:11101870, ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:19524513}. | 15.1 | |||||
| kccRIPK2 | Receptor-interacting serine/threonine-protein kinase 2 | 2 | 75 | 90.93 | ND | 85.30 | 0.06 | ND | 1.4 | Mammalian | Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node. | Kinase | Not Available | Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. {ECO:0000269|PubMed:14638696, ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:18079694, ECO:0000269|PubMed:21123652, ECO:0000269|PubMed:21887730}. | 15.1 | |||
| kccRK | Rhodopsin kinase | 36 | 1893 | 96.72 | ND | 98.10 | 0.65 | ND | 0.8 | Mammalian | Retinal-specific. Expressed in rods and cones cells. {ECO:0000269|PubMed:11717351}. | Kinase | Night blindness, congenital stationary, Oguchi type 2 (CSNBO2) [MIM:613411]: A non-progressive retinal disorder characterized by impaired night vision, often associated with nystagmus and myopia. Congenital stationary night blindness Oguchi type is associated with fundus discoloration and abnormally slow dark adaptation. {ECO:0000269|PubMed:17070587, ECO:0000269|PubMed:9020843}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade. This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination. {ECO:0000269|PubMed:15946941}. | 15.1 | |||
| kccRN5A | 2-5A-dependent ribonuclease | 1 | 62 | 99.75 | ND | 99.69 | 0.72 | ND | 0.9 | Mammalian | Highly expressed in spleen and thymus followed by prostate, testis, uterus, small intestine, colon and peripheral blood leukocytes. | Hydrolase | Prostate cancer, hereditary, 1 (HPC1) [MIM:601518]: A condition associated with familial predisposition to cancer of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Endoribonuclease that functions in the interferon (IFN) antiviral response. In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress- response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. Might play a central role in the regulation of mRNA turnover. {ECO:0000269|PubMed:11585831}. | 15.1 | |||
| kccRNAS1 | Ribonuclease pancreatic | 1 | 46 | 99.54 | ND | 98.62 | 0.51 | ND | 0.7 | Mammalian | Pancreas and other tissues and body fluids (indicating it may have other physiological functions besides its role in digestion). | Enzyme | Endonuclease that catalyzes the cleavage of RNA on the 3' side of pyrimidine nucleotides. Acts on single-stranded and double-stranded RNA. {ECO:0000269|PubMed:17350650}. | Ribonuclease pancreatic unknown: Guanidine, L-Aspartic Acid | 15.1 | |||
| kccROCK1 | Rho-associated protein kinase 1 | 47 | 877 | 96.15 | ND | 92.52 | 0.52 | ND | 0.9 | Mammalian | Detected in blood platelets. {ECO:0000269|PubMed:8617235}. | Kinase | Asthma
Atherosclerotic cardiovascular disease Cardiac allograft vasculopathy Glaucoma Hepatic fibrosis Hypertensive vascular disease Intimal hyperplasia Liver fibrogenesis Primary pulmonary hypertension Pulmonary hypertension Restenosis Vascular disease Ventricular hypertrophy | Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A. Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress. Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Required for centrosome positioning and centrosome-dependent exit from mitosis. Plays a role in terminal erythroid differentiation. May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles. Promotes keratinocyte terminal differentiation. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization. {ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:10652353, ECO:0000269|PubMed:11018042, ECO:0000269|PubMed:11283607, ECO:0000269|PubMed:17158456, ECO:0000269|PubMed:18573880, ECO:0000269|PubMed:18694941, ECO:0000269|PubMed:19036714, ECO:0000269|PubMed:19131646, ECO:0000269|PubMed:19181962, ECO:0000269|PubMed:19997641, ECO:0000269|PubMed:21072057, ECO:0000269|PubMed:8617235, ECO:0000269|PubMed:9722579}. | Ribonuclease pancreatic unknown: Guanidine, L-Aspartic Acid | 15.1 | ||
| kccROCK2 | Rho-associated protein kinase 2 | 51 | 1016 | 97.93 | ND | 95.59 | 0.44 | ND | 1.0 | Mammalian | Kinase | Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation. {ECO:0000269|PubMed:10579722, ECO:0000269|PubMed:15699075, ECO:0000269|PubMed:16574662, ECO:0000269|PubMed:17015463, ECO:0000269|PubMed:19131646, ECO:0000269|PubMed:19997641, ECO:0000269|PubMed:21084279, ECO:0000269|PubMed:21147781}. | Ribonuclease pancreatic unknown: Guanidine, L-Aspartic Acid | 15.1 | ||||
| kccRON | Macrophage-stimulating protein receptor | 11 | 238 | 95.00 | ND | 88.33 | 0.01 | ND | 1.6 | Mammalian | Expressed in colon, skin, lung and bone marrow. {ECO:0000269|PubMed:8062829}. | Kinase | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to MST1 ligand. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces autophosphorylation of RON on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1 or the adapter GAB1. Recruitment of these downstream effectors by RON leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. RON signaling activates the wound healing response by promoting epithelial cell migration, proliferation as well as survival at the wound site. Plays also a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Alternatively, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligand. {ECO:0000269|PubMed:18836480, ECO:0000269|PubMed:7939629, ECO:0000269|PubMed:9764835}. | 15.1 | ||||
| kccRORA | Nuclear receptor ROR-alpha | 4 | 66 | 85.11 | ND | 99.22 | 0.38 | ND | 0.4 | Mammalian | Widely expressed in a number of tissues. Expressed in both regulatory T-cells (Treg) and effector T-cells (Teff). {ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:7916608}. | Nuclear receptor | Cholesterol-related diseases
Chronic inflammatory diseases | Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium- mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti- inflammatory role by inducing CHUK expression and inhibiting NF- kappa-B signaling. {ECO:0000269|PubMed:10478845, ECO:0000269|PubMed:11053433, ECO:0000269|PubMed:11252722, ECO:0000269|PubMed:11554739, ECO:0000269|PubMed:12467577, ECO:0000269|PubMed:14570920, ECO:0000269|PubMed:15781255, ECO:0000269|PubMed:15790933, ECO:0000269|PubMed:16462772, ECO:0000269|PubMed:17512500, ECO:0000269|PubMed:18005000, ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19965867, ECO:0000269|PubMed:21499262, ECO:0000269|PubMed:7926749, ECO:0000269|PubMed:9328355, ECO:0000269|PubMed:9862959}. | Ribonuclease pancreatic unknown: Guanidine, L-Aspartic Acid | 15.1 | ||
| kccROS1 | Proto-oncogene tyrosine-protein kinase ROS | 6 | 188 | 96.85 | ND | 91.23 | 0.12 | ND | 1.6 | Mammalian | Expressed in brain. Expression is increased in primary gliomas. {ECO:0000269|PubMed:8143271}. | Kinase | Note=A chromosomal aberration involving ROS1 is found in a glioblastoma multiforme sample. An intra-chromosomal deletion del(6)(q21q21) is responsible for the formation of GOPC-ROS1 chimeric protein which is localized to the Golgi and has a constitutive receptor tyrosine kinase activity. A SLC34A2-ROS1 chimeric protein produced in non-small cell lung cancer cells also retains a constitutive kinase activity. A third type of chimeric protein CD74-ROS1 was also identified in those cells. {ECO:0000269|PubMed:12661006}. | Orphan receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2. {ECO:0000269|PubMed:11094073, ECO:0000269|PubMed:16885344}. | 15.1 | |||
| kccRPA1 | DNA-directed RNA polymerase I subunit RPA1 | 15 | 221 | 94.29 | ND | 97.87 | 0.60 | ND | 0.5 | Mammalian | Enzyme | DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic core component of RNA polymerase I which synthesizes ribosomal RNA precursors. Forms the polymerase active center together with the second largest subunit. A single stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol I. A bridging helix emanates from RPA1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol I by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition (By similarity). {ECO:0000250}. | 15.1 | |||||
| kccRXFP1 | Relaxin receptor 1 | 3 | 900 | 85.42 | ND | 87.62 | 0.07 | ND | 0.7 | Mammalian | Expressed in the brain, kidney, testis, placenta, uterus, ovary, adrenal, prostate, skin and heart. Not detected in spleen. {ECO:0000269|PubMed:16051677}. | Family A G protein-coupled receptor | Receptor for relaxins. The activity of this receptor is mediated by G proteins leading to stimulation of adenylate cyclase and an increase of cAMP. Binding of the ligand may also activate a tyrosine kinase pathway that inhibits the activity of a phosphodiesterase that degrades cAMP. | 15.1 | ||||
| kccRXRA | Retinoic acid receptor RXR-alpha | 16 | 468 | 95.03 | ND | 96.77 | 0.62 | ND | 0.8 | Mammalian | Highly expressed in liver, also found in lung, kidney and heart. | Arthralgia | Nuclear receptor | Prostate cancer | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes. {ECO:0000269|PubMed:10195690, ECO:0000269|PubMed:11162439, ECO:0000269|PubMed:11915042, ECO:0000269|PubMed:20215566}. | Retinoic acid receptor RXR-alpha agonist: Acitretin, Alitretinoin, Bexarotene Retinoic acid receptor RXR-alpha other: Etodolac Retinoic acid receptor RXR-alpha other/unknown: Adapalene | 15.1 | |
| kccRXRB | Retinoic acid receptor RXR-beta | 6 | 165 | 99.33 | ND | 99.97 | 0.39 | ND | 0.6 | Mammalian | Expressed in a variety of tumor cell lines. {ECO:0000269|PubMed:8381386}. | Nuclear receptor | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (By similarity). Specifically binds 9-cis retinoic acid (9C-RA). {ECO:0000250}. | Retinoic acid receptor RXR-beta agonist: Acitretin, Adapalene, Alitretinoin, Bexarotene, Tazarotene, Tretinoin | 15.1 | |||
| kccRXRG | Retinoic acid receptor RXR-gamma | 9 | 159 | 97.92 | ND | 96.97 | 0.49 | ND | 0.6 | Mammalian | Nuclear receptor | Cancer, unspecific | Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid (By similarity). {ECO:0000250}. | Retinoic acid receptor RXR-gamma agonist: Acitretin, Adapalene, Alitretinoin, Bexarotene, Tretinoin | 15.1 | |||
| kccS12A5 | Solute carrier family 12 member 5 | 2 | 52 | 99.59 | ND | 94.93 | 0.28 | ND | 0.3 | Mammalian | Brain specific. Detected in neuronal cells. | Electrochemical transporter | Mediates electroneutral potassium-chloride cotransport in mature neurons. Transport occurs under isotonic conditions, but is activated 20-fold by cell swelling. Important for Cl(-) homeostasis in neurons. | Solute carrier family 12 member 5 inhibitor: Bumetanide Solute carrier family 12 member 5 substrate: Potassium Chloride Solute carrier family 12 member 5 unknown: Potassium Chloride | 15.1 | |||
| kccS15A2 | Solute carrier family 15 member 2 | 8 | 97 | 98.79 | ND | 97.44 | 0.09 | ND | 0.4 | Mammalian | Electrochemical transporter | Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. | Solute carrier family 15 member 2 inhibitor: Aminolevulinic acid, Amoxicillin, Ampicillin, Azidocillin, Benzylpenicillin, Cefaclor, Cefadroxil, Cefalotin, Cefdinir, Cefepime, Cefixime, Cefmetazole, Cefotaxime, Cefradine, Ceftazidime, Ceftibuten, Ceftriaxone, Cefuroxime, Cephalexin, Chlorpropamide, Cloxacillin, Cyclacillin, Dicloxacillin, Glyburide, Nateglinide, Oxacillin, Tolbutamide, Valaciclovir Solute carrier family 15 member 2 substrate: Benazepril, Cilazapril, Fosinopril, Moexipril, Perindopril, Quinapril, Ramipril, Spirapril, Trandolapril Solute carrier family 15 member 2 unknown: Ampicillin, Benzylpenicillin, Cefotaxime, Oxacillin, Tranexamic Acid, Valganciclovir | 15.1 | ||||
| kccS1PR1 | Sphingosine 1-phosphate receptor 1 | 53 | 1091 | 96.18 | ND | 97.02 | 0.65 | ND | 0.7 | Mammalian | Endothelial cells, and to a lesser extent, in vascular smooth muscle cells, fibroblasts, melanocytes, and cells of epithelioid origin. | Family A G protein-coupled receptor | Autoimmune diseases | G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization and bone homeostasis (By similarity). Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3- phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury. {ECO:0000250, ECO:0000269|PubMed:10982820, ECO:0000269|PubMed:11230698, ECO:0000269|PubMed:11583630, ECO:0000269|PubMed:11604399, ECO:0000269|PubMed:19286607, ECO:0000269|PubMed:22344443, ECO:0000269|PubMed:8626678, ECO:0000269|PubMed:9488656}. | 15.1 | |||
| kccS1PR3 | Sphingosine 1-phosphate receptor 3 | 27 | 835 | 96.45 | ND | 98.15 | 0.56 | ND | 0.6 | Mammalian | Expressed in all tissues, but most abundantly in heart, placenta, kidney, and liver. | Family A G protein-coupled receptor | Receptor for the lysosphingolipid sphingosine 1- phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis. {ECO:0000269|PubMed:10617617}. | 15.1 | ||||
| kccS1PR4 | Sphingosine 1-phosphate receptor 4 | 11 | 389 | 87.03 | ND | 89.96 | 0.42 | ND | 0.8 | Mammalian | Specifically expressed in fetal and adult lymphoid and hematopoietic tissue as well as in lung. Considerable level of expression in adult and fetal spleen as well as adult peripheral leukocytes and lung. Lower expression in adult thymus, lymph node, bone marrow, and appendix as well as in fetal liver, thymus, and lung. | Family A G protein-coupled receptor | Receptor for the lysosphingolipid sphingosine 1- phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. May be involved in cell migration processes that are specific for lymphocytes. {ECO:0000269|PubMed:10679247, ECO:0000269|PubMed:10753843}. | 15.1 | ||||
| kccS1PR5 | Sphingosine 1-phosphate receptor 5 | 14 | 210 | 93.52 | ND | 97.60 | 0.35 | ND | 1.0 | Mammalian | Widely expressed in the brain, most prominently in the corpus callosum, which is predominantly white matter. Detected in spleen, peripheral blood leukocytes, placenta, lung, aorta and fetal spleen. Low-level signal detected in many tissue extracts. Overexpressed in leukemic large granular lymphocytes. Isoform 1 is predominantly expressed in peripheral tissues. Isoform 2 is expressed in brain, spleen and peripheral blood leukocytes. {ECO:0000269|PubMed:11705398, ECO:0000269|PubMed:12234605, ECO:0000269|PubMed:12427546}. | Family A G protein-coupled receptor | Receptor for the lysosphingolipid sphingosine 1- phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. Is coupled to both the G(i/0)alpha and G(12) subclass of heteromeric G-proteins (By similarity). May play a regulatory role in the transformation of radial glial cells into astrocytes and may affect proliferative activity of these cells. {ECO:0000250}. | Sphingosine 1-phosphate receptor 5 modulator: Fingolimod | 15.1 | |||
| kccS27A1 | Long-chain fatty acid transport protein 1 | 3 | 59 | 99.96 | ND | 99.89 | 0.01 | ND | 0.3 | Mammalian | Highest levels of expression are detected in muscle and adipose tissue small, intermediate levels in small intestine, and barely detectable in liver. {ECO:0000269|PubMed:10873384}. | Electrochemical transporter | Involved in translocation of long-chain fatty acids (LFCA) across the plasma membrane. The LFCA import appears to be hormone-regulated in a tissue-specific manner. In adipocytes, but not myocytes, insulin induces a rapid translocation of FATP1 from intracellular compartments to the plasma membrane, paralleled by increased LFCA uptake. May act directly as a bona fide transporter, or alternatively, in a cytoplasmic or membrane- associated multimeric protein complex to trap and draw fatty acids towards accumulation. Plays a pivotal role in regulating available LFCA substrates from exogenous sources in tissues undergoing high levels of beta-oxidation or triglyceride synthesis. May be involved in regulation of cholesterol metabolism. Has acyl-CoA ligase activity for long-chain and very-long-chain fatty acids (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccS29A1 | Equilibrative nucleoside transporter 1 | 4 | 216 | 99.86 | ND | 99.92 | 0.23 | ND | 1.0 | Nature11159 | Mammalian | Detected in erythrocytes (at protein level). Expressed in heart, brain, mammary gland, erythrocytes and placenta, and also in fetal liver and spleen. {ECO:0000269|PubMed:12527552, ECO:0000269|PubMed:23219802}. | Electrochemical transporter | Malaria | Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) and is sodium-independent. It has a higher affinity for adenosine. Inhibited by dipyridamole and dilazep (anticancer chemotherapeutics drugs). | Equilibrative nucleoside transporter 1 inducer: Pemetrexed Equilibrative nucleoside transporter 1 substrate: Cytarabine, Fludarabine, Fluorouracil, Gemcitabine, Mercaptopurine, Ribavirin Equilibrative nucleoside transporter 1 unknown: Didanosine, Ethanol, Zalcitabine | 15.1 | |
| kccS5A1 | 3-oxo-5-alpha-steroid 4-dehydrogenase 1 | 15 | 364 | 98.32 | ND | 98.88 | 0.61 | ND | 0.8 | Mammalian | Liver and prostate (at a low level). | Oxidoreductase | Acne
Alopecia, unspecified Benign prostate hyperplasia Hirsutism Prostate cancer | Converts testosterone into 5-alpha-dihydrotestosterone and progesterone or corticosterone into their corresponding 5- alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology. | 3-oxo-5-alpha-steroid 4-dehydrogenase 1 antagonist: Spironolactone 3-oxo-5-alpha-steroid 4-dehydrogenase 1 inhibitor: Dutasteride, Finasteride, Levonorgestrel | 15.1 | ||
| kccS5A2 | 3-oxo-5-alpha-steroid 4-dehydrogenase 2 | 12 | 393 | 96.08 | ND | 98.35 | 0.74 | ND | 0.7 | Mammalian | Expressed in high levels in the prostate and many other androgen-sensitive tissues. | Gynaecomastia | Oxidoreductase | Pseudovaginal perineoscrotal hypospadias (PPSH) [MIM:264600]: A form of male pseudohermaphroditism in which 46,XY males show ambiguous genitalia at birth, including perineal hypospadias and a blind perineal pouch, and develop masculinization at puberty. The name of the disorder stems from the finding of a blind-ending perineal opening resembling a vagina and a severely hypospadiac penis with the urethra opening onto the perineum. {ECO:0000269|PubMed:10718838, ECO:0000269|PubMed:10999800, ECO:0000269|PubMed:1522235, ECO:0000269|PubMed:15528927, ECO:0000269|PubMed:15770495, ECO:0000269|PubMed:16098368, ECO:0000269|PubMed:16181229, ECO:0000269|PubMed:7554313, ECO:0000269|PubMed:8626825, ECO:0000269|PubMed:8768837, ECO:0000269|PubMed:9208814, ECO:0000269|PubMed:9745434, ECO:0000269|PubMed:9843052}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Converts testosterone (T) into 5-alpha- dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology. | 3-oxo-5-alpha-steroid 4-dehydrogenase 2 antagonist: Spironolactone 3-oxo-5-alpha-steroid 4-dehydrogenase 2 inhibitor: Azelaic Acid, Dutasteride, Finasteride | 15.1 | |
| kccS6A12 | Sodium- and chloride-dependent betaine transporter | 1 | 51 | 100.00 | ND | 99.91 | 0.20 | ND | 0.1 | Mammalian | Liver, heart, skeletal muscle, placenta, and a widespread distribution in the brain. | Electrochemical transporter | Transports betaine and GABA. May have a role in regulation of GABAergic transmission in the brain through the reuptake of GABA into presynaptic terminals, as well as in osmotic regulation. | 3-oxo-5-alpha-steroid 4-dehydrogenase 2 antagonist: Spironolactone 3-oxo-5-alpha-steroid 4-dehydrogenase 2 inhibitor: Azelaic Acid, Dutasteride, Finasteride | 15.1 | |||
| kccSAHH | Adenosylhomocysteinase | 3 | 126 | 99.36 | ND | 99.98 | 0.42 | ND | 0.7 | Mammalian | Enzyme | Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:613752]: A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy. {ECO:0000269|PubMed:15024124, ECO:0000269|PubMed:16736098, ECO:0000269|PubMed:19177456, ECO:0000269|PubMed:20852937}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Adenosylhomocysteine is a competitive inhibitor of S- adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine. {ECO:0000269|PubMed:12590576}. | 3-oxo-5-alpha-steroid 4-dehydrogenase 2 antagonist: Spironolactone 3-oxo-5-alpha-steroid 4-dehydrogenase 2 inhibitor: Azelaic Acid, Dutasteride, Finasteride | 15.1 | |||
| kccSC5A1 | Sodium/glucose cotransporter 1 | 8 | 296 | 98.32 | ND | 99.82 | 0.66 | ND | 0.5 | Mammalian | Expressed mainly in intestine and kidney. | Electrochemical transporter | Congenital glucose/galactose malabsorption (GGM) [MIM:606824]: Intestinal monosaccharide transporter deficiency. It is an autosomal recessive disorder manifesting itself within the first weeks of life. It is characterized by severe diarrhea and dehydration which are usually fatal unless glucose and galactose are eliminated from the diet. {ECO:0000269|PubMed:10036327, ECO:0000269|PubMed:11406349, ECO:0000269|PubMed:2008213, ECO:0000269|PubMed:8195156}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Actively transports glucose into cells by Na(+) cotransport with a Na(+) to glucose coupling ratio of 2:1. Efficient substrate transport in mammalian kidney is provided by the concerted action of a low affinity high capacity and a high affinity low capacity Na(+)/glucose cotransporter arranged in series along kidney proximal tubules. | Sodium/glucose cotransporter 1 inhibitor: Canagliflozin | 15.1 | ||
| kccSC5A2 | Sodium/glucose cotransporter 2 | 12 | 692 | 99.15 | ND | 99.52 | 0.59 | ND | 0.6 | Mammalian | Electrochemical transporter | Renal glucosuria (GLYS1) [MIM:233100]: Autosomal recessive disorder characterized by a normal fasting serum glucose concentration and persistent isolated glucosuria, with a normal glucose tolerance test. {ECO:0000269|PubMed:14614622}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Sodium-dependent glucose transporter. Has a Na(+) to glucose coupling ratio of 1:1. Efficient substrate transport in mammalian kidney is provided by the concerted action of a low affinity high capacity and a high affinity low capacity Na(+)/glucose cotransporter arranged in series along kidney proximal tubules. | Sodium/glucose cotransporter 2 antagonist;inhibitor: Empagliflozin Sodium/glucose cotransporter 2 antagonist;inhibitor, competitive: Dapagliflozin Sodium/glucose cotransporter 2 inhibitor: Canagliflozin | 15.1 | |||
| kccSC6A1 | Sodium- and chloride-dependent GABA transporter 1 | 7 | 265 | 98.92 | ND | 99.93 | 0.77 | ND | 0.5 | Mammalian | Electrochemical transporter | Myoclonic-atonic epilepsy (MAE) [MIM:616421]: A form of epilepsy characterized by myoclonic-atonic and absence seizures, appearing in early childhood. Patients have delayed development before the onset of seizures and show varying degrees of intellectual disability following seizure onset. {ECO:0000269|PubMed:25865495}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Terminates the action of GABA by its high affinity sodium-dependent reuptake into presynaptic terminals. | Sodium- and chloride-dependent GABA transporter 1 Other: Clobazam Sodium- and chloride-dependent GABA transporter 1 inhibitor: Tiagabine | 15.1 | |||
| kccSC6A2 | Sodium-dependent noradrenaline transporter | 108 | 2303 | 96.52 | ND | 96.86 | 0.55 | ND | 0.7 | Nature11159 | Mammalian | Anticholinergic syndrome Blood glucose abnormal Conduction disorder Cycloplegia Dry mouth Ejaculation disorder Erectile dysfunction Hyperhidrosis Hypomania Insomnia Mania Orthostatic hypotension Palpitations Psychotic disorder Schizophrenia Sexual dysfunction Sleep disorder Tremor Weight decreased | Electrochemical transporter | Orthostatic intolerance (OI) [MIM:604715]: Syndrome characterized by lightheadedness, fatigue, altered mentation and syncope. It is associated with postural tachycardia. Plasma norepinephrine concentration is abnormally high. {ECO:0000269|PubMed:10684912}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals. | Sodium-dependent noradrenaline transporter binder: Loxapine, Mirtazapine Sodium-dependent noradrenaline transporter inducer: Debrisoquin, Guanethidine Sodium-dependent noradrenaline transporter inhibitor: Amitriptyline, Amoxapine, Bupropion, Chlorphenamine, Clomipramine, Cocaine, Desipramine, Desvenlafaxine, Dexmethylphenidate, Diethylpropion, Doxepin, Duloxetine, Ergotamine, Escitalopram, Imipramine, Levomilnacipran, Levonordefrin, Maprotiline, Mazindol, Methylphenidate, Mianserin, Milnacipran, Nefazodone, Nortriptyline, Orphenadrine, Paroxetine, Phenmetrazine, Phentermine, Protriptyline, Pseudoephedrine, Reboxetine, Sibutramine, Tapentadol, Tramadol, Trimipramine, Venlafaxine Sodium-dependent noradrenaline transporter inverse agonist: Ephedrine Sodium-dependent noradrenaline transporter negative modulator: Dextroamphetamine, Methamphetamine, Phendimetrazine Sodium-dependent noradrenaline transporter partial agonist: Guanadrel Sodium-dependent noradrenaline transporter stimulator: Amphetamine Sodium-dependent noradrenaline transporter substrate: Droxidopa, Iobenguane, Norepinephrine Sodium-dependent noradrenaline transporter substrate;inhibitor: Citalopram Sodium-dependent noradrenaline transporter unknown: Atomoxetine, Dextromethorphan, Dopamine, Ketamine, Pethidine | 15.1 | |
| kccSC6A3 | Sodium-dependent dopamine transporter | 126 | 4400 | 95.26 | ND | 96.46 | 0.65 | ND | 0.7 | Nature11159 | Mammalian | Highly expressed in substantia nigra. {ECO:0000269|PubMed:7637582}. | Dry mouth Ejaculation disorder Hyperhidrosis Insomnia Mydriasis Nervousness Palpitations Restlessness Tachycardia Tremor | Electrochemical transporter | Parkinsonism-dystonia infantile (PKDYS) [MIM:613135]: A neurodegenerative disorder characterized by infantile onset of parkinsonism and dystonia. Other neurologic features include global developmental delay, bradykinesia and pyramidal tract signs. {ECO:0000269|PubMed:19478460}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals. {ECO:0000269|PubMed:15505207}. | Sodium-dependent dopamine transporter binder: Amoxapine, Atomoxetine, Loxapine, Mianserin, Mirtazapine Sodium-dependent dopamine transporter inducer: Dopamine Sodium-dependent dopamine transporter inhibitor: Benzatropine, Benzphetamine, Bupropion, Chloroprocaine, Chlorphenamine, Cocaine, Dexmethylphenidate, Diethylpropion, Diphenylpyraline, Duloxetine, Escitalopram, Fencamfamine, Lisdexamfetamine, Mazindol, Methylphenidate, Modafinil, Nefazodone, Phenmetrazine, Phentermine, Procaine, Pseudoephedrine, Sertraline, Sibutramine, Trimipramine, Venlafaxine Sodium-dependent dopamine transporter negative modulator: Amphetamine, Dextroamphetamine, Methamphetamine Sodium-dependent dopamine transporter substrate;inhibitor: Citalopram Sodium-dependent dopamine transporter unknown: Imipramine, Ioflupane I 123, Pethidine | 15.1 |
| kccSC6A4 | Sodium-dependent serotonin transporter | 149 | 5856 | 95.74 | ND | 96.79 | 0.68 | ND | 0.7 | Nature11159 | Mammalian | Expressed in platelets (at protein level). {ECO:0000269|PubMed:17506858}. | Anticholinergic syndrome Blood glucose abnormal Conduction disorder Cycloplegia Dependence Dry mouth Erectile dysfunction Extrapyramidal disorder Galactorrhoea Hyperhidrosis Hypomania Insomnia Libido disorder Mania Nervousness Orthostatic hypotension Palpitations Psychotic disorder Schizophrenia Sexual dysfunction Sleep disorder Tachycardia Tremor Urinary retention Weight decreased | Electrochemical transporter | Schizophrenia | Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner. {ECO:0000269|PubMed:17506858, ECO:0000269|PubMed:18227069, ECO:0000269|PubMed:19270731}. | Sodium-dependent serotonin transporter antagonist;Inhibitor: Butriptyline Sodium-dependent serotonin transporter binder: Amphetamine, Loxapine, Mirtazapine Sodium-dependent serotonin transporter binding: Pethidine Sodium-dependent serotonin transporter inhibitor: Amitriptyline, Amoxapine, Chlorphenamine, Citalopram, Clomipramine, Cocaine, Desipramine, Desvenlafaxine, Dexfenfluramine, Dexmethylphenidate, Dextromethorphan, Doxepin, Duloxetine, Escitalopram, Fluoxetine, Fluvoxamine, Imipramine, Levomilnacipran, Mazindol, Methylphenidate, Mianserin, Milnacipran, Minaprine, Nefazodone, Nortriptyline, Paroxetine, Phentermine, Protriptyline, Pseudoephedrine, Sertraline, Sibutramine, Tapentadol, Tramadol, Trazodone, Trimipramine, Venlafaxine Sodium-dependent serotonin transporter negative modulator: Methamphetamine Sodium-dependent serotonin transporter other/unknown: Verapamil Sodium-dependent serotonin transporter substrate;inhibitor: Citalopram Sodium-dependent serotonin transporter unknown: Atomoxetine, Dopamine, Vilazodone | 15.1 |
| kccSC6A5 | Sodium- and chloride-dependent glycine transporter 2 | 8 | 405 | 99.45 | ND | 99.79 | 0.74 | ND | 0.3 | Mammalian | Expressed in medulla, and to a lesser extent in spinal cord and cerebellum. | Electrochemical transporter | Hyperekplexia 3 (HKPX3) [MIM:614618]: A neurologic disorder characterized by neonatal hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life- threatening neonatal apnea episodes. Notably, in some cases, symptoms resolved in the first year of life. {ECO:0000269|PubMed:16751771}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals. May be responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses. | Sodium- and chloride-dependent glycine transporter 2 unknown: Glycine | 15.1 | ||
| kccSC6A9 | Sodium- and chloride-dependent glycine transporter 1 | 23 | 669 | 98.94 | ND | 98.96 | 0.57 | ND | 0.7 | Mammalian | Isoform GlyT-1A and isoform GlyT-1B can be found in brain, kidney, pancreas, lung, placenta and liver but isoform GlyT-1C is only found in brain. | Electrochemical transporter | Disorders associated with NMDAR hypofunction | Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals. May play a role in regulation of glycine levels in NMDA receptor-mediated neurotransmission. | Sodium- and chloride-dependent glycine transporter 1 unknown: Glycine | 15.1 | ||
| kccSCN2A | Sodium channel protein type 2 subunit alpha | 10 | 162 | 91.56 | ND | 94.16 | 0.32 | ND | 0.5 | Mammalian | Voltage-gated ion channel | Seizures, benign familial infantile 3 (BFIS3) [MIM:607745]: An autosomal dominant disorder in which afebrile seizures occur in clusters during the first year of life, without neurologic sequelae. {ECO:0000269|PubMed:11371648, ECO:0000269|PubMed:12243921, ECO:0000269|PubMed:15048894, ECO:0000269|PubMed:20371507, ECO:0000269|PubMed:22612257}. Note=The disease is caused by mutations affecting the gene represented in this entry. Epileptic encephalopathy, early infantile, 11 (EIEE11) [MIM:613721]: An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269|PubMed:19783390, ECO:0000269|PubMed:19786696, ECO:0000269|PubMed:20956790, ECO:0000269|PubMed:23550958, ECO:0000269|PubMed:23935176}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. {ECO:0000269|PubMed:1325650}. | Sodium channel protein type 2 subunit alpha inhibitor: Lamotrigine, Propofol, Zonisamide Sodium channel protein type 2 subunit alpha unknown: Valproic Acid | 15.1 | |||
| kccSCN4A | Sodium channel protein type 4 subunit alpha | 1 | 81 | 82.29 | ND | 99.97 | 0.91 | ND | 0.3 | Mammalian | Apnoea Cardiac arrest Central nervous system stimulation Coma Convulsion Corneal disorder Death Dysarthria Foetal damage Hypoaesthesia oral Impaired healing Keratitis Loss of consciousness Methaemoglobinaemia Muscle twitching Myocardial depression Nervousness Presyncope Respiratory failure Sensitisation Tinnitus Vision blurred Visual pathway disorder | Voltage-gated ion channel | Paramyotonia congenita of von Eulenburg (PMC) [MIM:168300]: An autosomal dominant channelopathy characterized by myotonia, increased by exposure to cold, intermittent flaccid paresis, not necessarily dependent on cold or myotonia, lability of serum potassium, non-progressive nature and lack of atrophy or hypertrophy of muscles. In some patients, myotonia is not increased by cold exposure (paramyotonia without cold paralysis). Patients may have a combination phenotype of PMC and HYPP. {ECO:0000269|PubMed:10369308, ECO:0000269|PubMed:10727489, ECO:0000269|PubMed:1310898, ECO:0000269|PubMed:1316765, ECO:0000269|PubMed:1338909, ECO:0000269|PubMed:15790667, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:18166706, ECO:0000269|PubMed:19077043, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:8242056, ECO:0000269|PubMed:8308722, ECO:0000269|PubMed:8388676, ECO:0000269|PubMed:8580427}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodic paralysis hypokalemic 2 (HOKPP2) [MIM:613345]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:10599760, ECO:0000269|PubMed:10851391, ECO:0000269|PubMed:10944223, ECO:0000269|PubMed:11558801, ECO:0000269|PubMed:11591859, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:20522878, ECO:0000269|PubMed:21043388}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodic paralysis hyperkalemic (HYPP) [MIM:170500]: An autosomal dominant channelopathy characterized by episodic flaccid generalized muscle weakness associated with high levels of serum potassium. Concurrence of myotonia is found in HYPP patients. {ECO:0000269|PubMed:1659668, ECO:0000269|PubMed:1659948, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:7695243}. Note=The disease is caused by mutations affecting the gene represented in this entry. Periodic paralysis normokalemic (NKPP) [MIM:170500]: A disorder closely related to hyperkalemic periodic paralysis, but marked by a lack of alterations in potassium levels during attacks of muscle weakness. {ECO:0000269|PubMed:15596759, ECO:0000269|PubMed:18046642, ECO:0000269|PubMed:20522878}. Note=The disease is caused by mutations affecting the gene represented in this entry. Myotonia SCN4A-related (MYOSCN4A) [MIM:608390]: A phenotypically highly variable myotonia aggravated by potassium loading, and sometimes by cold. Myotonia is characterized by sustained muscle tensing that prevents muscles from relaxing normally. It causes muscle stiffness that can interfere with movement. In some people the stiffness is very mild, while in other cases it may be severe enough to interfere with walking, running, and other activities of daily life. Myotonia SCN4A- related includes myotonia permanens and myotonia fluctuans. In myotonia permanens, the myotonia is generalized and there is a hypertrophy of the muscle, particularly in the neck and the shoulder. Attacks of severe muscle stiffness of the thoracic muscles may be life threatening due to impaired ventilation. In myotonia fluctuans, the muscle stiffness may fluctuate from day to day, provoked by exercise. {ECO:0000269|PubMed:10218481, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:16832098, ECO:0000269|PubMed:17212350, ECO:0000269|PubMed:17998485, ECO:0000269|PubMed:18203179, ECO:0000269|PubMed:18337100, ECO:0000269|PubMed:19015483, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:8058156, ECO:0000269|PubMed:9392583}. Note=The disease is caused by mutations affecting the gene represented in this entry. Myasthenic syndrome, congenital, 16 (CMS16) [MIM:614198]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS16 is characterized by fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth. The fatigable weakness involves lid-elevator, external ocular, facial, limb and truncal muscles and an decremental response of the compound muscle action potential on repetitive stimulation. {ECO:0000269|PubMed:12766226}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle. | Sodium channel protein type 4 subunit alpha inhibitor: Diclofenac, Flecainide, Propofol, Zonisamide Sodium channel protein type 4 subunit alpha unknown: Valproic Acid | 15.1 | ||
| kccSCN5A | Sodium channel protein type 5 subunit alpha | 7 | 375 | 91.67 | ND | 93.75 | 0.66 | ND | 0.4 | Nature11159 | Mammalian | Found in jejunal circular smooth muscle cells (at protein level). Expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. Isoform 4 is expressed in brain. {ECO:0000269|PubMed:12358675}. | Apnoea Cardiac arrest Central nervous system stimulation Coma Corneal disorder Death Diplopia Dysarthria Foetal damage Hypoaesthesia oral Impaired healing Keratitis Loss of consciousness Methaemoglobinaemia Muscle twitching Myocardial depression Nervousness Nystagmus Presyncope Respiratory failure Sensitisation Tinnitus Tremor Ventricular fibrillation Vision blurred | Voltage-gated ion channel | Progressive familial heart block 1A (PFHB1A) [MIM:113900]: A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His- Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death. {ECO:0000269|PubMed:12569159, ECO:0000269|PubMed:12574143, ECO:0000269|PubMed:19251209}. Note=The disease is caused by mutations affecting the gene represented in this entry. Long QT syndrome 3 (LQT3) [MIM:603830]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:10377081, ECO:0000269|PubMed:10508990, ECO:0000269|PubMed:10627139, ECO:0000269|PubMed:10911008, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:11304498, ECO:0000269|PubMed:11997281, ECO:0000269|PubMed:12209021, ECO:0000269|PubMed:12673799, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:16922724, ECO:0000269|PubMed:18060054, ECO:0000269|PubMed:18708744, ECO:0000269|PubMed:18848812, ECO:0000269|PubMed:18929331, ECO:0000269|PubMed:7651517, ECO:0000269|PubMed:7889574, ECO:0000269|PubMed:8541846, ECO:0000269|PubMed:9506831, ECO:0000269|PubMed:9686753, ECO:0000269|Ref.31}. Note=The disease is caused by mutations affecting the gene represented in this entry. Brugada syndrome 1 (BRGDA1) [MIM:601144]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:11748104, ECO:0000269|PubMed:11901046, ECO:0000269|PubMed:12051963, ECO:0000269|PubMed:12106943, ECO:0000269|PubMed:15023552, ECO:0000269|PubMed:15338453, ECO:0000269|PubMed:15579534, ECO:0000269|PubMed:15851320, ECO:0000269|PubMed:16266370, ECO:0000269|PubMed:16325048, ECO:0000269|PubMed:16616735, ECO:0000269|PubMed:17075016, ECO:0000269|PubMed:17081365, ECO:0000269|PubMed:17198989, ECO:0000269|PubMed:18252757, ECO:0000269|PubMed:18341814, ECO:0000269|PubMed:18451998, ECO:0000269|PubMed:18456723, ECO:0000269|PubMed:18616619, ECO:0000269|PubMed:19251209, ECO:0000269|PubMed:19272188, ECO:0000269|PubMed:9521325}. Note=The disease is caused by mutations affecting the gene represented in this entry. Sick sinus syndrome 1 (SSS1) [MIM:608567]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS1 onset is in utero, infancy, or early childhood. {ECO:0000269|PubMed:14523039, ECO:0000269|PubMed:22795782}. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial paroxysmal ventricular fibrillation 1 (VF1) [MIM:603829]: A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity. {ECO:0000269|PubMed:10940383}. Note=The disease is caused by mutations affecting the gene represented in this entry. Sudden infant death syndrome (SIDS) [MIM:272120]: SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. {ECO:0000269|PubMed:18596570, ECO:0000269|PubMed:19302788}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Atrial standstill 1 (ATRST1) [MIM:108770]: A rare arrhythmia characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. {ECO:0000269|PubMed:12522116}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry. A mutation in SCN5A has been detected in combination with a rare GJA5 genotype in a large family with atrial standstill. Cardiomyopathy, dilated 1E (CMD1E) [MIM:601154]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:15466643}. Note=The disease is caused by mutations affecting the gene represented in this entry. Atrial fibrillation, familial, 10 (ATFB10) [MIM:614022]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:18088563, ECO:0000269|PubMed:18378609}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels. {ECO:0000269|PubMed:19074138}. | Sodium channel protein type 5 subunit alpha antagonist: Benzonatate Sodium channel protein type 5 subunit alpha inhibitor: Ajmaline, Aprindine, Carbamazepine, Cinchocaine, Cocaine, Disopyramide, Encainide, Ethotoin, Flecainide, Fosphenytoin, Hexylcaine, Indecainide, Lidocaine, Mexiletine, Moricizine, Oxcarbazepine, Phenytoin, Prilocaine, Procainamide, Propafenone, Quinidine, Quinidine barbiturate, Ranolazine, Riluzole, Tocainide, Zonisamide Sodium channel protein type 5 subunit alpha other: Verapamil Sodium channel protein type 5 subunit alpha unknown: Valproic Acid | 15.1 |
| kccSCN9A | Sodium channel protein type 9 subunit alpha | 32 | 1455 | 98.56 | ND | 98.80 | 0.60 | ND | 0.6 | Mammalian | Expressed strongly in dorsal root ganglion, with only minor levels elsewhere in the body, smooth muscle cells, MTC cell line and C-cell carcinoma. Isoform 1 is expressed preferentially in the central and peripheral nervous system. Isoform 2 is expressed preferentially in the dorsal root ganglion. {ECO:0000269|PubMed:15178348, ECO:0000269|PubMed:15302875, ECO:0000269|PubMed:7720699, ECO:0000269|PubMed:9169448}. | Cardiac arrest Central nervous system stimulation Coma Convulsion Corneal disorder Dysarthria Foetal damage Hypoaesthesia oral Impaired healing Keratitis Loss of consciousness Methaemoglobinaemia Muscle twitching Myocardial depression Nervousness Presyncope Respiratory failure Sensitisation Tinnitus Vision blurred | Voltage-gated ion channel | Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands. {ECO:0000269|PubMed:14985375, ECO:0000269|PubMed:15955112, ECO:0000269|PubMed:15958509, ECO:0000269|PubMed:16216943, ECO:0000269|PubMed:16392115, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784}. Note=The disease is caused by mutations affecting the gene represented in this entry. Indifference to pain, congenital, autosomal recessive (CIP) [MIM:243000]: A disorder characterized by congenital inability to perceive any form of pain, in any part of the body. All other sensory modalities are preserved and the peripheral and central nervous systems are apparently intact. Patients perceive the sensations of touch, warm and cold temperature, proprioception, tickle and pressure, but not painful stimuli. There is no evidence of a motor or sensory neuropathy, either axonal or demyelinating. {ECO:0000269|PubMed:20635406}. Note=The disease is caused by mutations affecting the gene represented in this entry. Paroxysmal extreme pain disorder (PEPD) [MIM:167400]: Autosomal dominant paroxysmal disorder of pain and autonomic dysfunction. The distinctive features are paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic manifestations such as skin flushing. {ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:25285947}. Note=The disease is caused by mutations affecting the gene represented in this entry. Generalized epilepsy with febrile seizures plus 7 (GEFS+7) [MIM:613863]: A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity. {ECO:0000269|PubMed:19763161}. Note=The disease is caused by mutations affecting the gene represented in this entry. Febrile seizures, familial, 3B (FEB3B) [MIM:613863]: Seizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy. {ECO:0000269|PubMed:19763161}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-sensitive Na(+) channel isoform. Plays a role in pain mechanisms, especially in the development of inflammatory pain (By similarity). {ECO:0000250}. | Sodium channel protein type 9 subunit alpha inhibitor: Lidocaine, Ranolazine, Zonisamide Sodium channel protein type 9 subunit alpha modulator: Rufinamide Sodium channel protein type 9 subunit alpha unknown: Lacosamide, Valproic Acid | 15.1 | |
| kccSCNAA | Sodium channel protein type 10 subunit alpha | 7 | 111 | 99.68 | ND | 97.54 | 0.05 | ND | 0.8 | Mammalian | Expressed in the dorsal root ganglia and sciatic nerve. {ECO:0000269|PubMed:9839820}. | Agitation Apnoea Cardiac arrest Central nervous system stimulation Coma Convulsion Corneal disorder Death Dysarthria Encephalopathy Foetal damage Hypoaesthesia oral Impaired healing Keratitis Loss of consciousness Methaemoglobinaemia Muscle twitching Myocardial depression Nervousness Presyncope Respiratory disorder Respiratory failure Restlessness Sensitisation Tinnitus Tremor Vasodilatation Vision blurred | Voltage-gated ion channel | Episodic pain syndrome, familial, 2 (FEPS2) [MIM:615551]: An autosomal dominant neurologic disorder characterized by adult- onset of paroxysmal pain mainly affecting the distal lower extremities. {ECO:0000269|PubMed:23115331}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium- selective channel through which sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms. {ECO:0000269|PubMed:9839820}. | Sodium channel protein type 10 subunit alpha inhibitor: Benzocaine, Bupivacaine, Chloroprocaine, Cinchocaine, Cocaine, Dyclonine, Hexylcaine, Levobupivacaine, Lidocaine, Mepivacaine, Orphenadrine, Oxybuprocaine, Procaine, Proparacaine, Ropivacaine Sodium channel protein type 10 subunit alpha unknown: Lacosamide, Valproic Acid | 15.1 | |
| kccSCRB1 | Scavenger receptor class B member 1 | 3 | 143 | 94.34 | ND | 91.14 | 0.62 | ND | 1.2 | Mammalian | Widely expressed. | CD36 | Atherosclerosis
Atherosclerotic cardiovascular disease Cardiovascular disease, unspecified Hypercholesterolemia Reproductive disorder | Receptor for different ligands such as phospholipids, cholesterol ester, lipoproteins, phosphatidylserine and apoptotic cells. Probable receptor for HDL, located in particular region of the plasma membrane, called caveolae. Facilitates the flux of free and esterified cholesterol between the cell surface and extracellular donors and acceptors, such as HDL and to a lesser extent, apoB-containing lipoproteins and modified lipoproteins. Probably involved in the phagocytosis of apoptotic cells, via its phosphatidylserine binding activity. Receptor for hepatitis C virus glycoprotein E2. Binding between SCARB1 and E2 was found to be independent of the genotype of the viral isolate. Plays an important role in the uptake of HDL cholesteryl ester (By similarity). {ECO:0000250}. (Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes. {ECO:0000269|PubMed:18000990}. | Scavenger receptor class B member 1 unknown: Phosphatidylserine | 15.1 | ||
| kccSENP6 | Sentrin-specific protease 6 | 13 | 558 | 95.21 | ND | 89.27 | 0.06 | ND | 0.9 | Mammalian | Highly expressed in reproductive organs, such as testis, ovary and prostate. | Enzyme | Protease that deconjugates SUMO1, SUMO2 and SUMO3 from targeted proteins. Processes preferentially poly-SUMO2 and poly- SUMO3 chains, but does not efficiently process SUMO1, SUMO2 and SUMO3 precursors. Deconjugates SUMO1 from RXRA, leading to transcriptional activation. Involved in chromosome alignment and spindle assembly, by regulating the kinetochore CENPH-CENPI-CENPK complex. Desumoylates PML and CENPI, protecting them from degradation by the ubiquitin ligase RNF4, which targets polysumoylated proteins for proteasomal degradation. Desumoylates also RPA1, thus preventing recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination. {ECO:0000269|PubMed:16912044, ECO:0000269|PubMed:17000875, ECO:0000269|PubMed:18799455, ECO:0000269|PubMed:20212317, ECO:0000269|PubMed:20705237, ECO:0000269|PubMed:21148299}. | 15.1 | ||||
| kccSENP7 | Sentrin-specific protease 7 | 16 | 644 | 91.79 | ND | 88.71 | 0.02 | ND | 1.0 | Mammalian | Enzyme | Protease that deconjugates SUMO2 and SUMO3 from targeted proteins, but not SUMO1. Catalyzes the deconjugation of poly-SUMO2 and poly-SUMO3 chains. Has very low efficiency in processing full- length SUMO proteins to their mature forms. {ECO:0000269|PubMed:18799455}. | 15.1 | |||||
| kccSENP8 | Sentrin-specific protease 8 | 13 | 709 | 85.63 | ND | 86.93 | 0.15 | ND | 0.9 | Mammalian | Broadly expressed, with highest levels in kidney and pancreas. {ECO:0000269|PubMed:12730221}. | Enzyme | Protease that catalyzes two essential functions in the NEDD8 pathway: processing of full-length NEDD8 to its mature form and deconjugation of NEDD8 from targeted proteins such as cullins or p53. {ECO:0000269|PubMed:12730221, ECO:0000269|PubMed:12759362, ECO:0000269|PubMed:12759363, ECO:0000269|PubMed:15242646, ECO:0000269|PubMed:15775960}. | 15.1 | ||||
| kccSEPR | Prolyl endopeptidase FAP {ECO:0000305} | 9 | 442 | 99.59 | ND | 99.88 | 0.74 | ND | 0.6 | Mammalian | Expressed in adipose tissue. Expressed in the dermal fibroblasts in the fetal skin. Expressed in the granulation tissue of healing wounds and on reactive stromal fibroblast in epithelial cancers. Expressed in activated fibroblast-like synoviocytes from inflamed synovial tissues. Expressed in activated hepatic stellate cells (HSC) and myofibroblasts from cirrhotic liver, but not detected in normal liver. Expressed in glioma cells (at protein level). Expressed in glioblastomas and glioma cells. Isoform 1 and isoform 2 are expressed in melanoma, carcinoma and fibroblast cell lines. {ECO:0000269|PubMed:10347120, ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:10644713, ECO:0000269|PubMed:16175601, ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:20707604, ECO:0000269|PubMed:24371721, ECO:0000269|PubMed:7911242}. | Protease | Atherogenesis
Inflammatory diseases Thrombosis | Cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth. Both plasma membrane and soluble forms exhibit post-proline cleaving endopeptidase activity, with a marked preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2 (PubMed:14751930, PubMed:16223769, PubMed:16480718, PubMed:16410248, PubMed:17381073, PubMed:18095711, PubMed:21288888, PubMed:24371721). Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vibronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219, PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769, PubMed:16651416, PubMed:18095711). Have also dipeptidyl peptidase activity, exhibiting the ability to hydrolyze the prolyl bond two residues from the N-terminus of synthetic dipeptide substrates provided that the penultimate residue is proline, with a preference for Ala-Pro, Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro (PubMed:10347120, PubMed:10593948, PubMed:16175601, PubMed:16223769, PubMed:16651416, PubMed:16410248, PubMed:17381073, PubMed:21314817, PubMed:24371721, PubMed:24717288). Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB) (PubMed:21314817). The plasma membrane form, in association with either DPP4, PLAUR or integrins, is involved in the pericellular proteolysis of the extracellular matrix (ECM), and hence promotes cell adhesion, migration and invasion through the ECM. Plays a role in tissue remodeling during development and wound healing. Participates in the cell invasiveness towards the ECM in malignant melanoma cancers. Enhances tumor growth progression by increasing angiogenesis, collagen fiber degradation and apoptosis and by reducing antitumor response of the immune system. Promotes glioma cell invasion through the brain parenchyma by degrading the proteoglycan brevican. Acts as a tumor suppressor in melanocytic cells through regulation of cell proliferation and survival in a serine protease activity-independent manner. {ECO:0000250|UniProtKB:P97321, ECO:0000269|PubMed:10347120, ECO:0000269|PubMed:10455171, ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:12376466, ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16175601, ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:16480718, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:17381073, ECO:0000269|PubMed:18095711, ECO:0000269|PubMed:20707604, ECO:0000269|PubMed:21288888, ECO:0000269|PubMed:21314817, ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:24371721, ECO:0000269|PubMed:24717288, ECO:0000269|PubMed:7923219, ECO:0000269|PubMed:9065413}. | 15.1 | |||
| kccSFRP1 | Secreted frizzled-related protein 1 | 1 | 59 | 100.00 | ND | 100.00 | 0.22 | ND | 0.2 | Mammalian | Widely expressed. Absent from lung, liver and peripheral blood leukocytes. Highest levels in heart and fetal kidney. Also expressed in testis, ovary, fetal brain and lung, leiomyomal cells, myometrial cells and vascular smooth muscle cells. Expressed in foreskin fibroblasts and in keratinocytes. {ECO:0000269|PubMed:9391078}. | secreted frizzled-related protein | Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP1 decreases intracellular beta-catenin levels (By similarity). Has antiproliferative effects on vascular cells, in vitro and in vivo, and can induce, in vivo, an angiogenic response. In vascular cell cycle, delays the G1 phase and entry into the S phase (By similarity). In kidney development, inhibits tubule formation and bud growth in metanephroi (By similarity). Inhibits WNT1/WNT4-mediated TCF-dependent transcription. {ECO:0000250}. | 15.1 | ||||
| kccSGK1 | Serine/threonine-protein kinase Sgk1 | 3 | 117 | 100.00 | ND | 100.00 | 0.80 | ND | 0.6 | Mammalian | Expressed in most tissues with highest levels in the pancreas, followed by placenta, kidney and lung. Isoform 2 is strongly expressed in brain and pancreas, weaker in heart, placenta, lung, liver and skeletal muscle. {ECO:0000269|PubMed:10548550, ECO:0000269|PubMed:18753299}. | Kinase | Leukemia, Myeloid
Myelodysplastic Syndrome Solid tumors | Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cellular enzymes, transcription factors, neuronal excitability, cell growth, proliferation, survival, migration and apoptosis. Plays an important role in cellular stress response. Contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Up-regulates Na(+) channels: SCNN1A/ENAC, SCN5A and ASIC1/ACCN2, K(+) channels: KCNJ1/ROMK1, KCNA1-5, KCNQ1-5 and KCNE1, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channels: BSND, CLCN2 and CFTR, glutamate transporters: SLC1A3/EAAT1, SLC1A2 /EAAT2, SLC1A1/EAAT3, SLC1A6/EAAT4 and SLC1A7/EAAT5, amino acid transporters: SLC1A5/ASCT2, SLC38A1/SN1 and SLC6A19, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, glutamate receptor: GRIK2/GLUR6. Up-regulates carriers: SLC9A3/NHE3, SLC12A1/NKCC2, SLC12A3/NCC, SLC5A3/SMIT, SLC2A1/GLUT1, SLC5A1/SGLT1 and SLC15A2/PEPT2. Regulates enzymes: GSK3A/B, PMM2 and Na(+)/K(+) ATPase, and transcription factors: CTNNB1 and nuclear factor NF-kappa-B. Stimulates sodium transport into epithelial cells by enhancing the stability and expression of SCNN1A/ENAC. This is achieved by phosphorylating the NEDD4L ubiquitin E3 ligase, promoting its interaction with 14-3-3 proteins, thereby preventing it from binding to SCNN1A/ENAC and targeting it for degradation. Regulates store-operated Ca(+2) entry (SOCE) by stimulating ORAI1 and STIM1. Regulates KCNJ1/ROMK1 directly via its phosphorylation or indirectly via increased interaction with SLC9A3R2/NHERF2. Phosphorylates MDM2 and activates MDM2-dependent ubiquitination of p53/TP53. Phosphorylates MAPT/TAU and mediates microtubule depolymerization and neurite formation in hippocampal neurons. Phosphorylates SLC2A4/GLUT4 and up-regulates its activity. Phosphorylates APBB1/FE65 and promotes its localization to the nucleus. Phosphorylates MAPK1/ERK2 and activates it by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Phosphorylates FBXW7 and plays an inhibitory role in the NOTCH1 signaling. Phosphorylates FOXO1 resulting in its relocalization from the nucleus to the cytoplasm. Phosphorylates FOXO3, promoting its exit from the nucleus and interference with FOXO3-dependent transcription. Phosphorylates BRAF and MAP3K3/MEKK3 and inhibits their activity. Phosphorylates SLC9A3/NHE3 in response to dexamethasone, resulting in its activation and increased localization at the cell membrane. Phosphorylates CREB1. Necessary for vascular remodeling during angiogenesis. Sustained high levels and activity may contribute to conditions such as hypertension and diabetic nephropathy. Isoform 2 exhibited a greater effect on cell plasma membrane expression of SCNN1A/ENAC and Na(+) transport than isoform 1. {ECO:0000269|PubMed:11154281, ECO:0000269|PubMed:11410590, ECO:0000269|PubMed:11696533, ECO:0000269|PubMed:12397388, ECO:0000269|PubMed:12590200, ECO:0000269|PubMed:12634932, ECO:0000269|PubMed:12650886, ECO:0000269|PubMed:12761204, ECO:0000269|PubMed:12911626, ECO:0000269|PubMed:14623317, ECO:0000269|PubMed:14706641, ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:15044175, ECO:0000269|PubMed:15234985, ECO:0000269|PubMed:15319523, ECO:0000269|PubMed:15496163, ECO:0000269|PubMed:15733869, ECO:0000269|PubMed:15737648, ECO:0000269|PubMed:15845389, ECO:0000269|PubMed:15888551, ECO:0000269|PubMed:16036218, ECO:0000269|PubMed:16443776, ECO:0000269|PubMed:16982696, ECO:0000269|PubMed:17382906, ECO:0000269|PubMed:18005662, ECO:0000269|PubMed:18304449, ECO:0000269|PubMed:18753299, ECO:0000269|PubMed:19447520, ECO:0000269|PubMed:19756449, ECO:0000269|PubMed:20511718, ECO:0000269|PubMed:20730100, ECO:0000269|PubMed:21865597}. | Scavenger receptor class B member 1 unknown: Phosphatidylserine | 15.1 | ||
| kccSGK2 | Serine/threonine-protein kinase Sgk2 | 12 | 204 | 93.62 | ND | 95.62 | 0.00 | ND | 1.1 | Mammalian | Highly expressed in liver, kidney and pancreas, and at lower levels in brain. {ECO:0000269|PubMed:10548550}. | Kinase | Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, survival and proliferation. Up- regulates Na(+) channels: SCNN1A/ENAC, K(+) channels: KCNA3/Kv1.3, KCNE1 and KCNQ1, amino acid transporter: SLC6A19, glutamate transporter: SLC1A6/EAAT4, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase. {ECO:0000269|PubMed:12397388, ECO:0000269|PubMed:12590200, ECO:0000269|PubMed:12632189, ECO:0000269|PubMed:12634932, ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:20511718, ECO:0000269|PubMed:21865597}. | 15.1 | ||||
| kccSGMR1 | Sigma non-opioid intracellular receptor 1 | 143 | 3126 | 93.89 | ND | 96.28 | 0.56 | ND | 0.8 | Mammalian | Widely expressed with higher expression in liver, colon, prostate, placenta, small intestine, heart and pancreas. Expressed in the retina by retinal pigment epithelial cells. {ECO:0000269|PubMed:11687279, ECO:0000269|PubMed:8954936, ECO:0000269|PubMed:9341151}. | Biliary colic Bladder disorder Cerebrovascular disorder Dependence Dermatitis contact Drug tolerance Dry mouth Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Miosis Mood altered Oliguria Respiratory depression Shock Ureteral spasm Withdrawal syndrome | Membrane receptor | Amyotrophic lateral sclerosis 16, juvenile (ALS16) [MIM:614373]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. {ECO:0000269|PubMed:21842496}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration. {ECO:0000269|PubMed:16472803, ECO:0000269|PubMed:9341151}. | Sigma non-opioid intracellular receptor 1 agonist: Amitriptyline, Captodiame, Dextromethorphan, Pentazocine Sigma non-opioid intracellular receptor 1 antagonist: Remoxipride Sigma non-opioid intracellular receptor 1 binder: Nortriptyline | 15.1 | |
| kccSHBG | Sex hormone-binding globulin | 3 | 92 | 93.10 | ND | 94.56 | 0.48 | ND | 0.8 | Mammalian | Isoform 1 and isoform 2 are present in liver and testis. | Secreted protein | Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol. Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentration. | Sex hormone-binding globulin binder: Spironolactone Sex hormone-binding globulin other/unknown: Testosterone Sex hormone-binding globulin substrate: Norethindrone Sex hormone-binding globulin unknown: Danazol, Drostanolone, Estradiol, Estropipate, Fluoxymesterone, Hydrocortisone, Methyltestosterone, Mitotane | 15.1 | |||
| kccSHH | Sonic hedgehog protein | 10 | 164 | 88.66 | ND | 93.24 | 0.63 | ND | 0.8 | Mammalian | Expressed in fetal intestine, liver, lung, and kidney. Not expressed in adult tissues. | hedgehog | Microphthalmia, isolated, with coloboma, 5 (MCOPCB5) [MIM:611638]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:12503095}. Note=The disease is caused by mutations affecting the gene represented in this entry. Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. {ECO:0000269|PubMed:10441331, ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728, ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953, ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572, ECO:0000269|PubMed:9302262}. Note=The disease is caused by mutations affecting the gene represented in this entry. Solitary median maxillary central incisor (SMMCI) [MIM:147250]: Rare dental anomaly characterized by the congenital absence of one maxillary central incisor. {ECO:0000269|PubMed:11471164, ECO:0000269|PubMed:15103725}. Note=The disease is caused by mutations affecting the gene represented in this entry. Triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]: Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. {ECO:0000269|PubMed:12837695, ECO:0000269|PubMed:18417549}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH expression. Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences (PubMed:12837695). {ECO:0000269|PubMed:12837695}. Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740]: An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. {ECO:0000269|PubMed:19847792, ECO:0000269|PubMed:24965254}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences. {ECO:0000303|PubMed:19847792, ECO:0000303|PubMed:24965254}. Laurin-Sandrow syndrome (LSS) [MIM:135750]: A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome). {ECO:0000269|PubMed:24456159}. Note=The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5 (PubMed:24456159). | Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior- posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction. Activates the transcription of target genes by interacting with its receptor PTCH1 to prevent normal inhibition by PTCH1 on the constitutive signaling activity of SMO (By similarity). {ECO:0000250}. | 15.1 | |||
| kccSIR1 | NAD-dependent protein deacetylase sirtuin-1 | 5 | 304 | 80.87 | ND | 97.75 | 0.58 | ND | 0.7 | Mammalian | Widely expressed. {ECO:0000269|PubMed:10381378}. | Eraser | Diabetes Mellitus Type 2
Neurologic Disorders | NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A- mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insulin-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys-542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1- dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transactivation and contributes to its stability. Deacteylates MECOM/EVI1. Isoform 2 is shown to deacetylate 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop. In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. The viral Tat protein inhibits SIRT1 deacetylation activity toward RELA/NF-kappa-B p65, thereby potentiates its transcriptional activity and SIRT1 is proposed to contribute to T- cell hyperactivation during infection. Deacetylates PML at 'Lys- 487' and this deacetylation promotes PML control of PER2 nuclear localization. During the neurogenic transition, repress selective NOTCH1-target genes through histone deacetylation in a BCL6- dependent manner and leading to neuronal differentiation. Regulates the circadian expression of several core clock genes, including ARNTL/BMAL1, RORC, PER2 and CRY1 and plays a critical role in maintaining a controlled rhythmicity in histone acetylation, thereby contributing to circadian chromatin remodeling. Deacetylates ARNTL/BMAL1 and histones at the circadian gene promoters in order to facilitate repression by inhibitory components of the circadian oscillator. Deacetylates PER2, facilitating its ubiquitination and degradation by the proteosome. Protects cardiomyocytes against palmitate-induced apoptosis (PubMed:11672523, PubMed:12006491, PubMed:14976264, PubMed:14980222, PubMed:15126506, PubMed:15152190, PubMed:15205477, PubMed:15469825, PubMed:15692560, PubMed:16079181, PubMed:16166628, PubMed:16892051, PubMed:16998810, PubMed:17283066, PubMed:17334224, PubMed:17505061, PubMed:17612497, PubMed:17620057, PubMed:17936707, PubMed:18203716, PubMed:18296641, PubMed:18662546, PubMed:18687677, PubMed:19188449, PubMed:19220062, PubMed:19364925, PubMed:19690166, PubMed:19934257, PubMed:20097625, PubMed:20100829, PubMed:20203304, PubMed:20375098, PubMed:20620956, PubMed:20670893, PubMed:20817729, PubMed:20975832, PubMed:21149730, PubMed:21245319, PubMed:21471201, PubMed:21504832, PubMed:21555002, PubMed:21698133, PubMed:21701047, PubMed:21775285, PubMed:21807113, PubMed:21841822, PubMed:21890893, PubMed:21909281, PubMed:21947282, PubMed:22274616). Deacetylates XBP1 isoform 2; deacetylation decreases protein stability of XBP1 isoform 2 and inhibits its transcriptional activity (PubMed:20955178). Involved in the CCAR2-mediated regulation of PCK1 and NR1D1 (PubMed:24415752). Deacetylates CTNB1 at 'Lys-49' (PubMed:24824780). {ECO:0000250|UniProtKB:Q923E4, ECO:0000269|PubMed:11672523, ECO:0000269|PubMed:12006491, ECO:0000269|PubMed:14976264, ECO:0000269|PubMed:14980222, ECO:0000269|PubMed:15126506, ECO:0000269|PubMed:15152190, ECO:0000269|PubMed:15205477, ECO:0000269|PubMed:15469825, ECO:0000269|PubMed:15692560, ECO:0000269|PubMed:16079181, ECO:0000269|PubMed:16166628, ECO:0000269|PubMed:16892051, ECO:0000269|PubMed:16998810, ECO:0000269|PubMed:17283066, ECO:0000269|PubMed:17290224, ECO:0000269|PubMed:17334224, ECO:0000269|PubMed:17505061, ECO:0000269|PubMed:17612497, ECO:0000269|PubMed:17620057, ECO:0000269|PubMed:17936707, ECO:0000269|PubMed:18203716, ECO:0000269|PubMed:18296641, ECO:0000269|PubMed:18662546, ECO:0000269|PubMed:18687677, ECO:0000269|PubMed:19188449, ECO:0000269|PubMed:19220062, ECO:0000269|PubMed:19364925, ECO:0000269|PubMed:19690166, ECO:0000269|PubMed:19934257, ECO:0000269|PubMed:20097625, ECO:0000269|PubMed:20100829, ECO:0000269|PubMed:20203304, ECO:0000269|PubMed:20375098, ECO:0000269|PubMed:20620956, ECO:0000269|PubMed:20670893, ECO:0000269|PubMed:20817729, ECO:0000269|PubMed:20955178, ECO:0000269|PubMed:20975832, ECO:0000269|PubMed:21149730, ECO:0000269|PubMed:21245319, ECO:0000269|PubMed:21471201, ECO:0000269|PubMed:21504832, ECO:0000269|PubMed:21555002, ECO:0000269|PubMed:21698133, ECO:0000269|PubMed:21701047, ECO:0000269|PubMed:21775285, ECO:0000269|PubMed:21807113, ECO:0000269|PubMed:21841822, ECO:0000269|PubMed:21890893, ECO:0000269|PubMed:21909281, ECO:0000269|PubMed:21947282, ECO:0000269|PubMed:22274616, ECO:0000269|PubMed:24415752, ECO:0000269|PubMed:24824780}. SirtT1 75 kDa fragment: catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly. {ECO:0000269|PubMed:21987377}. | 15.1 | |||
| kccSIR2 | NAD-dependent protein deacetylase sirtuin-2 | 11 | 306 | 98.51 | ND | 99.78 | 0.71 | ND | 0.5 | Mammalian | Isoform 1 is expressed in heart, liver and skeletal muscle, weakly expressed in the cortex. Isoform 2 is strongly expressed in the cortex, weakly expressed in heart and liver. Weakly expressed in several malignancies including breast, liver, brain, kidney and prostate cancers compared to normal tissues. Weakly expressed in glioma cell lines compared to normal brain tissues (at protein level). Widely expressed. Highly expressed in heart, brain and skeletal muscle, while it is weakly expressed in placenta and lung. Down-regulated in many gliomas suggesting that it may act as a tumor suppressor gene in human gliomas possibly through the regulation of microtubule network. {ECO:0000269|PubMed:10381378, ECO:0000269|PubMed:10393250, ECO:0000269|PubMed:12963026, ECO:0000269|PubMed:16909107, ECO:0000269|PubMed:21791548, ECO:0000269|PubMed:22014574}. | Eraser | NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors. Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes. Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis. Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by SETD8 leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression. Deacetylates SETD8 modulating SETD8 chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys- 57' (H3K56ac) during the mitotic G2/M transition. Upon bacterium Listeria monocytogenes infection, deacetylates 'Lys-18' of histone H3 in a receptor tyrosine kinase MET- and PI3K/Akt-dependent manner, thereby inhibiting transcriptional activity and promoting late stages of listeria infection. During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function. Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1- mediated autophagy. Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation. Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia. Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation. Inhibits transcriptional activation by deacetylating p53/TP53 and EP300. Deacetylates also EIF5A. Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions. Plays a role as tumor suppressor. Isoform 1: Deacetylates EP300, alpha-tubulin and histone H3 and H4. Isoform 2: Deacetylates EP300, alpha-tubulin and histone H3 and H4. Isoform 5: Lacks deacetylation activity. | 15.1 | ||||
| kccSIR3 | NAD-dependent protein deacetylase sirtuin-3, mitochondrial | 1 | 56 | 90.13 | ND | 92.58 | 0.68 | ND | 0.7 | Mammalian | Widely expressed. {ECO:0000269|PubMed:10381378, ECO:0000269|PubMed:12374852}. | Eraser | NAD-dependent protein deacetylase. Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues. Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA and the ATP synthase subunit ATP5O. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels. {ECO:0000269|PubMed:16788062, ECO:0000269|PubMed:18680753, ECO:0000269|PubMed:18794531, ECO:0000269|PubMed:19535340, ECO:0000269|PubMed:24121500, ECO:0000269|PubMed:24252090}. | Serine/threonine-protein kinase SIK1 inhibitor: Dabrafenib | 15.1 | |||
| kccSL9A1 | Sodium/hydrogen exchanger 1 | 13 | 321 | 98.69 | ND | 99.20 | 0.73 | ND | 0.6 | Mammalian | Kidney and intestine. | Electrochemical transporter | Lichtenstein-Knorr syndrome (LIKNS) [MIM:616291]: An autosomal recessive neurologic disorder characterized by progressive cerebellar ataxia and severe progressive sensorineural hearing loss. {ECO:0000269|PubMed:25205112}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction. {ECO:0000269|PubMed:11350981, ECO:0000269|PubMed:15035633, ECO:0000269|PubMed:8901634}. | Sodium/hydrogen exchanger 1 inhibitor: Amiloride | 15.1 | ||
| kccSLK | STE20-like serine/threonine-protein kinase | 17 | 301 | 93.88 | ND | 87.50 | 0.08 | ND | 1.5 | Mammalian | Ubiquitously expressed. Highest expression is found in heart and in skeletal muscle. {ECO:0000269|PubMed:10699464}. | Kinase | Mediates apoptosis and actin stress fiber dissolution. {ECO:0000250}. | Sodium/hydrogen exchanger 1 inhibitor: Amiloride | 15.1 | |||
| kccSMN | Survival motor neuron protein | 104 | 4708 | 85.37 | ND | 87.71 | 0.09 | ND | 0.6 | Mammalian | Expressed in a wide variety of tissues. Expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. Also seen at high levels in spinal cord. Present in osteoclasts and mononuclear cells (at protein level). {ECO:0000269|PubMed:11551898, ECO:0000269|PubMed:9259265}. | Reader | Spinal muscular atrophy 1 (SMA1) [MIM:253300]: A form of spinal muscular atrophy, a group of neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. Autosomal recessive forms are classified according to the age of onset, the maximum muscular activity achieved, and survivorship. The severity of the disease is mainly determined by the copy number of SMN2, a copy gene which predominantly produces exon 7- skipped transcripts and only low amount of full-length transcripts that encode for a protein identical to SMN1. Only about 4% of SMA patients bear one SMN1 copy with an intragenic mutation. SMA1 is a severe form, with onset before 6 months of age. SMA1 patients never achieve the ability to sit. {ECO:0000269|PubMed:10732817, ECO:0000269|PubMed:15249625, ECO:0000269|PubMed:15580564, ECO:0000269|PubMed:7813012, ECO:0000269|PubMed:9147655}. Note=The disease is caused by mutations affecting the gene represented in this entry. Spinal muscular atrophy 2 (SMA2) [MIM:253550]: An autosomal recessive form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. It has intermediate severity, with onset between 6 and 18 months. Patients do not reach the motor milestone of standing, and survive into adulthood. {ECO:0000269|PubMed:10732802, ECO:0000269|PubMed:9158159, ECO:0000269|PubMed:9837824}. Note=The disease is caused by mutations affecting the gene represented in this entry. Spinal muscular atrophy 3 (SMA3) [MIM:253400]: An autosomal recessive form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. Onset is after 18 months. Patients develop ability to stand and walk and survive into adulthood. {ECO:0000269|PubMed:10732817, ECO:0000269|PubMed:9158159, ECO:0000269|PubMed:9837824}. Note=The disease is caused by mutations affecting the gene represented in this entry. Spinal muscular atrophy 4 (SMA4) [MIM:271150]: An autosomal recessive form of spinal muscular atrophy, a neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. Onset is in adulthood, disease progression is slow, and patients can stand and walk. Note=The disease is caused by mutations affecting the gene represented in this entry. | The SMN complex plays a catalyst role in the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. Thereby, plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP. In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. Dissociation by the SMN complex of CLNS1A from the trapped Sm proteins and their transfer to an SMN-Sm complex triggers the assembly of core snRNPs and their transport to the nucleus. Ensures the correct splicing of U12 intron-containing genes that may be important for normal motor and proprioceptive neurons development. May also play a role in the metabolism of small nucleolar ribonucleoprotein (snoRNPs). {ECO:0000269|PubMed:18984161, ECO:0000269|PubMed:23063131, ECO:0000269|PubMed:9845364}. | 15.1 | |||
| kccSMO | Smoothened homolog | 17 | 400 | 98.91 | ND | 97.98 | 0.57 | ND | 0.7 | Mammalian | Frizzled family G protein-coupled receptor | Cancers | G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia. {ECO:0000269|PubMed:19592253}. | Smoothened homolog agonist: Fluocinonide Smoothened homolog antagonist: Vismodegib | 15.1 | |||
| kccSO1B1 | Solute carrier organic anion transporter family member 1B1 | 9 | 137 | 88.84 | ND | 88.20 | 0.04 | ND | 1.1 | Mammalian | Highly expressed in liver, at the basolateral membranes of centrilobular hepatocytes. Not detected in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocyte. {ECO:0000269|PubMed:10358072, ECO:0000269|PubMed:10601278, ECO:0000269|PubMed:22232210}. | Electrochemical transporter | Hyperbilirubinemia, Rotor type (HBLRR) [MIM:237450]: An autosomal recessive form of primary conjugated hyperbilirubinemia. Affected individuals develop mild jaundice not associated with hemolysis shortly after birth or in childhood. They have delayed plasma clearance of the unconjugated anionic dye bromsulphthalein and prominent urinary excretion of coproporphyrin I. Hepatic pigmentation is normal. {ECO:0000269|PubMed:22232210}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver. {ECO:0000269|PubMed:10358072, ECO:0000269|PubMed:10601278, ECO:0000269|PubMed:12196548, ECO:0000269|PubMed:22232210}. | Solute carrier organic anion transporter family member 1B1 inhibitor: Acetylcysteine, Aminohippurate, Bezafibrate, Cabazitaxel, Caspofungin, Cyclosporine, Dabrafenib, Eltrombopag, Estradiol, Estrone, Gemfibrozil, Idelalisib, Indinavir, Irinotecan, L-Carnitine, Lovastatin, Nelfinavir, Pantoprazole, Pazopanib, Pioglitazone, Quinidine, Rifampicin, Rilpivirine, Ritonavir, Rosiglitazone, Saquinavir, Sirolimus, Verapamil Solute carrier organic anion transporter family member 1B1 substrate: Benzylpenicillin, Dinoprostone, Ezetimibe, Gadoxetate, Liothyronine, Liotrix, Methotrexate, Mycophenolate mofetil, Olmesartan, Ouabain, Penicillamine, Pitavastatin, Repaglinide, Rosuvastatin, Sumatriptan, Valsartan Solute carrier organic anion transporter family member 1B1 substrate;inhibitor: Atorvastatin, Conjugated Estrogens, Digoxin, Pravastatin, SIMEPREVIR, Simvastatin Solute carrier organic anion transporter family member 1B1 unknown: Clarithromycin, Dextrothyroxine, Fexofenadine, Fluvastatin, Levothyroxine, Rifampicin | 15.1 | ||
| kccSO1B3 | Solute carrier organic anion transporter family member 1B3 | 6 | 98 | 90.81 | ND | 89.44 | 0.01 | ND | 1.0 | Mammalian | Highly expressed in liver, in particular at the basolateral membrane of hepatocytes near the central vein. Not detected in other tissues. Highly expressed in some cancer cell lines derived from colon, pancreas, liver and gall bladder. | Electrochemical transporter | Hyperbilirubinemia, Rotor type (HBLRR) [MIM:237450]: An autosomal recessive form of primary conjugated hyperbilirubinemia. Affected individuals develop mild jaundice not associated with hemolysis shortly after birth or in childhood. They have delayed plasma clearance of the unconjugated anionic dye bromsulphthalein and prominent urinary excretion of coproporphyrin I. Hepatic pigmentation is normal. {ECO:0000269|PubMed:22232210}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver. {ECO:0000269|PubMed:22232210}. | Solute carrier organic anion transporter family member 1B3 inhibitor: Cabazitaxel, Dabrafenib, Idelalisib, Pioglitazone, Rilpivirine Solute carrier organic anion transporter family member 1B3 substrate: Atorvastatin, Caspofungin, Conjugated Estrogens, Digoxin, Docetaxel, Gadoxetate, Liothyronine, Liotrix, Methotrexate, Mycophenolate mofetil, Olmesartan, Ouabain, Paclitaxel, Pitavastatin, Pravastatin, Valsartan Solute carrier organic anion transporter family member 1B3 substrate;inhibitor: Rifampicin Solute carrier organic anion transporter family member 1B3 unknown: Clarithromycin, Estradiol, Fexofenadine, Fluvastatin, Levothyroxine, Rifampicin, Rosuvastatin | 15.1 | ||
| kccSOAT1 | Sterol O-acyltransferase 1 | 39 | 1007 | 98.41 | ND | 99.35 | 0.70 | ND | 0.5 | Mammalian | Enzyme | Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol. Plays a role in lipoprotein assembly and dietary cholesterol absorption. In addition to its acyltransferase activity, it may act as a ligase. | Sterol O-acyltransferase 1 inhibitor: Ezetimibe, Hesperetin | 15.1 | ||||
| kccSOAT2 | Sterol O-acyltransferase 2 | 2 | 109 | 96.46 | ND | 95.35 | 0.78 | ND | 0.7 | Mammalian | Expression seems confined in hepatocytes and enterocytes. {ECO:0000269|PubMed:16331323}. | Enzyme | Not Available | Plays a role in lipoprotein assembly and dietary cholesterol absorption. In addition to its acyltransferase activity, it may act as a ligase. May provide cholesteryl esters for lipoprotein secretion from hepatocytes and intestinal mucosa. | Sterol O-acyltransferase 2 inhibitor: Hesperetin | 15.1 | ||
| kccSPHK1 | Sphingosine kinase 1 | 9 | 145 | 95.17 | ND | 97.47 | 0.51 | ND | 0.8 | Mammalian | Widely expressed with highest levels in adult liver, kidney, heart and skeletal muscle. {ECO:0000269|PubMed:10802064}. | Enzyme | Late-Stage Ovarian cancer
Prostate cancer | Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol. {ECO:0000269|PubMed:20577214, ECO:0000269|PubMed:23602659}. | Sphingosine kinase 1 substrate: Fingolimod | 15.1 | ||
| kccSPHK2 | Sphingosine kinase 2 | 3 | 93 | 97.05 | ND | 96.23 | 0.60 | ND | 0.4 | Mammalian | Enzyme | Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro- dihydrosphingosine, D-erythro-sphingosine and L-threo- dihydrosphingosine. Binds phosphoinositides. {ECO:0000269|PubMed:19168031}. | 15.1 | |||||
| kccSRC | Proto-oncogene tyrosine-protein kinase Src | 71 | 2680 | 96.09 | ND | 96.75 | 0.61 | ND | 0.8 | Mammalian | Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues. | Diarrhoea | Kinase | Note=SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells. | Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein- coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin- 43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1. Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors. Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation. Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr- 1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of ADRBK1, leading to beta- arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor. Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus. Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase. Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr- 128'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Required for podosome formation (By similarity). {ECO:0000250|UniProtKB:P05480, ECO:0000269|PubMed:11389730, ECO:0000269|PubMed:12615910, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:16186108, ECO:0000269|PubMed:18586953, ECO:0000269|PubMed:19419966, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20525694, ECO:0000269|PubMed:21309750, ECO:0000269|PubMed:21411625, ECO:0000269|PubMed:22710723, ECO:0000269|PubMed:2498394, ECO:0000269|PubMed:3093483, ECO:0000269|PubMed:7853507, ECO:0000269|PubMed:8755529, ECO:0000269|PubMed:8759729}. | Proto-oncogene tyrosine-protein kinase Src Inhibitor: Nintedanib Proto-oncogene tyrosine-protein kinase Src inhibitor: Bosutinib, Ponatinib Proto-oncogene tyrosine-protein kinase Src multitarget: Dasatinib | 15.1 | |
| kccSRMS | Tyrosine-protein kinase Srms | 2 | 100 | 92.13 | ND | 83.32 | 0.35 | ND | 1.1 | Mammalian | Highly expressed in most breast cancers (at protein level). | Kinase | Non-receptor tyrosine-protein kinase which phosphorylates DOK1 on tyrosine residues. May be involved in proliferation or differentiation of keratinocytes in the skin. {ECO:0000269|PubMed:23822091}. | 15.1 | ||||
| kccSRPK1 | SRSF protein kinase 1 | 12 | 221 | 90.61 | ND | 90.37 | 0.26 | ND | 1.1 | Mammalian | Isoform 2 is predominantly expressed in the testis but is also present at lower levels in heart, ovary, small intestine, liver, kidney, pancreas and skeletal muscle. Isoform 1 is only seen in the testis, at lower levels than isoform 2. Highly expressed in different erythroid and lymphoid cell lines, with isoform 2 being far more abundant than isoform 1. {ECO:0000269|PubMed:10390541, ECO:0000269|PubMed:11509566, ECO:0000269|PubMed:20708644}. | Kinase | Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation. {ECO:0000269|PubMed:10049757, ECO:0000269|PubMed:10390541, ECO:0000269|PubMed:11509566, ECO:0000269|PubMed:12134018, ECO:0000269|PubMed:14555757, ECO:0000269|PubMed:15034300, ECO:0000269|PubMed:16122776, ECO:0000269|PubMed:16209947, ECO:0000269|PubMed:18155240, ECO:0000269|PubMed:18687337, ECO:0000269|PubMed:19240134, ECO:0000269|PubMed:19477182, ECO:0000269|PubMed:19886675, ECO:0000269|PubMed:20708644, ECO:0000269|PubMed:8208298, ECO:0000269|PubMed:9237760}. | 15.1 | ||||
| kccSSR1 | Somatostatin receptor type 1 | 7 | 592 | 98.92 | ND | 99.58 | 0.58 | ND | 0.6 | Mammalian | Fetal kidney, fetal liver, and adult pancreas, brain, lung, jejunum and stomach. | Family A G protein-coupled receptor | Cushing's disease
Neuroblastoma Refractory Renal Cell Carcinoma | Receptor for somatostatin with higher affinity for somatostatin-14 than -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and Na(+)/H(+) exchanger via pertussis toxin insensitive G proteins. | Somatostatin receptor type 1 unknown: Octreotide, Pasireotide | 15.1 | ||
| kccSSR2 | Somatostatin receptor type 2 | 9 | 741 | 99.10 | ND | 99.48 | 0.77 | ND | 0.6 | Mammalian | Expressed in both pancreatic alpha- and beta- cells (at protein level). Expressed at higher levels in the pancreas than other somatostatin receptors. Also expressed in the cerebrum and kidney and, in lesser amounts, in the jejunum, colon and liver. In the developing nervous system, expressed in the cortex where it is located in the preplate at early stages and is enriched in the outer part of the germinal zone at later stages. In the cerebellum, expressed in the deep part of the external granular layer at gestational week 19. This pattern persists until birth but disappears at adulthood. {ECO:0000269|PubMed:19434240, ECO:0000269|PubMed:22932785}. | Family A G protein-coupled receptor | Cancer, unspecified
Cushing's disease Neuroblastoma | Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization. {ECO:0000269|PubMed:15231824, ECO:0000269|PubMed:18653781, ECO:0000269|PubMed:19434240, ECO:0000269|PubMed:22495673, ECO:0000269|PubMed:22932785}. | Somatostatin receptor type 2 binder: Octreotide Somatostatin receptor type 2 inducer: Vapreotide Somatostatin receptor type 2 unknown: Pasireotide | 15.1 | ||
| kccSSR3 | Somatostatin receptor type 3 | 13 | 621 | 99.00 | ND | 99.55 | 0.60 | ND | 0.6 | Mammalian | Brain, pituitary and pancreas. {ECO:0000269|PubMed:1337145}. | Family A G protein-coupled receptor | Cushing's disease | Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. {ECO:0000269|PubMed:1337145}. | Somatostatin receptor type 3 unknown: Pasireotide | 15.1 | ||
| kccSSR4 | Somatostatin receptor type 4 | 9 | 555 | 99.27 | ND | 99.55 | 0.73 | ND | 0.6 | Mammalian | Specifically expressed in fetal and adult brain, lung tissue, stomach, and in lesser quantities in the kidney, pituitary and adrenals. | Family A G protein-coupled receptor | Solid tumors | Receptor for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. It is functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade. Mediates antiproliferative action of somatostatin in tumor cells. | 15.1 | |||
| kccSSR5 | Somatostatin receptor type 5 | 9 | 585 | 98.45 | ND | 97.08 | 0.55 | ND | 0.7 | Mammalian | Adult pituitary gland, heart, small intestine, adrenal gland, cerebellum and fetal hypothalamus. No expression in fetal or adult kidney, liver, pancreas, uterus, spleen, lung, thyroid or ovary. {ECO:0000269|PubMed:12072395, ECO:0000269|PubMed:7908405, ECO:0000269|PubMed:8078491}. | Family A G protein-coupled receptor | Cushing's disease | Receptor for somatostatin 28 and to a lesser extent for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. Increases cell growth inhibition activity of SSTR2 following heterodimerization. {ECO:0000269|PubMed:12072395, ECO:0000269|PubMed:7908405, ECO:0000269|PubMed:8078491, ECO:0000269|PubMed:8373420}. | Somatostatin receptor type 5 agonist: Vapreotide Somatostatin receptor type 5 unknown: Octreotide, Pasireotide | 15.1 | ||
| kccST14 | Suppressor of tumorigenicity 14 protein | 7 | 182 | 99.26 | ND | 99.99 | 0.46 | ND | 0.8 | Mammalian | Protease | Ichthyosis, congenital, autosomal recessive 11 (ARCI11) [MIM:602400]: A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. {ECO:0000269|PubMed:17273967, ECO:0000269|PubMed:18843291}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Degrades extracellular matrix. Proposed to play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Involved in the terminal differentiation of keratinocytes through prostasin (PRSS8) activation and filaggrin (FLG) processing. {ECO:0000269|PubMed:18843291}. | Somatostatin receptor type 5 agonist: Vapreotide Somatostatin receptor type 5 unknown: Octreotide, Pasireotide | 15.1 | |||
| kccST17A | Serine/threonine-protein kinase 17A | 13 | 275 | 91.59 | ND | 84.85 | 0.29 | ND | 1.3 | Mammalian | Highly expressed in placenta. Lower levels in heart, lung, skeletal muscle, kidney and pancreas. {ECO:0000269|PubMed:9786912}. | Kinase | Acts as a positive regulator of apoptosis. Also acts as a regulator of cellular reactive oxygen species. {ECO:0000269|PubMed:21489989, ECO:0000269|PubMed:9786912}. | 15.1 | ||||
| kccSTAT3 | Signal transducer and activator of transcription 3 | 8 | 494 | 86.11 | ND | 86.08 | 0.27 | ND | 0.9 | Mammalian | Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. | Transcription factor | Hyperimmunoglobulin E recurrent infection syndrome, autosomal dominant (AD-HIES) [MIM:147060]: A rare disorder of immunity and connective tissue characterized by immunodeficiency, chronic eczema, recurrent Staphylococcal infections, increased serum IgE, eosinophilia, distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures. {ECO:0000269|PubMed:17676033, ECO:0000269|PubMed:17881745, ECO:0000269|PubMed:23342295}. Note=The disease is caused by mutations affecting the gene represented in this entry. Autoimmune disease, multisystem, infantile-onset (ADMIO) [MIM:615952]: A disorder characterized by early childhood onset of a spectrum of autoimmune manifestations affecting multiple organs, including insulin-dependent diabetes mellitus and autoimmune enteropathy or celiac disease. Other features include short stature, non-specific dermatitis, hypothyroidism, autoimmune arthritis, and delayed puberty. {ECO:0000269|PubMed:25038750}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF and other growth factors. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Binds to the interleukin-6 (IL-6)- responsive elements identified in the promoters of various acute- phase protein genes. Activated by IL31 through IL31RA. Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity. Plays an important role in host defense in methicillin-resistant S.aureus lung infection by regulating the expression of the antimicrobial lectin REG3G (By similarity). {ECO:0000250}. | 15.1 | |||
| kccSTAT6 | Signal transducer and activator of transcription 6 | 2 | 95 | 90.87 | ND | 91.07 | 0.46 | ND | 0.6 | Mammalian | transcription factor STAT | Carries out a dual function: signal transduction and activation of transcription. Involved in IL4/interleukin-4- and IL3/interleukin-3-mediated signaling. {ECO:0000269|PubMed:17210636}. | 15.1 | |||||
| kccSTF1 | Steroidogenic factor 1 | 14 | 197 | 90.26 | ND | 90.43 | 0.31 | ND | 1.2 | Mammalian | Nuclear receptor | 46,XY sex reversal 3 (SRXY3) [MIM:612965]: A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. {ECO:0000269|PubMed:10369247, ECO:0000269|PubMed:11932325, ECO:0000269|PubMed:17200175, ECO:0000269|PubMed:17694559}. Note=The disease is caused by mutations affecting the gene represented in this entry. Adrenocortical insufficiency, without ovarian defect (ACIWOD) [MIM:184757]: A disorder that is characterized by severe 'slackness,' muscular hypotonia. There is decreased sodium, increased potassium and elevated ACTH. {ECO:0000269|PubMed:11038323}. Note=The disease is caused by mutations affecting the gene represented in this entry. Premature ovarian failure 7 (POF7) [MIM:612964]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:19246354}. Note=The disease is caused by mutations affecting the gene represented in this entry. Spermatogenic failure 8 (SPGF8) [MIM:613957]: An infertility disorder characterized by spermatogenesis failure and severe oligozoospermia. {ECO:0000269|PubMed:20887963}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transcriptional activator. Seems to be essential for sexual differentiation and formation of the primary steroidogenic tissues. Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1. The SFPQ-NONO- NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional avtivity. Binds phosphatidylcholine (By similarity). Binds phospholipids with a phosphatidylinositol (PI) headgroup, in particular PI(3,4)P2 and PI(3,4,5)P3. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. {ECO:0000250, ECO:0000269|PubMed:17210646}. | Somatostatin receptor type 5 agonist: Vapreotide Somatostatin receptor type 5 unknown: Octreotide, Pasireotide | 15.1 | |||
| kccSTK10 | Serine/threonine-protein kinase 10 | 1 | 66 | 92.39 | ND | 88.82 | 0.25 | ND | 0.1 | Mammalian | Highly expressed in rapidly proliferating tissues (spleen, placenta, and peripheral blood leukocytes). Also expressed in brain, heart, skeletal muscle, colon, thymus, kidney, liver, small intestine and lung. {ECO:0000269|PubMed:12639966}. | Kinase | Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:16175573}. Note=The disease may be caused by mutations affecting the gene represented in this entry. | Serine/threonine-protein kinase involved in regulation of lymphocyte migration. Phosphorylates MSN, and possibly PLK1. Involved in regulation of lymphocyte migration by mediating phosphorylation of ERM proteins such as MSN. Acts as a negative regulator of MAP3K1/MEKK1. May also act as a cell cycle regulator by acting as a polo kinase kinase: mediates phosphorylation of PLK1 in vitro; however such data require additional evidences in vivo. {ECO:0000269|PubMed:11903060, ECO:0000269|PubMed:12639966, ECO:0000269|PubMed:19255442}. | 15.1 | |||
| kccSTK3 | Serine/threonine-protein kinase 3 | 18 | 358 | 96.68 | ND | 91.90 | 0.14 | ND | 1.3 | Mammalian | Expressed at high levels in adult kidney, skeletal and placenta tissues and at very low levels in adult heart, lung and brain tissues. {ECO:0000269|PubMed:8566796}. | Kinase | Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38. {ECO:0000250, ECO:0000269|PubMed:15688006, ECO:0000269|PubMed:16930133, ECO:0000269|PubMed:18328708, ECO:0000269|PubMed:18362890, ECO:0000269|PubMed:19525978, ECO:0000269|PubMed:20212043, ECO:0000269|PubMed:21076410, ECO:0000269|PubMed:21104395, ECO:0000269|PubMed:8566796, ECO:0000269|PubMed:8816758}. | 15.1 | ||||
| kccSTK33 | Serine/threonine-protein kinase 33 | 2 | 92 | 93.12 | ND | 83.00 | 0.37 | ND | 1.0 | Mammalian | Highly expressed in testis, fetal lung and heart, followed by pituitary gland, kidney, interventricular septum, pancreas, heart, trachea, thyroid gland and uterus. Weak hybridization signals were observed in the following tissues: amygdala, aorta, esophagus, colon ascending, colon transverse, skeletal muscle, spleen, peripheral blood leukocyte, lymph node, bone marrow, placenta, prostate, liver, salivary gland, mammary gland, some tumor cell lines, fetal brain, fetal liver, fetal spleen and fetal thymus. No signal at all was detectable in RNA from tissues of the nervous system. {ECO:0000269|PubMed:11738831, ECO:0000269|PubMed:16176263}. | Kinase | Serine/threonine protein kinase which phosphorylates VIME. May play a specific role in the dynamic behavior of the intermediate filament cytoskeleton by phosphorylation of VIME (By similarity). Not essential for the survival of KRAS-dependent AML cell lines. {ECO:0000250, ECO:0000269|PubMed:21742770}. | 15.1 | ||||
| kccSTS | Steryl-sulfatase | 11 | 283 | 99.47 | ND | 99.77 | 0.50 | ND | 0.7 | Mammalian | Enzyme | Ichthyosis, X-linked (IXL) [MIM:308100]: A keratinization disorder manifesting with mild erythroderma and generalized exfoliation of the skin within a few weeks after birth. Affected boys later develop large, polygonal, dark brown scales, especially on the neck, extremities, trunk, and buttocks. {ECO:0000269|PubMed:10679952, ECO:0000269|PubMed:10844566, ECO:0000269|PubMed:1539590, ECO:0000269|PubMed:9252398}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Conversion of sulfated steroid precursors to estrogens during pregnancy. | Steryl-sulfatase inhibitor: Norelgestromin | 15.1 | |||
| kccSUIS | Sucrase-isomaltase, intestinal | 8 | 124 | 99.86 | ND | 99.82 | 0.48 | ND | 0.9 | Mammalian | Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon. {ECO:0000269|PubMed:1677636}. | Enzyme | Congenital sucrase-isomaltase deficiency (CSID) [MIM:222900]: Autosomal recessive intestinal disorder that is clinically characterized by fermentative diarrhea, abdominal pain, and cramps upon ingestion of sugar. The symptoms are the consequence of absent or drastically reduced enzymatic activities of sucrase and isomaltase. The prevalence of CSID is 0.02 % in individuals of European descent and appears to be much higher in Greenland, Alaskan, and Canadian native people. CSID arises due to post-translational perturbations in the intracellular transport, polarized sorting, aberrant processing, and defective function of SI. {ECO:0000269|PubMed:10903344, ECO:0000269|PubMed:11340066, ECO:0000269|PubMed:14724820, ECO:0000269|PubMed:16329100, ECO:0000269|PubMed:8609217}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Plays an important role in the final stage of carbohydrate digestion. Isomaltase activity is specific for both alpha-1,4- and alpha-1,6-oligosaccharides. {ECO:0000269|PubMed:20356844}. | Sucrase-isomaltase, intestinal inhibitor: Acarbose, Scopolamine | 15.1 | ||
| kccSYIC | Isoleucine--tRNA ligase, cytoplasmic | 4 | 51 | 99.96 | ND | 99.93 | 0.31 | ND | 0.8 | Mammalian | Enzyme | Autoimmune diseases | Isoleucine--tRNA ligase, cytoplasmic unknown: L-Isoleucine | 15.1 | ||||
| kccSYK | Lysine--tRNA ligase | 5 | 113 | 91.23 | ND | 90.22 | 0.61 | ND | 0.6 | Mammalian | Enzyme | Charcot-Marie-Tooth disease, recessive, intermediate type, B (CMTRIB) [MIM:613641]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:20920668}. Note=The disease is caused by mutations affecting the gene represented in this entry. Deafness, autosomal recessive, 89 (DFNB89) [MIM:613916]: A form of non-syndromic deafness characterized by bilateral, prelingual, moderate to severe hearing loss affecting all frequencies. {ECO:0000269|PubMed:23768514}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages. Catalyzes the synthesis of diadenosine oligophosphate (Ap4A), a signaling molecule involved in the activation of MITF transcriptional activity. Interacts with HIV-1 virus GAG protein, facilitating the selective packaging of tRNA(3)(Lys), the primer for reverse transcription initiation. {ECO:0000269|PubMed:15851690, ECO:0000269|PubMed:5338216}. | Lysine--tRNA ligase unknown: L-Lysine | 15.1 | |||
| kccSYMC | Methionine--tRNA ligase, cytoplasmic | 4 | 70 | 99.77 | ND | 99.98 | 0.93 | ND | 0.2 | Mammalian | Enzyme | Infantile liver failure syndrome 2 (ILFS2) [MIM:615486]: A life-threatening disorder of hepatic function that manifests with liver failure in the first months of life. Clinical features include failure to thrive, hypotonia, intermittent lactic acidosis, aminoaciduria, hypothyroidism, interstitial lung disease, anemia, liver canalicular cholestasis, steatosis, and iron deposition. {ECO:0000269|PubMed:24103465}. Note=The disease is caused by mutations affecting the gene represented in this entry. Charcot-Marie-Tooth disease 2U (CMT2U) [MIM:616280]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2U is a slowly progressive, autosomal dominant form characterized by late-adult onset. {ECO:0000269|PubMed:23729695, ECO:0000269|PubMed:24354524}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Methionine--tRNA ligase, cytoplasmic substrate: L-Methionine | 15.1 | ||||
| kccT23O | Tryptophan 2,3-dioxygenase {ECO:0000255|HAMAP-Rule:MF_03020} | 1 | 72 | 99.88 | ND | 99.78 | 0.24 | ND | 1.3 | Mammalian | Enzyme | Incorporates oxygen into the indole moiety of tryptophan. Has a broad specificity towards tryptamine and derivatives including D- and L-tryptophan, 5-hydroxytryptophan and serotonin (By similarity). {ECO:0000250}. | Tryptophan 2,3-dioxygenase {ECO:0000255|HAMAP-Rule:MF_03020} inhibitor: Nalidixic Acid, Tolmetin Tryptophan 2,3-dioxygenase {ECO:0000255|HAMAP-Rule:MF_03020} substrate: L-Tryptophan | 15.1 | ||||
| kccTA2R | Thromboxane A2 receptor | 33 | 960 | 98.42 | ND | 98.84 | 0.68 | ND | 0.7 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Bleeding disorder, platelet-type 13 (BDPLT13) [MIM:614009]: A disorder characterized by reduced platelet aggregation and a tendency to mild mucocutaneous bleeding. {ECO:0000269|PubMed:7929844}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C. Isoform 1 activates adenylyl cyclase. Isoform 2 inhibits adenylyl cyclase. {ECO:0000269|PubMed:8613548}. | Thromboxane A2 receptor antagonist: Ridogrel | 15.1 | ||
| kccTAAR1 | Trace amine-associated receptor 1 | 30 | 536 | 83.89 | ND | 89.51 | 0.32 | ND | 1.1 | Mammalian | Detected in low levels in discrete regions within the central nervous system and in several peripheral tissues. Moderately expressed in stomach. Low levels in amygdala, kidney, and lung, and small intestine. Trace amounts in cerebellum, dorsal root ganglia, hippocampus, hypothalamus, liver, medulla, pancreas, pituitary, pontine reticular formation, prostate, skeletal muscle and spleen. | Family A G protein-coupled receptor | Receptor for trace amines, including beta- phenylethylamine (b-PEA), p-tyramine (p-TYR), octopamine and tryptamine, with highest affinity for b-PEA and p-TYR. Unresponsive to classical biogenic amines, such as epinephrine and histamine and only partially activated by dopamine and serotonine. Trace amines are biogenic amines present in very low levels in mammalian tissues. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood. The signal transduced by this receptor is mediated by the G(s)-class of G-proteins which activate adenylate cyclase. {ECO:0000269|PubMed:15718104}. | Trace amine-associated receptor 1 agonist: Amphetamine, Dextroamphetamine, Methamphetamine, Propylhexedrine | 15.1 | |||
| kccTAOK1 | Serine/threonine-protein kinase TAO1 | 16 | 344 | 95.92 | ND | 91.94 | 0.21 | ND | 1.0 | Mammalian | Highly expressed in the testis, and to a lower extent also expressed in brain, placenta, colon and skeletal muscle. {ECO:0000269|PubMed:13679851, ECO:0000269|PubMed:9786855}. | Kinase | Serine/threonine-protein kinase involved in various processes such as p38/MAPK14 stress-activated MAPK cascade, DNA damage response and regulation of cytoskeleton stability. Phosphorylates MAP2K3, MAP2K6 and MARK2. Acts as an activator of the p38/MAPK14 stress-activated MAPK cascade by mediating phosphorylation and subsequent activation of the upstream MAP2K3 and MAP2K6 kinases. Involved in G-protein coupled receptor signaling to p38/MAPK14. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of MAP2K3 and MAP2K6. Acts as a regulator of cytoskeleton stability by phosphorylating 'Thr-208' of MARK2, leading to activate MARK2 kinase activity and subsequent phosphorylation and detachment of MAPT/TAU from microtubules. Also acts as a regulator of apoptosis: regulates apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation via activation of the MAPK8/JNK cascade. {ECO:0000269|PubMed:12665513, ECO:0000269|PubMed:13679851, ECO:0000269|PubMed:16407310, ECO:0000269|PubMed:17396146, ECO:0000269|PubMed:17900936}. | 15.1 | ||||
| kccTAU | Microtubule-associated protein tau | 158 | 6244 | 83.23 | ND | 84.92 | 0.14 | ND | 0.6 | Mammalian | Expressed in neurons. Isoform PNS-tau is expressed in the peripheral nervous system while the others are expressed in the central nervous system. | Note=In Alzheimer disease, the neuronal cytoskeleton in the brain is progressively disrupted and replaced by tangles of paired helical filaments (PHF) and straight filaments, mainly composed of hyperphosphorylated forms of TAU (PHF-TAU or AD P- TAU). O-GlcNAcylation is greatly reduced in Alzheimer disease brain cerebral cortex leading to an increase in TAU/MAPT phosphorylations. {ECO:0000269|PubMed:14517953}. Frontotemporal dementia (FTD) [MIM:600274]: A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons. {ECO:0000269|PubMed:10208578, ECO:0000269|PubMed:10214944, ECO:0000269|PubMed:10489057, ECO:0000269|PubMed:10553987, ECO:0000269|PubMed:10802785, ECO:0000269|PubMed:11071507, ECO:0000269|PubMed:11117541, ECO:0000269|PubMed:11585254, ECO:0000269|PubMed:11889249, ECO:0000269|PubMed:11921059, ECO:0000269|PubMed:12473774, ECO:0000269|PubMed:12509859, ECO:0000269|PubMed:15883319, ECO:0000269|PubMed:16240366, ECO:0000269|PubMed:9629852, ECO:0000269|PubMed:9641683, ECO:0000269|PubMed:9736786, ECO:0000269|PubMed:9789048, ECO:0000269|PubMed:9973279}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pick disease of the brain (PIDB) [MIM:172700]: A rare form of dementia pathologically defined by severe atrophy, neuronal loss and gliosis. It is characterized by the occurrence of tau-positive inclusions, swollen neurons (Pick cells) and argentophilic neuronal inclusions known as Pick bodies that disproportionally affect the frontal and temporal cortical regions. Clinical features include aphasia, apraxia, confusion, anomia, memory loss and personality deterioration. {ECO:0000269|PubMed:10604746, ECO:0000269|PubMed:11089577, ECO:0000269|PubMed:11117542, ECO:0000269|PubMed:11601501, ECO:0000269|PubMed:11891833}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Defects in MAPT are a cause of corticobasal degeneration (CBD). It is marked by extrapyramidal signs and apraxia and can be associated with memory loss. Neuropathologic features may overlap Alzheimer disease, progressive supranuclear palsy, and Parkinson disease. Progressive supranuclear palsy 1 (PSNP1) [MIM:601104]: Characterized by akinetic-rigid syndrome, supranuclear gaze palsy, pyramidal tract dysfunction, pseudobulbar signs and cognitive capacities deterioration. Neurofibrillary tangles and gliosis but no amyloid plaques are found in diseased brains. Most cases appear to be sporadic, with a significant association with a common haplotype including the MAPT gene and the flanking regions. Familial cases show an autosomal dominant pattern of transmission with incomplete penetrance; genetic analysis of a few cases showed the occurrence of tau mutations, including a deletion of Asn-613. {ECO:0000269|PubMed:10534245, ECO:0000269|PubMed:11220749, ECO:0000269|PubMed:12325083, ECO:0000269|PubMed:14991828, ECO:0000269|PubMed:14991829, ECO:0000269|PubMed:16157753}. Note=The disease is caused by mutations affecting the gene represented in this entry. Parkinson-dementia syndrome (PARDE) [MIM:260540]: A syndrome characterized by parkinsonism, tremor, rigidity, dementia, ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration occurs in the hippocampus, basal ganglia and brainstem nuclei. Note=The disease is caused by mutations affecting the gene represented in this entry. | Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. The C-terminus binds axonal microtubules while the N- terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both. Axonal polarity is predetermined by TAU/MAPT localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization. {ECO:0000269|PubMed:21985311}. | Microtubule-associated protein tau unknown: Docetaxel, Paclitaxel | 15.1 | |||
| kccTBA1A | Tubulin alpha-1A chain | 12 | 209 | 95.66 | ND | 94.68 | 0.44 | ND | 0.6 | Mammalian | Expressed at a high level in fetal brain. {ECO:0000269|PubMed:17584854}. | Structural protein | Lissencephaly 3 (LIS3) [MIM:611603]: A classic type lissencephaly associated with psychomotor retardation and seizures. Features include agyria or pachygyria or laminar heterotopia, severe mental retardation, motor delay, variable presence of seizures, and abnormalities of corpus callosum, hippocampus, cerebellar vermis and brainstem. {ECO:0000269|PubMed:17584854}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. | Tubulin alpha-1A chain adduct: Vinblastine Tubulin alpha-1A chain inhibitor: Albendazole, Mebendazole | 15.1 | ||
| kccTBB1 | Tubulin beta-1 chain | 5 | 69 | 94.73 | ND | 99.97 | 0.27 | ND | 0.5 | Mammalian | Hematopoietic cell-specific. Major isotype in leukocytes, where it represents 50% of all beta-tubulins. {ECO:0000269|PubMed:20191564}. | Structural protein | Macrothrombocytopenia, autosomal dominant, TUBB1-related (MAD-TUBB1) [MIM:613112]: A congenital blood disorder characterized by increased platelet size and decreased number of circulating platelets. {ECO:0000269|PubMed:18849486}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity). {ECO:0000250}. | Tubulin beta-1 chain binder: Cabazitaxel Tubulin beta-1 chain inhibitor: Colchicine, Paclitaxel, Vindesine Tubulin beta-1 chain unknown: Docetaxel | 15.1 | ||
| kccTBB2B | Tubulin beta-2B chain | 11 | 193 | 99.44 | ND | 99.56 | 0.22 | ND | 0.4 | Mammalian | High expression in brain. {ECO:0000269|PubMed:20191564}. | Structural protein | Polymicrogyria, symmetric or asymmetric (PMGYSA) [MIM:610031]: A malformation of the cortex in which the brain surface is irregular and characterized by an excessive number of small gyri with abnormal lamination. Polymicrogyria is a heterogeneous disorder, considered to be the result of postmigratory abnormal cortical organization. {ECO:0000269|PubMed:19465910}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity). TUBB2B is implicated in neuronal migration. {ECO:0000250, ECO:0000269|PubMed:19465910}. | Tubulin beta-1 chain binder: Cabazitaxel Tubulin beta-1 chain inhibitor: Colchicine, Paclitaxel, Vindesine Tubulin beta-1 chain unknown: Docetaxel | 15.1 | ||
| kccTBK1 | Serine/threonine-protein kinase TBK1 | 9 | 226 | 97.09 | ND | 94.12 | 0.45 | ND | 1.4 | Mammalian | Ubiquitous with higher expression in testis. Expressed in the ganglion cells, nerve fiber layer and microvasculature of the retina. {ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:21447600}. | Kinase | Glaucoma 1, open angle, P (GLC1P) [MIM:177700]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1P is characterized by early onset, thin central corneas and low intraocular pressure. {ECO:0000269|PubMed:21447600, ECO:0000269|PubMed:22306015}. Note=The disease may be caused by mutations affecting the gene represented in this entry. A copy number variation on chromosome 12q14 consisting of a 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been found in individuals affected by glaucoma. TBK1 is the most likely candidate for the disorder (PubMed:21447600). {ECO:0000269|PubMed:21447600}. Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (FTDALS4) [MIM:616439]: A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. {ECO:0000269|PubMed:25803835, ECO:0000269|PubMed:25943890}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser- 177', thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates and activates AKT1. Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates Borna disease virus (BDV) P protein. {ECO:0000269|PubMed:10581243, ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:11839743, ECO:0000269|PubMed:12692549, ECO:0000269|PubMed:12702806, ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:15485837, ECO:0000269|PubMed:15489227, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:21931631, ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23453972, ECO:0000269|PubMed:23746807}. | 15.1 | |||
| kccTERA | Transitional endoplasmic reticulum ATPase | 2 | 117 | 99.86 | ND | 99.97 | 0.80 | ND | 0.3 | Mammalian | Primary active transporter | Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]: An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance. {ECO:0000269|PubMed:15034582, ECO:0000269|PubMed:15732117, ECO:0000269|PubMed:16247064}. Note=The disease is caused by mutations affecting the gene represented in this entry. Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia (ALS14) [MIM:613954]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS14 may develop frontotemporal dementia. {ECO:0000269|PubMed:21145000}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1L, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1L-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage. Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation. {ECO:0000250|UniProtKB:P46462, ECO:0000269|PubMed:15456787, ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:21118995, ECO:0000269|PubMed:22020440, ECO:0000269|PubMed:22120668, ECO:0000269|PubMed:22607976, ECO:0000269|PubMed:23042605, ECO:0000269|PubMed:23042607}. | Tubulin beta-1 chain binder: Cabazitaxel Tubulin beta-1 chain inhibitor: Colchicine, Paclitaxel, Vindesine Tubulin beta-1 chain unknown: Docetaxel | 15.1 | |||
| kccTERT | Telomerase reverse transcriptase | 13 | 500 | 94.99 | ND | 95.99 | 0.39 | ND | 0.7 | Mammalian | Expressed at a high level in thymocyte subpopulations, at an intermediate level in tonsil T-lymphocytes, and at a low to undetectable level in peripheral blood T- lymphocytes. {ECO:0000269|PubMed:8676067, ECO:0000269|PubMed:9389643}. | Enzyme | Note=Activation of telomerase has been implicated in cell immortalization and cancer cell pathogenesis. Aplastic anemia (AA) [MIM:609135]: A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements. It is characterized by peripheral pancytopenia and marrow hypoplasia. {ECO:0000269|PubMed:15885610, ECO:0000269|PubMed:16627250, ECO:0000269|PubMed:16990594, ECO:0000269|PubMed:19760749}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Genetic variations in TERT are associated with coronary artery disease (CAD). Dyskeratosis congenita, autosomal dominant, 2 (DKCA2) [MIM:613989]: A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. {ECO:0000269|PubMed:15885610, ECO:0000269|PubMed:16247010}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pulmonary fibrosis, and/or bone marrow failure, telomere- related, 1 (PFBMFT1) [MIM:614742]: A disease associated with shortened telomeres. Pulmonary fibrosis is the most common manifestation. Other manifestations include aplastic anemia due to bone marrow failure, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome and acute myeloid leukemia. Phenotype, age at onset, and severity are determined by telomere length. {ECO:0000269|PubMed:15814878, ECO:0000269|PubMed:17460043, ECO:0000269|PubMed:21436073, ECO:0000269|PubMed:21483807, ECO:0000269|PubMed:22512499}. Note=The disease is caused by mutations affecting the gene represented in this entry. Dyskeratosis congenita, autosomal recessive, 4 (DKCB4) [MIM:613989]: A severe form of dyskeratosis congenita, a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. {ECO:0000269|PubMed:16332973, ECO:0000269|PubMed:17785587, ECO:0000269|PubMed:18042801}. Note=The disease is caused by mutations affecting the gene represented in this entry. Pulmonary fibrosis, idiopathic (IPF) [MIM:178500]: A lung disease characterized by shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees of inflammation and fibrosis on biopsy. In some cases, the disorder can be rapidly progressive and characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Melanoma, cutaneous malignant 9 (CMM9) [MIM:615134]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:23348503}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA- dependent extension of 3'-chromosomal termini with the 6- nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis. {ECO:0000269|PubMed:14963003, ECO:0000269|PubMed:15082768, ECO:0000269|PubMed:15857955, ECO:0000269|PubMed:17026956, ECO:0000269|PubMed:17264120, ECO:0000269|PubMed:17296728, ECO:0000269|PubMed:17548608, ECO:0000269|PubMed:19188162, ECO:0000269|PubMed:19567472, ECO:0000269|PubMed:19571879, ECO:0000269|PubMed:19777057, ECO:0000269|PubMed:9389643}. | Telomerase reverse transcriptase inhibitor: Zidovudine | 15.1 | ||
| kccTF | Tissue factor | 3 | 75 | 99.68 | ND | 99.91 | 0.88 | ND | 0.6 | Mammalian | Lung, placenta and pancreas. {ECO:0000269|PubMed:12652293}. | Surface antigen | Atherosclerosis
Coronary syndromes Disseminated intravascular coagulation Gliomas Over-expression of TF Sepsis Thrombotic disease | Initiates blood coagulation by forming a complex with circulating factor VII or VIIa. The [TF:VIIa] complex activates factors IX or X by specific limited protolysis. TF plays a role in normal hemostasis by initiating the cell-surface assembly and propagation of the coagulation protease cascade. {ECO:0000269|PubMed:12652293}. | Telomerase reverse transcriptase inhibitor: Zidovudine | 15.1 | ||
| kccTF65 | Transcription factor p65 | 5 | 96 | 85.69 | ND | 99.94 | 0.78 | ND | 0.2 | Mammalian | Transcription factor | Note=A chromosomal aberration involving C11orf95 is found in more than two-thirds of supratentorial ependymomas. Translocation with C11orf95 produces a C11orf95-RELA fusion protein. C11orf95-RELA translocations are potent oncogenes that probably transform neural stem cells by driving an aberrant NF- kappa-B transcription program (PubMed:24553141). {ECO:0000269|PubMed:24553141}. | NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681). {ECO:0000269|PubMed:10928981, ECO:0000269|PubMed:12748188, ECO:0000269|PubMed:15790681, ECO:0000269|PubMed:17000776, ECO:0000269|PubMed:17620405, ECO:0000269|PubMed:19058135, ECO:0000269|PubMed:19103749, ECO:0000269|PubMed:20547752}. | 15.1 | ||||
| kccTGFR1 | TGF-beta receptor type-1 | 17 | 642 | 99.62 | ND | 99.06 | 0.66 | ND | 0.6 | Mammalian | Found in all tissues examined, most abundant in placenta and least abundant in brain and heart. | Kinase | Loeys-Dietz syndrome 1 (LDS1) [MIM:609192]: An aortic aneurysm syndrome with widespread systemic involvement, characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. Some patients have craniosynostosis, exotropy, micrognathia and retrognathia, structural brain abnormalities, and intellectual deficit. {ECO:0000269|PubMed:15731757, ECO:0000269|PubMed:16596670, ECO:0000269|PubMed:16791849, ECO:0000269|PubMed:16928994, ECO:0000269|PubMed:19883511, ECO:0000269|PubMed:22113417}. Note=The disease is caused by mutations affecting the gene represented in this entry. TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:16791849). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS1 by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS1 by the OMIM resource. {ECO:0000269|PubMed:16791849}. Multiple self-healing squamous epithelioma (MSSE) [MIM:132800]: A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars. {ECO:0000269|PubMed:21358634}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non- canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation. {ECO:0000269|PubMed:15761148, ECO:0000269|PubMed:16754747, ECO:0000269|PubMed:18758450, ECO:0000269|PubMed:7774578, ECO:0000269|PubMed:8752209, ECO:0000269|PubMed:8980228, ECO:0000269|PubMed:9346908}. | Telomerase reverse transcriptase inhibitor: Zidovudine | 15.1 | ||
| kccTGM1 | Protein-glutamine gamma-glutamyltransferase K | 4 | 73 | 99.93 | ND | 99.91 | 0.23 | ND | 0.2 | Mammalian | Enzyme | Ichthyosis, congenital, autosomal recessive 1 (ARCI1) [MIM:242300]: A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. {ECO:0000269|PubMed:11251583, ECO:0000269|PubMed:11511296, ECO:0000269|PubMed:19890349, ECO:0000269|PubMed:7773290, ECO:0000269|PubMed:7824952, ECO:0000269|PubMed:9326318}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Responsible for cross- linking epidermal proteins during formation of the stratum corneum. | Protein-glutamine gamma-glutamyltransferase K substrate: L-Glutamine | 15.1 | |||
| kccTGM2 | Protein-glutamine gamma-glutamyltransferase 2 | 12 | 255 | 99.46 | ND | 99.89 | 0.60 | ND | 0.6 | Mammalian | Enzyme | Burns and Burn Infections
Coeliac disease Fibrosis Neurodegenerative diseases Renal fibrosis Scar Tissue | Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. | Protein-glutamine gamma-glutamyltransferase 2 substrate: L-Glutamine | 15.1 | |||
| kccTHA | Thyroid hormone receptor alpha | 25 | 389 | 98.16 | ND | 97.92 | 0.78 | ND | 0.7 | VirtualToxLab | Mammalian | Nuclear receptor | Hypothyroidism, congenital, non-goitrous, 6 (CHNG6) [MIM:614450]: A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance. {ECO:0000269|PubMed:22168587}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:19926848}. | Thyroid hormone receptor alpha agonist: Dextrothyroxine, Levothyroxine, Liothyronine, Liotrix | 15.1 | ||
| kccTHAS | Thromboxane-A synthase | 46 | 849 | 97.86 | ND | 97.10 | 0.39 | ND | 0.7 | Mammalian | Platelets, lung, kidney, spleen, macrophages and lung fibroblasts. | Cytochrome P450 | Ghosal hematodiaphyseal dysplasia (GHDD) [MIM:231095]: Rare autosomal recessive disorder characterized by increased bone density with predominant diaphyseal involvement and aregenerative corticosteroid-sensitive anemia. Aregenerative anemia is characterized by bone marrow failure, so that functional marrow cells are regenerated slowly or not at all. {ECO:0000269|PubMed:18264100}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=Thromboxane synthetase deficiency has been detected in some patients with a bleeding disorder due to platelet dysfunction. {ECO:0000269|PubMed:6101498}. | Thromboxane-A synthase antagonist: Sulfasalazine Thromboxane-A synthase inhibitor: Ridogrel | 15.1 | |||
| kccTHB | Thyroid hormone receptor beta | 23 | 1281 | 89.36 | ND | 87.25 | 0.64 | ND | 1.0 | VirtualToxLab | Mammalian | Nuclear receptor | Generalized thyroid hormone resistance (GTHR) [MIM:188570]: A disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). {ECO:0000269|PubMed:10660344, ECO:0000269|PubMed:1314846, ECO:0000269|PubMed:1324420, ECO:0000269|PubMed:1563081, ECO:0000269|PubMed:1587388, ECO:0000269|PubMed:1619012, ECO:0000269|PubMed:1653889, ECO:0000269|PubMed:1661299, ECO:0000269|PubMed:16804041, ECO:0000269|PubMed:1846005, ECO:0000269|PubMed:19268523, ECO:0000269|PubMed:2153155, ECO:0000269|PubMed:2510172, ECO:0000269|PubMed:7833659, ECO:0000269|PubMed:8175986, ECO:0000269|PubMed:8514853, ECO:0000269|PubMed:8664910, ECO:0000269|PubMed:8889584}. Note=The disease is caused by mutations affecting the gene represented in this entry. Generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:274300]: An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. Note=The disease is caused by mutations affecting the gene represented in this entry. Selective pituitary thyroid hormone resistance (PRTH) [MIM:145650]: Variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established. {ECO:0000269|PubMed:7528740, ECO:0000269|PubMed:8381821}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, ECO:0000269|PubMed:16781732, ECO:0000269|PubMed:17418816, ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:18798561, ECO:0000269|PubMed:19926848}. | Thyroid hormone receptor beta agonist: Dextrothyroxine, Levothyroxine, Liothyronine, Liotrix | 15.1 | ||
| kccTHRB | Prothrombin | 131 | 5235 | 92.87 | ND | 96.08 | 0.72 | ND | 0.8 | Mammalian | Expressed by the liver and secreted in plasma. | Protease | Factor II deficiency (FA2D) [MIM:613679]: A very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels. {ECO:0000269|PubMed:1349838, ECO:0000269|PubMed:1354985, ECO:0000269|PubMed:1421398, ECO:0000269|PubMed:14962227, ECO:0000269|PubMed:2719946, ECO:0000269|PubMed:3242619, ECO:0000269|PubMed:3567158, ECO:0000269|PubMed:3771562, ECO:0000269|PubMed:3801671, ECO:0000269|PubMed:6405779, ECO:0000269|PubMed:7792730, ECO:0000269|PubMed:7865694}. Note=The disease is caused by mutations affecting the gene represented in this entry. Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Thrombophilia due to thrombin defect (THPH1) [MIM:188050]: A multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=The disease is caused by mutations affecting the gene represented in this entry. A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Pregnancy loss, recurrent, 2 (RPRGL2) [MIM:614390]: A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions. {ECO:0000269|PubMed:11506076}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing. {ECO:0000269|PubMed:2856554}. | Prothrombin activator: Menadione Prothrombin inhibitor: Argatroban, Dabigatran etexilate, Suramin, Ximelagatran Prothrombin other/unknown: Proflavine | 15.1 | ||
| kccTIE1 | Tyrosine-protein kinase receptor Tie-1 | 1 | 68 | 91.72 | ND | 83.52 | 0.00 | ND | 1.3 | Mammalian | Specifically expressed in developing vascular endothelial cells. | Kinase | Transmembrane tyrosine-protein kinase that may modulate TEK/TIE2 activity and contribute to the regulation of angiogenesis. {ECO:0000269|PubMed:20227369}. | 15.1 | ||||
| kccTIE2 | Angiopoietin-1 receptor | 26 | 673 | 98.06 | ND | 96.01 | 0.57 | ND | 0.8 | Mammalian | Detected in umbilical vein endothelial cells. Proteolytic processing gives rise to a soluble extracellular domain that is detected in blood plasma (at protein level). Predominantly expressed in endothelial cells and their progenitors, the angioblasts. Has been directly found in placenta and lung, with a lower level in umbilical vein endothelial cells, brain and kidney. {ECO:0000269|PubMed:11806244, ECO:0000269|PubMed:8382358}. | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Mental disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Dominantly inherited venous malformations (VMCM) [MIM:600195]: An error of vascular morphogenesis characterized by dilated, serpiginous channels. {ECO:0000269|PubMed:10369874, ECO:0000269|PubMed:19888299, ECO:0000269|PubMed:8980225}. Note=The disease is caused by mutations affecting the gene represented in this entry. Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation. | Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post- natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1. {ECO:0000269|PubMed:12816861, ECO:0000269|PubMed:14665640, ECO:0000269|PubMed:15284220, ECO:0000269|PubMed:15851516, ECO:0000269|PubMed:18366015, ECO:0000269|PubMed:18425119, ECO:0000269|PubMed:18425120, ECO:0000269|PubMed:19223473, ECO:0000269|PubMed:20651738, ECO:0000269|PubMed:9204896}. | Angiopoietin-1 receptor inhibitor: Ponatinib, Regorafenib, Vandetanib Angiopoietin-1 receptor unknown: Ampicillin | 15.1 | |
| kccTKT | Transketolase | 2 | 48 | 96.96 | ND | 95.39 | 0.01 | ND | 0.5 | Mammalian | Enzyme | Thiamine deficiency | Catalyzes the transfer of a two-carbon ketol group from a ketose donor to an aldose acceptor, via a covalent intermediate with the cofactor thiamine pyrophosphate. | 15.1 | ||||
| kccTLR2 | Toll-like receptor 2 | 1 | 45 | 94.44 | ND | 99.94 | 0.69 | ND | 0.8 | Mammalian | Highly expressed in peripheral blood leukocytes, in particular in monocytes, in bone marrow, lymph node and in spleen. Also detected in lung and in fetal liver. Levels are low in other tissues. | Membrane receptor | Skin diseases | Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components. Cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. May also promote apoptosis in response to lipoproteins. Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR6. | Angiopoietin-1 receptor inhibitor: Ponatinib, Regorafenib, Vandetanib Angiopoietin-1 receptor unknown: Ampicillin | 15.1 | ||
| kccTLR4 | Toll-like receptor 4 | 5 | 109 | 91.58 | ND | 96.19 | 0.72 | ND | 0.4 | Mammalian | Highly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes, macrophages, dendritic cells and several types of T-cells. {ECO:0000269|PubMed:9237759, ECO:0000269|PubMed:9435236}. | Membrane receptor | Macular degeneration, age-related, 10 (ARMD10) [MIM:611488]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. {ECO:0000269|PubMed:10835634, ECO:0000269|PubMed:17478729, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20711192, ECO:0000269|PubMed:9237759}. | Toll-like receptor 4 inhibitor: Naloxone | 15.1 | ||
| kccTLR7 | Toll-like receptor 7 | 6 | 154 | 99.88 | ND | 99.96 | 0.69 | ND | 0.6 | Mammalian | Detected in brain, placenta, spleen, stomach, small intestine, lung and in plasmacytoid pre-dendritic cells. | Toll-like and Il-1 receptors | Basal cell carcinoma
Hepatitis C Skin cancer | Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR7 is a nucleotide-sensing TLR which is activated by single-stranded RNA. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity). {ECO:0000250}. | Toll-like receptor 7 agonist: Imiquimod Toll-like receptor 7 antagonist: Hydroxychloroquine | 15.1 | ||
| kccTLR9 | Toll-like receptor 9 | 6 | 141 | 82.06 | ND | 82.85 | 0.00 | ND | 1.0 | Mammalian | Highly expressed in spleen, lymph node, tonsil and peripheral blood leukocytes, especially in plasmacytoid pre- dendritic cells. Levels are much lower in monocytes and CD11c+ immature dendritic cells. Also detected in lung and liver. | Toll-like and Il-1 receptors | Autoimmune diseases
Colorectal Cancer Rheumatoid arthritis, unspecified Systemic Lupus Erythematosus | Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Controls lymphocyte response to Helicobacter infection. {ECO:0000269|PubMed:11564765, ECO:0000269|PubMed:17932028}. | Toll-like receptor 9 antagonist: Hydroxychloroquine Toll-like receptor 9 unknown: Chloroquine | 15.1 | ||
| kccTMIG3 | Transmembrane domain-containing protein TMIGD3 {ECO:0000305} | 55 | 2904 | 96.23 | ND | 95.67 | 0.69 | ND | 0.7 | Mammalian | 15.1 | |||||||
| kccTMPS6 | Transmembrane protease serine 6 | 1 | 52 | 99.99 | ND | 99.98 | 0.77 | ND | 0.3 | Mammalian | Liver specific. {ECO:0000269|PubMed:12149247}. | Protease | Iron-refractory iron deficiency anemia (IRIDA) [MIM:206200]: Key features include congenital hypochromic microcytic anemia, very low mean corpuscular erythrocyte volume, low transferrin saturation, abnormal iron absorption characterized by no hematologic improvement following treatment with oral iron, and abnormal iron utilization characterized by a sluggish, incomplete response to parenteral iron. {ECO:0000269|PubMed:18408718, ECO:0000269|PubMed:18603562, ECO:0000269|PubMed:19357398, ECO:0000269|PubMed:19592582, ECO:0000269|PubMed:19708871, ECO:0000269|PubMed:19747362, ECO:0000269|PubMed:20232450, ECO:0000269|PubMed:20704562, ECO:0000269|PubMed:21618415, ECO:0000269|PubMed:22581667, ECO:0000269|PubMed:25156943, ECO:0000269|PubMed:25588876}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations leading to abrogation of TMPRSS6 activity are associated with IRIDA due to elevated levels of hepcidin, a negative regulator of plasma iron pool (PubMed:20232450). {ECO:0000269|PubMed:20232450}. | Serine protease which hydrolyzes a range of proteins including type I collagen, fibronectin and fibrinogen. Can also activate urokinase-type plasminogen activator with low efficiency. May play a specialized role in matrix remodeling processes in liver. Through the cleavage of HFE2, a regulator of the expression of the iron absorption-regulating hormone hepicidin/HAMP, plays a role in iron homeostasis. {ECO:0000269|PubMed:12149247, ECO:0000269|PubMed:18408718, ECO:0000303|PubMed:25156943}. | 15.1 | |||
| kccTNFA | Tumor necrosis factor | 13 | 258 | 81.88 | ND | 91.33 | 0.59 | ND | 0.8 | Mammalian | Secreted protein | Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). {ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918). {ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:22517918, ECO:0000269|PubMed:23396208}. The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. {ECO:0000269|PubMed:16829952}. | Tumor necrosis factor antagonist: Epinephrine Tumor necrosis factor inhibitor: Amrinone, Pomalidomide, Thalidomide Tumor necrosis factor other/unknown: Clenbuterol, Pranlukast Tumor necrosis factor unknown: Chloroquine, Glucosamine, Pseudoephedrine | 15.1 | |||
| kccTNKS1 | Tankyrase-1 | 11 | 130 | 98.56 | ND | 94.51 | 0.45 | ND | 0.9 | Mammalian | Ubiquitous; highest levels in testis. | Enzyme | Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1. Stimulates 26S proteasome activity. {ECO:0000269|PubMed:10988299, ECO:0000269|PubMed:11739745, ECO:0000269|PubMed:16076287, ECO:0000269|PubMed:19759537, ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:22864114, ECO:0000269|PubMed:23622245}. | 15.1 | ||||
| kccTNKS2 | Tankyrase-2 | 10 | 147 | 98.16 | ND | 98.04 | 0.07 | ND | 1.6 | Mammalian | Highly expressed in placenta, skeletal muscle, liver, brain, kidney, heart, thymus, spinal cord, lung, peripheral blood leukocytes, pancreas, lymph nodes, spleen, prostate, testis, ovary, small intestine, colon, mammary gland, breast and breast carcinoma, and in common-type meningioma. Highly expressed in fetal liver, heart and brain. | Enzyme | Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP- ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. Stimulates 26S proteasome activity. {ECO:0000269|PubMed:11739745, ECO:0000269|PubMed:11802774, ECO:0000269|PubMed:19759537, ECO:0000269|PubMed:21478859, ECO:0000269|PubMed:23622245}. | 15.1 | ||||
| kccTNR1A | Tumor necrosis factor receptor superfamily member 1A | 3 | 95 | 99.95 | ND | 99.94 | 0.35 | ND | 0.3 | Mammalian | Membrane receptor | Familial hibernian fever (FHF) [MIM:142680]: A hereditary periodic fever syndrome characterized by recurrent fever, abdominal pain, localized tender skin lesions and myalgia. Reactive amyloidosis is the main complication and occurs in 25% of cases. {ECO:0000269|PubMed:10199409, ECO:0000269|PubMed:10902757, ECO:0000269|PubMed:11443543, ECO:0000269|PubMed:13130484, ECO:0000269|PubMed:14610673}. Note=The disease is caused by mutations affecting the gene represented in this entry. Multiple sclerosis 5 (MS5) [MIM:614810]: A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheath, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. {ECO:0000269|PubMed:22801493}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. An intronic mutation affecting alternative splicing and skipping of exon 6 directs increased expression of isoform 4 a transcript encoding a C-terminally truncated protein which is secreted and may function as a TNF antagonist. | Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate- specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase. | Tumor necrosis factor antagonist: Epinephrine Tumor necrosis factor inhibitor: Amrinone, Pomalidomide, Thalidomide Tumor necrosis factor other/unknown: Clenbuterol, Pranlukast Tumor necrosis factor unknown: Chloroquine, Glucosamine, Pseudoephedrine | 15.1 | |||
| kccTOP1 | DNA topoisomerase 1 | 4 | 317 | 97.48 | ND | 99.81 | 0.69 | ND | 0.5 | Mammalian | Endothelial cells. {ECO:0000269|PubMed:19168442}. | Alopecia Anaemia Stomatitis | Isomerase | Note=A chromosomal aberration involving TOP1 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with NUP98. | Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component ARNTL/BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the ARNTL/BMAL1 promoter. {ECO:0000250|UniProtKB:Q13472, ECO:0000269|PubMed:14594810, ECO:0000269|PubMed:16033260, ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:22904072, ECO:0000269|PubMed:2833744}. | DNA topoisomerase 1 inhibitor: Irinotecan, Lucanthone, Sodium stibogluconate, Topotecan | 15.1 | |
| kccTOP2A | DNA topoisomerase 2-alpha | 6 | 157 | 85.82 | ND | 91.56 | 0.27 | ND | 0.6 | Mammalian | Isomerase | Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity). {ECO:0000250|UniProtKB:Q01320, ECO:0000269|PubMed:18790802, ECO:0000269|PubMed:22013166, ECO:0000269|PubMed:22323612}. | DNA topoisomerase 2-alpha inhibitor: Amsacrine, Ciprofloxacin, Daunorubicin, Dexrazoxane, Doxorubicin, Enoxacin, Epirubicin, Etoposide, Finafloxacin, Idarubicin, Levofloxacin, Lomefloxacin, Lucanthone, Mitoxantrone, Moxifloxacin, Norfloxacin, Ofloxacin, Pefloxacin, Podofilox, Sparfloxacin, Teniposide, Trovafloxacin, Valrubicin DNA topoisomerase 2-alpha unknown: Dactinomycin | 15.1 | ||||
| kccTOP2B | DNA topoisomerase 2-beta | 2 | 47 | 99.77 | ND | 99.94 | 0.83 | ND | 0.3 | Mammalian | Alopecia Anaemia Bone marrow failure Haemorrhagic diathesis Mucosal inflammation Stomatitis | Isomerase | Cancer, unspecific | Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. {ECO:0000269|PubMed:10684600}. | DNA topoisomerase 2-beta inhibitor: Daunorubicin, Etoposide DNA topoisomerase 2-beta unknown: Dactinomycin, Dexrazoxane | 15.1 | ||
| kccTOPK | Lymphokine-activated killer T-cell-originated protein kinase | 4 | 96 | 93.50 | ND | 94.50 | 0.07 | ND | 1.4 | Mammalian | Expressed in the testis and placenta. In the testis, restrictedly expressed in outer cell layer of seminiferous tubules. {ECO:0000269|PubMed:10781613, ECO:0000269|PubMed:11378444}. | Kinase | Phosphorylates MAP kinase p38. Seems to be active only in mitosis. May also play a role in the activation of lymphoid cells. When phosphorylated, forms a complex with TP53, leading to TP53 destabilization and attenuation of G2/M checkpoint during doxorubicin-induced DNA damage. {ECO:0000269|PubMed:10781613, ECO:0000269|PubMed:17482142}. | 15.1 | ||||
| kccTPA | Tissue-type plasminogen activator | 19 | 425 | 98.14 | ND | 96.67 | 0.51 | ND | 0.6 | Mammalian | Synthesized in numerous tissues (including tumors) and secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, and milk. | Protease | Note=Increased activity of TPA results in increased fibrinolysis of fibrin blood clots that is associated with excessive bleeding. Defective release of TPA results in hypofibrinolysis that can lead to thrombosis or embolism. | Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation, in cell migration and many other physiopathological events. Plays a direct role in facilitating neuronal migration. | Tissue-type plasminogen activator antagonist: Aminocaproic Acid Tissue-type plasminogen activator negative modulator: Ibuprofen Tissue-type plasminogen activator other/unknown: Iloprost | 15.1 | ||
| kccTPH1 | Tryptophan 5-hydroxylase 1 | 3 | 49 | 100.00 | ND | 100.00 | 0.75 | ND | 0.3 | Mammalian | Isoform 2 seems to be less widely expressed than isoform 1. | Enzyme | Tryptophan 5-hydroxylase 1 cofactor: Tetrahydrobiopterin Tryptophan 5-hydroxylase 1 substrate: L-Tryptophan | 15.1 | ||||
| kccTPOR | Thrombopoietin receptor | 13 | 232 | 99.83 | ND | 99.89 | 0.28 | ND | 0.6 | Mammalian | Expressed at a low level in a large number of cells of hematopoietic origin. Isoform 1 and isoform 2 are always found to be coexpressed. | Membrane receptor | Congenital amegakaryocytic thrombocytopenia (CAMT) [MIM:604498]: Disease characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies. {ECO:0000269|PubMed:16470591}. Note=The disease is caused by mutations affecting the gene represented in this entry. Thrombocythemia 2 (THCYT2) [MIM:601977]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes. {ECO:0000269|PubMed:14764528, ECO:0000269|PubMed:23441089, ECO:0000269|PubMed:25538044}. Note=The disease is caused by mutations affecting the gene represented in this entry. Myelofibrosis with myeloid metaplasia (MMM) [MIM:254450]: A chronic myeloproliferative disorder characterized by replacement of the bone marrow by fibrous tissue, extramedullary hematopoiesis, anemia, leukoerythroblastosis and hepatosplenomegaly. {ECO:0000269|PubMed:16834459, ECO:0000269|PubMed:16868251}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for thrombopoietin. May represent a regulatory molecule specific for TPO-R-dependent immune responses. | Thrombopoietin receptor agonist: Eltrombopag | 15.1 | ||
| kccTPP2 | Tripeptidyl-peptidase 2 | 2 | 79 | 99.87 | ND | 99.92 | 0.47 | ND | 0.9 | Mammalian | Protease | Eating disorders
Obesity Psychiatric illness | Component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. May be able to complement the 26S proteasome function to some extent under conditions in which the latter is inhibited. Stimulates adipogenesis (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccTRAP1 | Heat shock protein 75 kDa, mitochondrial | 2 | 41 | 95.45 | ND | 99.45 | 0.14 | ND | 0.7 | Mammalian | Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung, placenta and bladder. Expression is higly reduced in bladder cancer and renal cell carcinoma specimens compared to healthy tissues, but it is increased in other type of tumors. {ECO:0000269|PubMed:23564345}. | Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, most likely through stabilization of mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA. {ECO:0000269|PubMed:23525905, ECO:0000269|PubMed:23564345, ECO:0000269|PubMed:23747254}. | 15.1 | |||||
| kccTRPA1 | Transient receptor potential cation channel subfamily A member 1 | 21 | 420 | 87.31 | ND | 97.23 | 0.71 | ND | 0.7 | Mammalian | Expressed at very low level. Expressed at very low level in human fibroblasts and at a moderate level in liposarcoma cells. {ECO:0000269|PubMed:10066796}. | Voltage-gated ion channel | Episodic pain syndrome, familial, 1 (FEPS1) [MIM:615040]: An autosomal dominant neurologic disorder characterized by onset in infancy of episodic debilitating upper body pain triggered by fasting, cold, and physical stress. The period of intense pain is accompanied by breathing difficulties, tachycardia, sweating, generalized pallor, peribuccal cyanosis, and stiffness of the abdominal wall. Affected individuals do not manifest altered pain sensitivity outside the episodes. {ECO:0000269|PubMed:20547126}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as a ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity). {ECO:0000250|UniProtKB:Q8BLA8, ECO:0000269|PubMed:20547126, ECO:0000269|PubMed:25389312, ECO:0000269|PubMed:25855297}. | Transient receptor potential cation channel subfamily A member 1 inducer: Menthol | 15.1 | ||
| kccTRPC4 | Short transient receptor potential channel 4 | 79 | 1165 | 83.93 | ND | 85.58 | 0.11 | ND | 1.0 | Mammalian | Strongly expressed in placenta. Expressed at lower levels in heart, pancreas, kidney and brain. Expressed in endothelial cells. Isoform alpha was found to be the predominant isoform. Isoform beta was not found in pancreas and brain. {ECO:0000269|PubMed:19996314}. | transient receptor | Form a receptor-activated non-selective calcium permeant cation channel. Acts as a cell-cell contact-dependent endothelial calcium entry channel. Probably operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Mediates cation entry, with an enhanced permeability to barium over calcium. May also be activated by intracellular calcium store depletion. {ECO:0000269|PubMed:16144838, ECO:0000269|PubMed:19996314}. | 15.1 | ||||
| kccTRPM8 | Transient receptor potential cation channel subfamily M member 8 | 10 | 184 | 98.31 | ND | 98.54 | 0.66 | ND | 0.6 | Mammalian | Expressed in prostate. Also expressed in prostate tumors and in non-prostatic primary tumors such as colon, lung, breast and skin tumors. {ECO:0000269|PubMed:11325849, ECO:0000269|PubMed:12858355, ECO:0000269|PubMed:16174775, ECO:0000269|PubMed:22128173}. | Voltage-gated ion channel | Analgesics
Irritation Pain | Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonist menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration (PubMed:25559186). Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel. {ECO:0000269|PubMed:15306801, ECO:0000269|PubMed:16174775, ECO:0000269|PubMed:22128173, ECO:0000269|PubMed:25559186}. | Transient receptor potential cation channel subfamily M member 8 inducer: Menthol | 15.1 | ||
| kccTRPV1 | Transient receptor potential cation channel subfamily V member 1 | 66 | 1987 | 98.35 | ND | 98.56 | 0.63 | ND | 0.7 | Mammalian | Widely expressed at low levels. Expression is elevated in dorsal root ganglia. In skin, expressed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands (at protein level). {ECO:0000269|PubMed:11050376, ECO:0000269|PubMed:11243859, ECO:0000269|PubMed:14987252}. | Voltage-gated ion channel | Acute migraine
Analgesics Chronic pathological pain Osteoarthritis pain Pain, Acute or Chronic Urinary incontinence | Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Can be activated by endogenous compounds, including 12- hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis (By similarity). Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. {ECO:0000250, ECO:0000269|PubMed:11050376, ECO:0000269|PubMed:11226139, ECO:0000269|PubMed:11243859, ECO:0000269|PubMed:12077606}. | Transient receptor potential cation channel subfamily V member 1 inducer: Aspartame, Icosapent Transient receptor potential cation channel subfamily V member 1 unknown: Alpha-Linolenic Acid | 15.1 | ||
| kccTRY1 | Trypsin-1 | 77 | 1593 | 97.33 | ND | 98.36 | 0.68 | ND | 0.6 | Mammalian | Protease | Pancreatitis, hereditary (PCTT) [MIM:167800]: A disease characterized by pancreas inflammation, permanent destruction of the pancreatic parenchyma, maldigestion, and severe abdominal pain attacks. {ECO:0000269|PubMed:10204851, ECO:0000269|PubMed:10381903, ECO:0000269|PubMed:10930381, ECO:0000269|PubMed:11073545, ECO:0000269|PubMed:11788572, ECO:0000269|PubMed:11866271, ECO:0000269|PubMed:14695529, ECO:0000269|PubMed:15776435, ECO:0000269|PubMed:8841182, ECO:0000269|PubMed:9322498, ECO:0000269|PubMed:9633818}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. | Has activity against the synthetic substrates Boc-Phe- Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val- Pro-Arg-Mec. The single-chain form is more active than the two- chain form against all of these substrates. {ECO:0000269|PubMed:7945238}. | Thioredoxin reductase 1, cytoplasmic inhibitor: Arsenic trioxide Thioredoxin reductase 1, cytoplasmic unknown: Flavin adenine dinucleotide | 15.1 | |||
| kccTRY2 | Trypsin-2 | 2 | 169 | 98.48 | ND | 98.05 | 0.46 | ND | 0.5 | Mammalian | Expressed in Paneth cells, at the base of small intestinal crypts. {ECO:0000269|PubMed:12021776}. | Protease | In the ileum, may be involved in defensin processing, including DEFA5. {ECO:0000269|PubMed:12021776}. | Thioredoxin reductase 1, cytoplasmic inhibitor: Arsenic trioxide Thioredoxin reductase 1, cytoplasmic unknown: Flavin adenine dinucleotide | 15.1 | |||
| kccTRYB1 | Tryptase alpha/beta-1 | 11 | 183 | 98.14 | ND | 99.92 | 0.59 | ND | 0.8 | Mammalian | Isoform 1 and isoform 2 are expressed in lung, stomach, spleen, heart and skin; in these tissues, isoform 1 is predominant. Isoform 2 is expressed in aorta, spleen, and breast tumor, with highest levels in the endothelial cells of some blood vessels surrounding the aorta, as well as those surrounding the tumor and low levels, if any, in mast cells (at protein level). {ECO:0000269|PubMed:18854315}. | Protease | Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type. May play a role in innate immunity. Isoform 2 cleaves large substrates, such as fibronectin, more efficiently than isoform 1, but seems less efficient toward small substrates (PubMed:18854315). {ECO:0000250, ECO:0000250|UniProtKB:P21845, ECO:0000269|PubMed:18854315}. | Thioredoxin reductase 1, cytoplasmic inhibitor: Arsenic trioxide Thioredoxin reductase 1, cytoplasmic unknown: Flavin adenine dinucleotide | 15.1 | |||
| kccTS101 | Tumor susceptibility gene 101 protein | 4 | 207 | 86.34 | ND | 82.66 | 0.00 | ND | 0.8 | Mammalian | Heart, brain, placenta, lung, liver, skeletal, kidney and pancreas. | Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Binds to ubiquitinated cargo proteins and is required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs). Mediates the association between the ESCRT-0 and ESCRT-I complex. Required for completion of cytokinesis; the function requires CEP55. May be involved in cell growth and differentiation. Acts as a negative growth regulator. Involved in the budding of many viruses through an interaction with viral proteins that contain a late-budding motif P-[ST]-A-P. This interaction is essential for viral particle budding of numerous retroviruses. {ECO:0000269|PubMed:11916981, ECO:0000269|PubMed:17556548, ECO:0000269|PubMed:17853893, ECO:0000269|PubMed:21070952, ECO:0000269|PubMed:21757351}. | 15.1 | |||||
| kccTSPO | Translocator protein 2 | 21 | 718 | 99.13 | ND | 98.86 | 0.57 | ND | 0.7 | Mammalian | TspO/BZRP | Binds cholesterol and mediates its redistribution during erythropoiesis which may play a role in erythrocyte maturation. {ECO:0000269|PubMed:19729679}. | 15.1 | |||||
| kccTSSK1 | Testis-specific serine/threonine-protein kinase 1 | 4 | 116 | 88.10 | ND | 89.22 | 0.01 | ND | 1.0 | Mammalian | Testis-specific. Present in sperm (at protein level). {ECO:0000269|PubMed:15044604, ECO:0000269|PubMed:20729278}. | Kinase | Testis-specific serine/threonine-protein kinase required during spermatid development. Phosphorylates 'Ser-288' of TSKS. Involved in the late stages of spermatogenesis, during the reconstruction of the cytoplasm. During spermatogenesis, required for the transformation of a ring-shaped structure around the base of the flagellum originating from the chromatoid body. {ECO:0000269|PubMed:15733851, ECO:0000269|PubMed:19530700}. | 15.1 | ||||
| kccTTHY | Transthyretin | 7 | 82 | 82.20 | ND | 82.05 | 0.04 | ND | 0.3 | Mammalian | Detected in serum and cerebrospinal fluid (at protein level). Highly expressed in choroid plexus epithelial cells. Detected in retina pigment epithelium and liver. {ECO:0000269|PubMed:10328977, ECO:0000269|PubMed:3714052}. | Amyloidosis, transthyretin-related (AMYL-TTR) [MIM:105210]: A hereditary generalized amyloidosis due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor. {ECO:0000269|PubMed:10036587, ECO:0000269|PubMed:10071047, ECO:0000269|PubMed:10211412, ECO:0000269|PubMed:10436378, ECO:0000269|PubMed:10439117, ECO:0000269|PubMed:10611950, ECO:0000269|PubMed:10627135, ECO:0000269|PubMed:10694917, ECO:0000269|PubMed:10842705, ECO:0000269|PubMed:10842718, ECO:0000269|PubMed:10882995, ECO:0000269|PubMed:11445644, ECO:0000269|PubMed:11866053, ECO:0000269|PubMed:12050338, ECO:0000269|PubMed:12557757, ECO:0000269|PubMed:12771253, ECO:0000269|PubMed:1301926, ECO:0000269|PubMed:1351039, ECO:0000269|PubMed:1362222, ECO:0000269|PubMed:1436517, ECO:0000269|PubMed:1517749, ECO:0000269|PubMed:1520326, ECO:0000269|PubMed:1520336, ECO:0000269|PubMed:15214015, ECO:0000269|PubMed:15217993, ECO:0000269|PubMed:1544214, ECO:0000269|PubMed:15478468, ECO:0000269|PubMed:1570831, ECO:0000269|PubMed:1656975, ECO:0000269|PubMed:1734866, ECO:0000269|PubMed:17453626, ECO:0000269|PubMed:17503405, ECO:0000269|PubMed:17577687, ECO:0000269|PubMed:17635579, ECO:0000269|PubMed:1932142, ECO:0000269|PubMed:2046936, ECO:0000269|PubMed:2161654, ECO:0000269|PubMed:23317988, ECO:0000269|PubMed:2363717, ECO:0000269|PubMed:2891727, ECO:0000269|PubMed:3022108, ECO:0000269|PubMed:3135807, ECO:0000269|PubMed:3722385, ECO:0000269|PubMed:3818577, ECO:0000269|PubMed:6487335, ECO:0000269|PubMed:6583672, ECO:0000269|PubMed:6651852, ECO:0000269|PubMed:7655883, ECO:0000269|PubMed:7850982, ECO:0000269|PubMed:7910950, ECO:0000269|PubMed:7914929, ECO:0000269|PubMed:7923855, ECO:0000269|PubMed:8019560, ECO:0000269|PubMed:8038017, ECO:0000269|PubMed:8081397, ECO:0000269|PubMed:8095302, ECO:0000269|PubMed:8133316, ECO:0000269|PubMed:8257997, ECO:0000269|PubMed:8352764, ECO:0000269|PubMed:8579098, ECO:0000269|PubMed:8990019, ECO:0000269|PubMed:9066351, ECO:0000269|PubMed:9605286, ECO:0000269|Ref.90}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hyperthyroxinemia, dystransthyretinemic (DTTRH) [MIM:145680]: A condition characterized by elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities. {ECO:0000269|PubMed:1979335}. Note=The disease is caused by mutations affecting the gene represented in this entry. Carpal tunnel syndrome 1 (CTS1) [MIM:115430]: A condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis. {ECO:0000269|PubMed:8309582}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain. {ECO:0000269|PubMed:3714052}. | Transthyretin unknown: Diclofenac, Diethylstilbestrol, Diflunisal, Dimethyl sulfoxide, Levothyroxine, Liothyronine, Liotrix | 15.1 | |||
| kccTTK | Dual specificity protein kinase TTK | 8 | 189 | 97.72 | ND | 98.30 | 0.67 | ND | 0.8 | Mammalian | Present in rapidly proliferating cell lines. | Kinase | Cancer, unspecific | Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint. {ECO:0000269|PubMed:18243099}. | Transthyretin unknown: Diclofenac, Diethylstilbestrol, Diflunisal, Dimethyl sulfoxide, Levothyroxine, Liothyronine, Liotrix | 15.1 | ||
| kccTXK | Tyrosine-protein kinase TXK | 2 | 81 | 94.70 | ND | 88.36 | 0.06 | ND | 1.2 | Mammalian | Expressed in T-cells and some myeloid cell lines. Expressed in Th1/Th0 cells with IFN-gamma-producing potential. {ECO:0000269|PubMed:10523612, ECO:0000269|PubMed:7951233}. | Kinase | Non-receptor tyrosine kinase that plays a redundant role with ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T- cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of TXK to the cell membrane, where it is phosphorylated at Tyr-420. Phosphorylation leads to TXK full activation. Contributes also to signaling from many receptors and participates in multiple downstream pathways, including regulation of the actin cytoskeleton. Like ITK, can phosphorylate PLCG1, leading to its localization in lipid rafts and activation, followed by subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. With PARP1 and EEF1A1, TXK forms a complex that acts as a T-helper 1 (Th1) cell- specific transcription factor and binds the promoter of IFNG to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Phosphorylates both PARP1 and EEF1A1. Phosphorylates also key sites in LCP2 leading to the up-regulation of Th1 preferred cytokine IL-2. Phosphorylates 'Tyr- 201' of CTLA4 which leads to the association of PI-3 kinase with the CTLA4 receptor. {ECO:0000269|PubMed:10523612, ECO:0000269|PubMed:11564877, ECO:0000269|PubMed:11859127, ECO:0000269|PubMed:17177976, ECO:0000269|PubMed:9813138}. | 15.1 | ||||
| kccTYDP1 | Tyrosyl-DNA phosphodiesterase 1 | 6 | 878 | 81.03 | ND | 83.33 | 0.03 | ND | 0.8 | Mammalian | Ubiquitously expressed. Similar expression throughout the central nervous system (whole brain, amygdala, caudate nucleus, cerebellum, cerebral cortex, frontal lobe, hippocampus, medulla oblongata, occipital lobe, putamen, substantia nigra, temporal lobe, thalamus, nucleus accumbens and spinal cord) and increased expression in testis and thymus. {ECO:0000269|PubMed:12244316, ECO:0000269|PubMed:17948061}. | Enzyme | Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy (SCAN1) [MIM:607250]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAN1 is an autosomal recessive cerebellar ataxia (ARCA) associated with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus and steppage gait as seen in Charcot-Marie-Tooth neuropathy. All affected individuals have normal intelligence. {ECO:0000269|PubMed:12244316}. Note=The disease is caused by mutations affecting the gene represented in this entry. | DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate. {ECO:0000269|PubMed:12023295, ECO:0000269|PubMed:15111055, ECO:0000269|PubMed:15811850, ECO:0000269|PubMed:16141202, ECO:0000269|PubMed:22822062}. | 15.1 | |||
| kccTYDP2 | Tyrosyl-DNA phosphodiesterase 2 | 2 | 68 | 96.19 | ND | 95.44 | 0.76 | ND | 0.4 | Mammalian | Widely expressed. {ECO:0000269|PubMed:10764746}. | Enzyme | DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'- phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'- tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'- tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl- RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF- beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non- canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress. {ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:21030584, ECO:0000269|PubMed:21921940, ECO:0000269|PubMed:21980489, ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062, ECO:0000269|PubMed:22908287}. | 15.1 | ||||
| kccTYK2 | Non-receptor tyrosine-protein kinase TYK2 | 13 | 376 | 97.38 | ND | 93.69 | 0.23 | ND | 1.3 | Mammalian | Observed in all cell lines analyzed. Expressed in a variety of lymphoid and non-lymphoid cell lines. {ECO:0000269|PubMed:2156206}. | Kinase | Immunodeficiency 35 (IMD35) [MIM:611521]: A primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE. {ECO:0000269|PubMed:17088085}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. {ECO:0000269|PubMed:7526154}. | Transthyretin unknown: Diclofenac, Diethylstilbestrol, Diflunisal, Dimethyl sulfoxide, Levothyroxine, Liothyronine, Liotrix | 15.1 | ||
| kccTYPH | Thymidine phosphorylase | 7 | 144 | 98.60 | ND | 96.95 | 0.61 | ND | 0.5 | Mammalian | Enzyme | Mitochondrial DNA depletion syndrome 1, MNGIE type (MTDPS1) [MIM:603041]: A multisystem disease associated with mitochondrial dysfunction. It is clinically characterized by onset between the second and fifth decades of life, ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), diffuse leukoencephalopathy, cachexia, peripheral neuropathy, and myopathy. {ECO:0000269|PubMed:12177387, ECO:0000269|PubMed:9924029}. Note=The disease is caused by mutations affecting the gene represented in this entry. | May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro. {ECO:0000269|PubMed:1590793}. Catalyzes the reversible phosphorolysis of thymidine. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis. {ECO:0000269|PubMed:1590793}. | Thymidine phosphorylase inhibitor: Cidofovir Thymidine phosphorylase substrate: Capecitabine, Floxuridine, Fluorouracil, Trifluridine | 15.1 | |||
| kccTYRO | Tyrosinase | 2 | 54 | 80.39 | ND | 88.46 | 0.67 | ND | 0.6 | Mammalian | Oxidoreductase | Albinism, oculocutaneous, 1A (OCA1A) [MIM:203100]: An autosomal recessive disorder in which the biosynthesis of melanin pigment is absent in skin, hair, and eyes. It is characterized by complete lack of tyrosinase activity due to production of an inactive enzyme. Patients present with a life-long absence of melanin pigment after birth, and manifest increased sensitivity to ultraviolet radiation with predisposition to skin cancer. Visual anomalies include decreased acuity, nystagmus, strabismus and photophobia. {ECO:0000269|PubMed:10571953, ECO:0000269|PubMed:10671066, ECO:0000269|PubMed:10987646, ECO:0000269|PubMed:11295837, ECO:0000269|PubMed:11858948, ECO:0000269|PubMed:1487241, ECO:0000269|PubMed:15146472, ECO:0000269|PubMed:1642278, ECO:0000269|PubMed:1899321, ECO:0000269|PubMed:1943686, ECO:0000269|PubMed:1970634, ECO:0000269|PubMed:22981120, ECO:0000269|PubMed:2342539, ECO:0000269|PubMed:23504663, ECO:0000269|PubMed:24934919, ECO:0000269|PubMed:7902671, ECO:0000269|PubMed:7955413, ECO:0000269|PubMed:8128955, ECO:0000269|PubMed:8644824, ECO:0000269|PubMed:9259202}. Note=The disease is caused by mutations affecting the gene represented in this entry. Albinism, oculocutaneous, 1B (OCA1B) [MIM:606952]: An autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. It is characterized by partial lack of tyrosinase activity. Patients have white hair at birth that rapidly turns yellow or blond. They manifest the development of minimal-to-moderate amounts of cutaneous and ocular pigment. Some patients may have with white hair in the warmer areas (scalp and axilla) and progressively darker hair in the cooler areas (extremities). This variant phenotype is due to a loss of tyrosinase activity above 35-37 degrees C. {ECO:0000269|PubMed:10987646, ECO:0000269|PubMed:1900309, ECO:0000269|PubMed:1903591, ECO:0000269|PubMed:8128955}. Note=The disease is caused by mutations affecting the gene represented in this entry. | This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds. Catalyzes the rate-limiting conversions of tyrosine to DOPA, DOPA to DOPA-quinone and possibly 5,6-dihydroxyindole to indole-5,6 quinone. | Tyrosinase inhibitor: Azelaic Acid, Mimosine, Monobenzone | 15.1 | |||
| kccTYRO3 | Tyrosine-protein kinase receptor TYRO3 | 9 | 397 | 96.10 | ND | 86.85 | 0.34 | ND | 1.1 | Mammalian | Abundant in the brain and lower levels in other tissues. | Kinase | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:20546121}. (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:25277499, PubMed:22156524, PubMed:22673088). Acts as a receptor for ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:17005688). {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:22156524, ECO:0000269|PubMed:22673088, ECO:0000269|PubMed:25277499}. | 15.1 | ||||
| kccTYSY | Thymidylate synthase | 27 | 785 | 97.86 | ND | 98.04 | 0.61 | ND | 0.8 | Mammalian | Transferase | Breast cancer
Colorectal cancer Fungal diseases Gastric cancer Hepatocellular carcinoma Malaria Ovarian cancer Pancreatic cancer Proliferative diseases | Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. {ECO:0000269|PubMed:21876188}. | Thymidylate synthase inhibitor: Capecitabine, Gemcitabine, Leucovorin, Pemetrexed, Pralatrexate, Raltitrexed, Trifluridine, Trimethoprim Thymidylate synthase other/unknown: Fluorouracil Thymidylate synthase substrate: Fluorouracil, Methotrexate Thymidylate synthase unknown: Floxuridine | 15.1 | |||
| kccUBE2N | Ubiquitin-conjugating enzyme E2 N | 12 | 261 | 84.11 | ND | 84.45 | 0.02 | ND | 0.9 | Mammalian | Enzyme | The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. {ECO:0000269|PubMed:10089880, ECO:0000269|PubMed:14562038, ECO:0000269|PubMed:19269966, ECO:0000269|PubMed:20061386, ECO:0000269|PubMed:21512573}. | 15.1 | |||||
| kccUD2B7 | UDP-glucuronosyltransferase 2B7 | 1 | 69 | 99.13 | ND | 99.78 | 0.36 | ND | 0.7 | Mammalian | Enzyme | UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. {ECO:0000269|PubMed:17442341}. Its unique specificity for 3,4-catechol estrogens and estriol suggests it may play an important role in regulating the level and activity of these potent and active estrogen metabolites. Is also active with androsterone, hyodeoxycholic acid and tetrachlorocatechol (in vitro). {ECO:0000269|PubMed:17442341}. | UDP-glucuronosyltransferase 2B7 inhibitor: Chenodeoxycholic acid, Flunitrazepam UDP-glucuronosyltransferase 2B7 substrate: Atorvastatin, Carbamazepine, Codeine, Dapagliflozin, Diclofenac, Epirubicin, Etodolac, Ezetimibe, Flurbiprofen, Fluvastatin, Ibuprofen, Losartan, Lovastatin, Mitiglinide, Morphine, Mycophenolate mofetil, Mycophenolic acid, Naproxen, Oxazepam, Pitavastatin, Silodosin, Simvastatin, Suprofen, Tapentadol, Valproic Acid, Zidovudine UDP-glucuronosyltransferase 2B7 substrate;inhibitor: Indomethacin UDP-glucuronosyltransferase 2B7 unknown: Dabigatran etexilate | 15.1 | ||||
| kccUFO | Tyrosine-protein kinase receptor UFO | 18 | 372 | 96.16 | ND | 93.87 | 0.24 | ND | 1.4 | Mammalian | Highly expressed in metastatic colon tumors. Expressed in primary colon tumors. Weakly expressed in normal colon tissue. {ECO:0000269|PubMed:7896447}. | Kinase | Note=AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer. | Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, ALX binds and induces tyrosine phosphorylation of PI3- kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TNS2. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. {ECO:0000269|PubMed:10403904, ECO:0000269|PubMed:11484958, ECO:0000269|PubMed:12364394, ECO:0000269|PubMed:12490074, ECO:0000269|PubMed:15507525, ECO:0000269|PubMed:15733062, ECO:0000269|PubMed:1656220, ECO:0000269|PubMed:18840707}. (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:22156524, PubMed:22673088, PubMed:25277499, PubMed:21501828). Acts as a receptor for ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope (PubMed:17005688). {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:21501828, ECO:0000269|PubMed:22156524, ECO:0000269|PubMed:22673088, ECO:0000269|PubMed:25277499}. | 15.1 | |||
| kccUPP1 | Uridine phosphorylase 1 | 3 | 46 | 99.96 | ND | 100.00 | 0.86 | ND | 0.3 | Mammalian | Enzyme | Catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1- phosphate. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis. | Uridine phosphorylase 1 substrate: Fluorouracil | 15.1 | ||||
| kccUR2R | Urotensin-2 receptor | 15 | 245 | 99.84 | ND | 99.06 | 0.59 | ND | 0.7 | Mammalian | Most abundant expression in the heart and pancreas. | Family A G protein-coupled receptor | Congestive heart failure
Myocardial infarction | High affinity receptor for urotensin-2 and urotensin-2B. The activity of this receptor is mediated by a G-protein that activate a phosphatidylinositol-calcium second messenger system. {ECO:0000269|PubMed:14550283}. | 15.1 | |||
| kccUROK | Urokinase-type plasminogen activator | 38 | 880 | 98.49 | ND | 98.96 | 0.63 | ND | 0.7 | Mammalian | Expressed in the prostate gland and prostate cancers. {ECO:0000269|PubMed:15988036}. | Protease | Quebec platelet disorder (QPD) [MIM:601709]: An autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. {ECO:0000269|PubMed:20007542}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. | Urokinase-type plasminogen activator inhibitor: Amiloride | 15.1 | ||
| kccUTS2 | Urotensin-2 | 3 | 51 | 100.00 | ND | 100.00 | 0.57 | ND | 0.3 | Mammalian | Brain specific. | urotensin-2 | Cardiorenal disease
Cardiovascular disease, unspecified | Highly potent vasoconstrictor. | 15.1 | |||
| kccV1AR | Vasopressin V1a receptor | 32 | 919 | 98.89 | ND | 98.05 | 0.72 | ND | 0.6 | Nature11159 | Mammalian | Family A G protein-coupled receptor | Congestive heart failure
Dysmenorrhea, unspecified Hypertension Raynaud's syndrome Renal diseases Vasoconstriction Water-retaining diseases | Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl- inositol-calcium second messenger system. Has been involved in social behaviors, including affiliation and attachment. {ECO:0000269|PubMed:12082568}. | Vasopressin V1a receptor agonist: Felypressin Vasopressin V1a receptor antagonist: Conivaptan, Tolvaptan Vasopressin V1a receptor stimulator: Terlipressin Vasopressin V1a receptor unknown: Desmopressin | 15.1 | ||
| kccV1BR | Vasopressin V1b receptor | 9 | 492 | 96.46 | ND | 96.63 | 0.81 | ND | 0.6 | Mammalian | Family A G protein-coupled receptor | Adrenocorticotrophic hormone-secreting tumors
Emotional diseases Stress-related disorders | Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl- inositol-calcium second messenger system. | Vasopressin V1b receptor unknown: Desmopressin, Terlipressin | 15.1 | |||
| kccV2R | Vasopressin V2 receptor | 17 | 976 | 98.96 | ND | 99.04 | 0.74 | ND | 0.7 | Nature11159 | Mammalian | Kidney. | Family A G protein-coupled receptor | Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) [MIM:300539]: Characterized by an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypoosmolarity, and natriuresis. {ECO:0000269|PubMed:15872203}. Note=The disease is caused by mutations affecting the gene represented in this entry. Diabetes insipidus, nephrogenic, X-linked (XNDI) [MIM:304800]: A disorder caused by the inability of the renal collecting ducts to absorb water in response to arginine vasopressin. Characterized by excessive water drinking (polydipsia), excessive urine excretion (polyuria), persistent hypotonic urine, and hypokalemia. {ECO:0000269|PubMed:10694923, ECO:0000269|PubMed:10770218, ECO:0000269|PubMed:11232028, ECO:0000269|PubMed:11916004, ECO:0000269|PubMed:1303257, ECO:0000269|PubMed:1303271, ECO:0000269|PubMed:1356229, ECO:0000269|PubMed:16845277, ECO:0000269|PubMed:7560098, ECO:0000269|PubMed:7833930, ECO:0000269|PubMed:7984150, ECO:0000269|PubMed:7987330, ECO:0000269|PubMed:7999078, ECO:0000269|PubMed:8037205, ECO:0000269|PubMed:8045948, ECO:0000269|PubMed:8078903, ECO:0000269|PubMed:8267567, ECO:0000269|PubMed:8479490, ECO:0000269|PubMed:8514744, ECO:0000269|PubMed:9402087, ECO:0000269|PubMed:9452109, ECO:0000269|PubMed:9711877}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption. {ECO:0000269|PubMed:19440390}. | Vasopressin V2 receptor agonist: Desmopressin, Terlipressin Vasopressin V2 receptor antagonist: Conivaptan, Tolvaptan | 15.1 | |
| kccVACHT | Vesicular acetylcholine transporter | 13 | 201 | 97.95 | ND | 97.04 | 0.32 | ND | 0.9 | Mammalian | Peripheral and central cholinergic nervous systems. {ECO:0000269|PubMed:8071310}. | Electrochemical transporter | Involved in acetylcholine transport into synaptic vesicles. {ECO:0000269|PubMed:8071310}. | 15.1 | ||||
| kccVCAM1 | Vascular cell adhesion protein 1 | 2 | 151 | 99.55 | ND | 99.38 | 0.28 | ND | 0.7 | Mammalian | Expressed on inflammed vascular endothelium, as well as on macrophage-like and dendritic cell types in both normal and inflammed tissue. | Adhesion | Not Available | Important in cell-cell recognition. Appears to function in leukocyte-endothelial cell adhesion. Interacts with integrin alpha-4/beta-1 (ITGA4/ITGB1) on leukocytes, and mediates both adhesion and signal transduction. The VCAM1/ITGA4/ITGB1 interaction may play a pathophysiologic role both in immune responses and in leukocyte emigration to sites of inflammation. | Vascular cell adhesion protein 1 inhibitor: Carvedilol Vascular cell adhesion protein 1 unknown: Ethanol | 15.1 | ||
| kccVGFR1 | Vascular endothelial growth factor receptor 1 | 50 | 1061 | 97.12 | ND | 93.22 | 0.43 | ND | 1.1 | Mammalian | Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform 2 is strongly expressed in placenta. Isoform 3 is expressed in corneal epithelial cells (at protein level). Isoform 3 is expressed in vascular smooth muscle cells (VSMC). {ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:20512933}. | Kinase | Note=Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages. Note=Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia. | Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion. {ECO:0000269|PubMed:11141500, ECO:0000269|PubMed:11312102, ECO:0000269|PubMed:11811792, ECO:0000269|PubMed:12796773, ECO:0000269|PubMed:14633857, ECO:0000269|PubMed:15735759, ECO:0000269|PubMed:16685275, ECO:0000269|PubMed:18079407, ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:18583712, ECO:0000269|PubMed:18593464, ECO:0000269|PubMed:20512933, ECO:0000269|PubMed:20551949, ECO:0000269|PubMed:21752276, ECO:0000269|PubMed:7824266, ECO:0000269|PubMed:8248162, ECO:0000269|PubMed:8605350, ECO:0000269|PubMed:9299537}. | Vascular endothelial growth factor receptor 1 Inhibitor: Lenvatinib, Nintedanib Vascular endothelial growth factor receptor 1 antagonist: Sunitinib Vascular endothelial growth factor receptor 1 inhibitor: Pazopanib, Regorafenib, Sorafenib | 15.1 | ||
| kccVGFR2 | Vascular endothelial growth factor receptor 2 | 150 | 4601 | 96.58 | ND | 96.65 | 0.62 | ND | 0.8 | Mammalian | Detected in cornea (at protein level). Widely expressed. {ECO:0000269|PubMed:19668192}. | Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia | Kinase | Hemangioma, capillary infantile (HCI) [MIM:602089]: A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. {ECO:0000269|PubMed:11807987, ECO:0000269|PubMed:18931684}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. | Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC. {ECO:0000269|PubMed:10102632, ECO:0000269|PubMed:10368301, ECO:0000269|PubMed:10600473, ECO:0000269|PubMed:11387210, ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:1417831, ECO:0000269|PubMed:15026417, ECO:0000269|PubMed:15215251, ECO:0000269|PubMed:15962004, ECO:0000269|PubMed:16966330, ECO:0000269|PubMed:17303569, ECO:0000269|PubMed:18529047, ECO:0000269|PubMed:19668192, ECO:0000269|PubMed:19834490, ECO:0000269|PubMed:20080685, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20705758, ECO:0000269|PubMed:21893193, ECO:0000269|PubMed:7929439, ECO:0000269|PubMed:9160888, ECO:0000269|PubMed:9804796, ECO:0000269|PubMed:9837777}. | Vascular endothelial growth factor receptor 2 Inhibitor: Lenvatinib, Nintedanib Vascular endothelial growth factor receptor 2 antagonist: Sorafenib Vascular endothelial growth factor receptor 2 inhibitor: Pazopanib, Ponatinib, Regorafenib Vascular endothelial growth factor receptor 2 multitarget: Sunitinib | 15.1 | |
| kccVGFR3 | Vascular endothelial growth factor receptor 3 | 34 | 529 | 95.34 | ND | 93.50 | 0.27 | ND | 1.4 | Mammalian | Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney. {ECO:0000269|PubMed:1327515, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:7675451}. | Kinase | Lymphedema, hereditary, 1A (LMPH1A) [MIM:153100]: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment. {ECO:0000269|PubMed:10835628, ECO:0000269|PubMed:10856194, ECO:0000269|PubMed:9817924}. Note=The disease is caused by mutations affecting the gene represented in this entry. Hemangioma, capillary infantile (HCI) [MIM:602089]: A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. {ECO:0000269|PubMed:11807987}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Note=Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases. | Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3- kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr- 185', and of AKT1 at 'Ser-473'. {ECO:0000269|PubMed:11532940, ECO:0000269|PubMed:15102829, ECO:0000269|PubMed:15474514, ECO:0000269|PubMed:16076871, ECO:0000269|PubMed:16452200, ECO:0000269|PubMed:17210781, ECO:0000269|PubMed:19610651, ECO:0000269|PubMed:19779139, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20431062, ECO:0000269|PubMed:20445537, ECO:0000269|PubMed:21273538, ECO:0000269|PubMed:7675451, ECO:0000269|PubMed:8700872, ECO:0000269|PubMed:9435229}. | Vascular endothelial growth factor receptor 3 Inhibitor: Lenvatinib, Nintedanib Vascular endothelial growth factor receptor 3 antagonist: Sorafenib, Sunitinib Vascular endothelial growth factor receptor 3 inhibitor: Regorafenib Vascular endothelial growth factor receptor 3 unknown: Pazopanib | 15.1 | ||
| kccVMAT2 | Synaptic vesicular amine transporter | 7 | 190 | 98.73 | ND | 99.75 | 0.54 | ND | 0.8 | Mammalian | Electrochemical transporter | Cocaine dependence
Neurodegenerative diseases | Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Requisite for vesicular amine storage prior to secretion via exocytosis. | Synaptic vesicular amine transporter binder: Norepinephrine Synaptic vesicular amine transporter inducer: Benzphetamine, Dextroamphetamine Synaptic vesicular amine transporter inhibitor: Amphetamine, Deserpidine, Ephedrine, Isometheptene, Methamphetamine, Reserpine, Tetrabenazine Synaptic vesicular amine transporter unknown: Propylhexedrine | 15.1 | |||
| kccWDR5 | WD repeat-containing protein 5 | 3 | 54 | 99.86 | ND | 93.70 | 0.30 | ND | 0.6 | Mammalian | WD repeat WDR5/wds | Contributes to histone modification. May position the N- terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation. {ECO:0000269|PubMed:16600877, ECO:0000269|PubMed:16829960, ECO:0000269|PubMed:19103755, ECO:0000269|PubMed:19556245, ECO:0000269|PubMed:20018852}. | 15.1 | |||||
| kccWEE1 | Wee1-like protein kinase | 8 | 315 | 99.34 | ND | 97.19 | 0.72 | ND | 0.5 | Mammalian | Kinase | Cancer | Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation. | Synaptic vesicular amine transporter binder: Norepinephrine Synaptic vesicular amine transporter inducer: Benzphetamine, Dextroamphetamine Synaptic vesicular amine transporter inhibitor: Amphetamine, Deserpidine, Ephedrine, Isometheptene, Methamphetamine, Reserpine, Tetrabenazine Synaptic vesicular amine transporter unknown: Propylhexedrine | 15.1 | |||
| kccWNT3 | Proto-oncogene Wnt-3 | 2 | 65 | 99.86 | ND | 99.96 | 0.59 | ND | 0.5 | Mammalian | Wnt | Tetraamelia syndrome, autosomal recessive (TETAMS) [MIM:273395]: A rare human genetic disorder characterized by complete absence of all four limbs and other anomalies such as craniofacial, nervous system, pulmonary, skeletal and urogenital defects. {ECO:0000269|PubMed:14872406}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Ligand for members of the frizzled family of seven transmembrane receptors. Wnt-3 and Wnt-3a play distinct roles in cell-cell signaling during morphogenesis of the developing neural tube (By similarity). {ECO:0000250}. | 15.1 | ||||
| kccWNT3A | Protein Wnt-3a | 10 | 226 | 82.99 | ND | 87.30 | 0.41 | ND | 1.0 | Mammalian | Moderately expressed in placenta and at low levels in adult lung, spleen, and prostate. | Wnt | Ligand for members of the frizzled family of seven transmembrane receptors. Wnt-3 and Wnt-3a play distinct roles in cell-cell signaling during morphogenesis of the developing neural tube. | 15.1 | ||||
| kccXDH | Xanthine dehydrogenase/oxidase | 11 | 447 | 94.60 | ND | 96.08 | 0.71 | ND | 0.7 | Mammalian | Detected in milk (at protein level). {ECO:0000269|Ref.12}. | Oxidoreductase | Xanthinuria 1 (XU1) [MIM:278300]: A disorder characterized by excretion of very large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. Xanthinuria 1 is due to isolated xanthine dehydrogenase deficiency. Patients can metabolize allopurinol. {ECO:0000269|PubMed:10844591, ECO:0000269|PubMed:11379872, ECO:0000269|PubMed:14551354, ECO:0000269|PubMed:9153281}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro). {ECO:0000269|PubMed:17301077}. | Xanthine dehydrogenase/oxidase conversion inhibitor: Trifluoperazine Xanthine dehydrogenase/oxidase inducer: Carboplatin, Cisplatin Xanthine dehydrogenase/oxidase inhibitor: Allopurinol, Chlorphenesin, Deferoxamine, Spermine Xanthine dehydrogenase/oxidase substrate: Allopurinol, Azathioprine, Daunorubicin, Doxorubicin, Menadione, Mercaptopurine, Nitrofural, Pyrazinamide Xanthine dehydrogenase/oxidase unknown: Carvedilol, Flavin adenine dinucleotide, L-Carnitine, Procarbazine | 15.1 | ||
| kccXIAP | E3 ubiquitin-protein ligase XIAP | 10 | 481 | 96.86 | ND | 99.22 | 0.67 | ND | 0.7 | Mammalian | Ubiquitous, except peripheral blood leukocytes. | Other cytosolic protein | Lymphoproliferative syndrome, X-linked, 2 (XLP2) [MIM:300635]: A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma. {ECO:0000269|PubMed:17080092}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta- catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program. {ECO:0000269|PubMed:11447297, ECO:0000269|PubMed:12121969, ECO:0000269|PubMed:14645242, ECO:0000269|PubMed:14685266, ECO:0000269|PubMed:17560374, ECO:0000269|PubMed:17967870, ECO:0000269|PubMed:19473982, ECO:0000269|PubMed:20154138, ECO:0000269|PubMed:21145488, ECO:0000269|PubMed:22103349, ECO:0000269|PubMed:22304967, ECO:0000269|PubMed:9230442}. | Xanthine dehydrogenase/oxidase conversion inhibitor: Trifluoperazine Xanthine dehydrogenase/oxidase inducer: Carboplatin, Cisplatin Xanthine dehydrogenase/oxidase inhibitor: Allopurinol, Chlorphenesin, Deferoxamine, Spermine Xanthine dehydrogenase/oxidase substrate: Allopurinol, Azathioprine, Daunorubicin, Doxorubicin, Menadione, Mercaptopurine, Nitrofural, Pyrazinamide Xanthine dehydrogenase/oxidase unknown: Carvedilol, Flavin adenine dinucleotide, L-Carnitine, Procarbazine | 15.1 | ||
| kccYES | Tyrosine-protein kinase Yes | 20 | 456 | 94.18 | ND | 92.08 | 0.38 | ND | 1.1 | Mammalian | Expressed in the epithelial cells of renal proximal tubules and stomach as well as hematopoietic cells in the bone marrow and spleen in the fetal tissues. In adult, expressed in epithelial cells of the renal proximal tubules and present in keratinocytes in the basal epidermal layer of epidermis. {ECO:0000269|PubMed:2021534, ECO:0000269|PubMed:2067846}. | Kinase | Philadelphia-positive leukemia | Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGRF, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin-dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis. {ECO:0000269|PubMed:11901164, ECO:0000269|PubMed:18479465, ECO:0000269|PubMed:19276087, ECO:0000269|PubMed:21566460, ECO:0000269|PubMed:21713032}. | Tyrosine-protein kinase Yes inhibitor: Dasatinib | 15.1 | ||
| kccZAP70 | Tyrosine-protein kinase ZAP-70 | 10 | 295 | 98.31 | ND | 95.71 | 0.50 | ND | 0.9 | Mammalian | Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells. {ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:16467082, ECO:0000269|PubMed:9378960}. | Kinase | Selective T-cell defect (STCD) [MIM:269840]: A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T-cells. {ECO:0000269|PubMed:11123350, ECO:0000269|PubMed:11412303, ECO:0000269|PubMed:18509675, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8202713}. Note=The disease is caused by mutations affecting the gene represented in this entry. | Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). {ECO:0000269|PubMed:11353765, ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:20135127, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8702662, ECO:0000269|PubMed:9489702}. | Tyrosine-protein kinase Yes inhibitor: Dasatinib | 15.1 | ||
| mcpCACO2 | Human Caco-2, Log permeability Apical->Basolacteral (cm/s) | 0 | 1377 | ND | ND | ND | 0.61 | 0.94 | 0.3 | ADME | ND | |||||||
| mcpCYP1A2 | Cytochrome P450 1A2 Class | 0 | 10552 | 93.80 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpCYP2C19 | Cytochrome P450 2C19 Class | 0 | 11159 | 89.98 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpCYP2C9 | Cytochrome P450 2C9 Class | 0 | 10980 | 90.51 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpCYP2D6 | Cytochrome P450 2D6 Class | 0 | 11860 | 91.57 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpCYP3A4 | Cytochrome P450 3A4 Class | 0 | 12748 | 92.40 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpHALFLIFE | Halflife (hr) | 0 | 622 | ND | ND | ND | 0.74 | 0.80 | 0.4 | ADME | ND | |||||||
| mcpHERG | hERG Class | 0 | 6544 | 91.64 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpLD50 | LD50 (mg/kg) | 0 | 4152 | ND | ND | ND | 0.74 | 0.95 | 0.4 | ADME | ND | |||||||
| mcpPAINS | PAINS Class | 0 | 6653 | 82.42 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpPAMPA | PAMPA, Log permeability (cm/s) | 0 | 2079 | ND | ND | ND | 0.69 | 0.96 | 0.5 | ADME | ND | |||||||
| mcpPGPINHIB | P-glycoprotein Inhibitor Class | 0 | 7583 | 96.36 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpPGPSUBST | P-glycoprotein Substrate Class | 0 | 6923 | 92.09 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21AHRAg | Tox21 aryl hydrocarbon receptor (AhR) Activator Class | 0 | 6876 | 88.89 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21AP1Ag | Tox21 AP-1 signaling pathway Agonist Class | 0 | 6626 | 79.63 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21ARAnt | Tox21 androgen receptor (AR) Antagonist Class | 0 | 6477 | 86.24 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21AREAg | Tox21 antioxidant response element (ARE) Agonist Class | 0 | 5558 | 78.60 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21ARMDAAnt | Tox21 androgen receptor (AR) Antagonist in MDA cell line Class | 0 | 6468 | 74.26 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21CP19A1Ant | Tox21 aromatase (CP19A1) Antagonist Class | 0 | 6168 | 82.06 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21ESR1Ag | Tox21 estrogen receptor alpha (ER-alpha) Agonist Class | 0 | 7624 | 80.61 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21ESR1Ant | Tox21 estrogen receptor alpha (ER-alpha) Antagonist Class | 0 | 6508 | 81.82 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21ESR1BG1Ant | Tox21 estrogen receptor alpha (ER-alpha) in BG1 cell line Antagonist Class | 0 | 6811 | 80.50 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21ESREAg | Tox21 endoplasmic reticulum stress response signaling (ESRE) Agonist | 0 | 6595 | 75.22 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21FXRAg | Tox21 farnesoid-X-receptor (FXR) Agonist Class | 0 | 6873 | 81.50 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21FXRAnt | Tox21 farnesoid-X-receptor (FXR) Antagonist class | 0 | 6199 | 84.63 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21GENOTOX | Tox21 genotoxicity in human embryonic kidney cells Class | 0 | 7722 | 80.25 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21GRAg | Tox21 glucocorticoid receptor (GR) Agonist Class | 0 | 7399 | 84.79 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21GRAnt | Tox21 glucocorticoid receptor (GR) Antagonist Class | 0 | 6366 | 88.98 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21HSEAg | Tox21 heat shock response signaling (HSE) Activator Class | 0 | 6444 | 71.08 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21MMPAnt | Tox21 mitochondrial membrane potential (MMP) Disruptor Class | 0 | 6048 | 89.73 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21P53Ag | Tox21 p53 signaling pathway Agonist Class | 0 | 7272 | 84.12 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21PPARDAg | Tox21 peroxisome proliferator-activated receptor delta (PPARd) Agonist | 0 | 6555 | 72.16 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21PPARGAg | Tox21 peroxisome proliferator-activated receptor gamma (PPARg) Agonist Class | 0 | 7106 | 81.10 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21PPARGAnt | Tox21 peroxisome proliferator-activated receptor gamma (PPARg) Antagonist Class | 0 | 5948 | 84.81 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21RARAnt | Tox21 retinoic acid receptor (RAR) Antagonist Class | 0 | 4936 | 80.41 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21RORGAnt | Tox21 retinoid-related orphan receptor gamma (ROR-gamma) Antagonist class | 0 | 5047 | 89.81 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21TRAnt | Tox21 thyroid receptor (TR) Antagonist Class | 0 | 5754 | 74.61 | ND | ND | ND | ND | ND | ADME | ND | |||||||
| mcpTox21VDRAnt | Tox21 vitamin D receptor (VDR) Antagonist Class | 0 | 6128 | 83.51 | ND | ND | ND | ND | ND | ADME | ND |