modelNAMENOF_TMPLCLNOF_LIGAUCClassAUCpKdAUCQ2R2pkdRMSEtagSpeciesTissueADRCategoryDiseaseFunctionDrug_Mechanismversion
dfa5HT1A5-hydroxytryptamine receptor 1A2550293.7489.67ND0.440.440.8Nature11159MammalianDetected 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 receptorPeriodic 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
dfa5HT1B5-hydroxytryptamine receptor 1B1118594.3789.71ND0.690.620.7MammalianDetected 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 receptorAnxiety 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
dfa5HT1D5-hydroxytryptamine receptor 1D1107195.5886.94ND0.730.720.8MammalianDetected 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 receptorMigraine
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
dfa5HT1E5-hydroxytryptamine receptor 1E49786.4282.41ND0.150.660.8MammalianDetected in brain. {ECO:0000269|PubMed:14744596}.Ejaculation disorder
Orthostatic hypotension
Family A G protein-coupled receptorNeurologic 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
dfa5HT1F5-hydroxytryptamine receptor 1F19199.8599.27ND0.590.040.5MammalianFamily A G protein-coupled receptorMigraine 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
dfa5HT2A5-hydroxytryptamine receptor 2A2365491.6782.43ND0.560.560.7Nature11159MammalianDetected 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 receptorAcute 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
dfa5HT2C5-hydroxytryptamine receptor 2C7253886.9483.84ND0.560.610.7Nature11159MammalianDetected 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 receptorAcute 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
dfa5HT3A5-hydroxytryptamine receptor 3A156793.9687.60ND0.790.800.6Nature11159MammalianExpressed 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 channelAlcohol 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
dfa5HT4R5-hydroxytryptamine receptor 4160496.9695.56ND0.680.610.6MammalianIsoform 5-HT4(A) is expressed in ileum, brain, and atrium, but not in the ventricle. {ECO:0000269|PubMed:15118808}.Family A G protein-coupled receptorAlzheimer'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, Prucalopride16.04
dfa5HT6R5-hydroxytryptamine receptor 62191196.0193.51ND0.650.660.6MammalianExpressed 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 receptorIrritable 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
dfa5HT7R5-hydroxytryptamine receptor 75130187.6091.63ND0.560.000.6MammalianIsoform 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 receptorMigraine
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
dfa5NTD5'-nucleotidase34498.7096.74ND0.050.690.4MammalianEnzymeCalcification 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
dfaA4Amyloid beta A4 protein423692.6690.67ND0.590.750.9MammalianExpressed 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 receptorAlzheimer 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
dfaAA1RAdenosine receptor A15550796.1391.03ND0.600.000.6Nature11159MammalianFamily A G protein-coupled receptorAnalgesics
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
dfaAA2ARAdenosine receptor A2a1463496.5086.31ND0.680.630.7Nature11159MammalianAngina pectoris
Flushing
Palpitations
Family A G protein-coupled receptorAnalgesics
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
dfaAA2BRAdenosine receptor A2b1190397.4283.22ND0.770.680.5MammalianPalpitationsFamily A G protein-coupled receptorAsthma 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
dfaAA3RAdenosine receptor A34302194.8691.51ND0.640.610.7Nature11159MammalianFamily A G protein-coupled receptorCancer, 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
dfaAAPK15'-AMP-activated protein kinase catalytic subunit alpha-1330787.0390.48ND0.280.800.6MammalianKinaseCatalytic 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
dfaAAPK25'-AMP-activated protein kinase catalytic subunit alpha-246899.8098.52ND0.710.930.5MammalianKinaseCatalytic 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
dfaABCC9ATP-binding cassette sub-family C member 924799.5899.96ND0.760.450.2MammalianPrimary active transporterCardiomyopathy, 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
dfaABCG2ATP-binding cassette sub-family G member 2135390.0282.64ND0.350.400.6MammalianHighly expressed in placenta. Low expression in small intestine, liver and colon. {ECO:0000269|PubMed:9850061, ECO:0000269|PubMed:9861027}.Anaemia
Thrombocytopenia
Primary active transporterHigh-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
dfaABL1Tyrosine-protein kinase ABL11106589.5985.84ND0.550.000.7MammalianWidely expressed.KinaseLeukemia, 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
dfaABL2Abelson tyrosine-protein kinase 258198.8997.71ND0.910.920.3MammalianWidely expressed.KinaseNon-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
dfaACACAAcetyl-CoA carboxylase 1232198.3295.68ND0.490.700.7MammalianExpressed in brain, placental, skeletal muscle, renal, pancreatic and adipose tissues; expressed at low level in pulmonary tissue; not detected in the liver.EnzymeAcetyl-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
dfaACACBAcetyl-CoA carboxylase 2430797.3499.62ND0.350.470.5MammalianWidely 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}.EnzymeObesity 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, Biotin15.11
dfaACEAngiotensin-converting enzyme1121997.8997.15ND0.330.470.7MammalianUbiquitously 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
ProteaseIschemic 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, Trandolapril15.11
dfaACE2Angiotensin-converting enzyme 215799.3696.98ND0.810.650.6MammalianExpressed 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}.ProteaseCardiovascular 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, Moexipril16.04
dfaACESAcetylcholinesterase5348492.2685.24ND0.650.000.8MammalianIsoform H is highly expressed in erythrocytes. {ECO:0000269|PubMed:2714437}.Diarrhoea
Nausea
Salivary hypersecretion
HydrolaseAlzheimer'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
dfaACH10Neuronal acetylcholine receptor subunit alpha-1015098.8299.52ND0.390.540.7Nature11159MammalianExpressed 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 channelAnalgesics
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
dfaACHA3Neuronal acetylcholine receptor subunit alpha-3213092.0792.36ND0.690.000.8MammalianLigand-gated ion channelAfter 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
dfaACHA4Neuronal acetylcholine receptor subunit alpha-4327394.2490.66ND0.660.760.9MammalianAgitation
Apnoea
Bradycardia
Bronchospasm
Death
Hypotension
Irritability
Laryngospasm
Lung disorder
Nystagmus
Respiratory depression
Respiratory disorder
Respiratory failure
Salivary hypersecretion
Shock
Ligand-gated ion channelEpilepsy, 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
dfaACHA7Neuronal acetylcholine receptor subunit alpha-75139489.9084.47ND0.650.000.7MammalianAgitation
Apnoea
Bradycardia
Bronchospasm
Irritability
Laryngospasm
Nystagmus
Respiratory depression
Respiratory disorder
Salivary hypersecretion
Shock
Ligand-gated ion channelAlzheimer'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
dfaACK1Activated CDC42 kinase 1628892.9992.32ND0.660.750.6MammalianThe 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}.KinaseNon-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 triphosphate15.11
dfaACLYATP-citrate synthase47299.0198.48ND0.670.540.4MammalianEnzymeHyperlipidemia
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
dfaACM2Muscarinic acetylcholine receptor M24167089.5386.69ND0.720.000.7Nature11159MammalianAnticholinergic 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 receptorMajor 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
dfaACM3Muscarinic acetylcholine receptor M32137292.9885.56ND0.750.670.8Nature11159MammalianAnticholinergic 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 receptorPrune 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
dfaACM4Muscarinic acetylcholine receptor M4758182.5581.79ND0.700.650.6MammalianAnticholinergic 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 receptorAnalgesics
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
dfaACM5Muscarinic acetylcholine receptor M5754182.7284.60ND0.680.560.6MammalianAnticholinergic syndrome
Constipation
Cycloplegia
Dry mouth
Dry skin
Extrapyramidal disorder
Mydriasis
Orthostatic hypotension
Tachycardia
Urinary incontinence
Urinary retention
Family A G protein-coupled receptorOpioid 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
dfaACODAcyl-CoA desaturase732497.8399.21ND0.440.510.7MammalianDetected 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}.EnzymeStearyl-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
dfaACOD1Acyl-CoA desaturase 1 {ECO:0000305}453299.2899.10ND0.340.470.6MammalianDetected 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}.EnzymeNote=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
dfaACOX1Peroxisomal acyl-coenzyme A oxidase 1151100.0099.94ND0.710.360.2MammalianWidely 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
dfaACROAcrosin18599.9299.87ND0.900.860.4MammalianProteaseAcrosin 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
dfaACV1BActivin receptor type-1B37989.8990.38ND0.560.930.3MammalianExpressed in many tissues, most strongly in kidney, pancreas, brain, lung, and liver.KinaseNote=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
dfaACVL1Serine/threonine-protein kinase receptor R357699.1696.46ND0.730.960.5MammalianKinaseTelangiectasia, 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
dfaACVR1Activin receptor type-1618892.3289.45ND0.580.760.5MammalianExpressed in normal parenchymal cells, endothelial cells, fibroblasts and tumor-derived epithelial cells.KinaseFibrodysplasia 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 triphosphate15.11
dfaADAAdenosine deaminase243793.6696.44ND0.660.720.7MammalianFound in all tissues, occurs in large amounts in T-lymphocytes and, at the time of weaning, in gastrointestinal tissues.HydrolaseSevere 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
dfaADA10Disintegrin and metalloproteinase domain-containing protein 10111299.7697.97ND0.250.540.6MammalianExpressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver. {ECO:0000269|PubMed:11511685, ECO:0000269|PubMed:9016778}.ProteaseReticulate 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
dfaADA17Disintegrin and metalloproteinase domain-containing protein 175142395.5398.85ND0.730.700.5MammalianUbiquitously 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.ProteaseInflammatory 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
dfaADA1AAlpha-1A adrenergic receptor4156593.1787.84ND0.650.680.7Nature11159MammalianExpressed 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 receptorBenign 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
dfaADA1BAlpha-1B adrenergic receptor1112692.1887.51ND0.670.560.6MammalianAnxiety
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 receptorShy-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
dfaADA1DAlpha-1D adrenergic receptor6113990.3892.80ND0.770.700.6MammalianAnxiety
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 receptorHypertension 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
dfaADA2AAlpha-2A adrenergic receptor579985.0684.50ND0.620.720.7Nature11159MammalianBradycardia
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 receptorHeart 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
dfaADA2BAlpha-2B adrenergic receptor740380.8882.34ND0.760.670.5Nature11159MammalianBradycardia
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 receptorEpilepsy, 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
dfaADA2CAlpha-2C adrenergic receptor746083.3484.22ND0.680.720.7Nature11159MammalianBradycardia
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 receptorNeuropsychiatric 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
dfaADCK3Atypical kinase ADCK3, mitochondrial {ECO:0000305}46799.9197.61ND0.620.660.2MammalianWidely expressed, with highest levels in adrenal gland, heart, pancreas, nasal mucosa, stomach, uterus and skeletal muscle. {ECO:0000269|PubMed:24270420}.EnzymeCoenzyme 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
dfaADCK4AarF domain-containing protein kinase 446680.9985.26ND0.840.900.2MammalianWidely expressed, including renal podocytes. {ECO:0000269|PubMed:24270420}.KinaseNephrotic 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
dfaADCY1Adenylate cyclase type 114899.9699.92ND0.010.480.2MammalianDetected 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}.EnzymeDeafness, 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 monophosphate16.04
dfaADCY5Adenylate cyclase type 545597.3299.21ND0.920.880.3MammalianDetected in pancreas islets (at protein level). Detected in pancreas islets. {ECO:0000269|PubMed:24740569}.EnzymeDyskinesia, 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
dfaADKAdenosine kinase343696.8995.55ND0.760.680.6MammalianWidely expressed. Highest level in placenta, liver, muscle and kidney.EnzymeHypermethioninemia 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
dfaADRB1Beta-1 adrenergic receptor4120593.6994.41ND0.680.380.6Nature11159MammalianAngina 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 receptorAnxiety 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
dfaADRB2Beta-2 adrenergic receptor3186689.8988.87ND0.610.660.8Nature11159MammalianAngina 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 receptorAnxiety 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
dfaADRB3Beta-3 adrenergic receptor1105899.2498.91ND0.580.600.7Nature11159MammalianExpressed 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 receptorCardiac 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
dfaAGTR1Type-1 angiotensin II receptor2151597.7396.67ND0.730.620.7Nature11159MammalianLiver, lung, adrenal and adrenocortical adenomas.DizzinessFamily A G protein-coupled receptorRenal 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, Valsartan16.04
dfaAGTR2Type-2 angiotensin II receptor449395.7898.63ND0.570.670.8MammalianIn 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 receptorHypertension Receptor for angiotensin II. Cooperates with MTUS1 to inhibit ERK2 activation and cell proliferation. {ECO:0000269|PubMed:15123706}.Type-2 angiotensin II receptor antagonist: Tasosartan16.04
dfaAGTRAType-1A angiotensin II receptor113099.0299.70ND0.840.730.6MammalianFamily A G protein-coupled receptorReceptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system.16.04
dfaAGTRBType-1B angiotensin II receptor131599.4299.20ND0.440.570.7MammalianReceptor for angiotensin II. Mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system.16.04
dfaAK1A1Alcohol dehydrogenase [NADP(+)]68697.8699.66ND0.790.060.3MammalianWidely 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}.EnzymeMethanol 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
dfaAK1BAAldo-keto reductase family 1 member B1036994.5581.53ND0.790.090.5MammalianFound in many tissues. Highly expressed in small intestine, colon and adrenal gland.EnzymeActs 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
dfaAK1C1Aldo-keto reductase family 1 member C1616298.0297.33ND0.870.840.4MammalianExpressed 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}.EnzymeConverts 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 acid15.11
dfaAK1C2Aldo-keto reductase family 1 member C2127098.8798.38ND0.840.710.3MammalianExpressed in fetal testes. Expressed in fetal and adult adrenal glands. {ECO:0000269|PubMed:21802064}.Enzyme46,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 acid15.11
dfaAK1C3Aldo-keto reductase family 1 member C3635990.1780.75ND0.570.660.5MammalianExpressed 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}.EnzymeCancer, 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
dfaAKT1RAC-alpha serine/threonine-protein kinase2145193.8989.19ND0.650.640.8MammalianExpressed 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}.KinaseBreast 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
dfaAKT2RAC-beta serine/threonine-protein kinase454693.7991.68ND0.640.740.6MammalianExpressed in all cell types so far analyzed.KinaseNote=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
dfaAKT3RAC-gamma serine/threonine-protein kinase135489.7790.40ND0.770.790.5MammalianIn 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.KinaseNote=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
dfaAL5APArachidonate 5-lipoxygenase-activating protein122599.7597.74ND0.670.580.7MammalianOther cytosolic proteinIschemic 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
dfaALBUSerum albumin1019486.8092.85ND0.300.710.4MammalianPlasma.Secreted proteinSerum 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
dfaALDH2Aldehyde dehydrogenase, mitochondrial36094.1993.97ND0.030.620.7MammalianOxidoreductaseAlcoholism Aldehyde dehydrogenase, mitochondrial inhibitor: Disulfiram, Nitric Oxide
Aldehyde dehydrogenase, mitochondrial substrate: Amyl Nitrite, Benzyl alcohol, Nitroglycerin
Aldehyde dehydrogenase, mitochondrial unknown: Guanidine
15.11
dfaALDOAFructose-bisphosphate aldolase A75797.1888.57ND0.050.820.4MammalianEnzymeGlycogen 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
dfaALDRAldose reductase7139396.5592.08ND0.710.700.6MammalianHighly expressed in embryonic epithelial cells (EUE) in response to osmotic stress. {ECO:0000269|PubMed:8435445}.Gastrointestinal disorderEnzymeAnalgesics
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: Sulindac15.11
dfaALKALK tyrosine kinase receptor575187.9188.01ND0.780.770.6MammalianExpressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells. {ECO:0000269|PubMed:9174053}.KinaseNote=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
dfaALKB3Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 {ECO:0000305}14199.9999.91ND0.480.420.2MammalianUbiquitous. 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}.EnzymeDioxygenase 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
dfaAMPBAminopeptidase B54495.7799.01ND0.760.630.4MammalianProteaseExopeptidase 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
dfaAMPEGlutamyl aminopeptidase14889.8493.84ND0.370.630.7MammalianExpressed by epithelial cells of the proximal tubule cells and the glomerulus of the nephron. Also found in a variety of other tissues.ProteaseHypertension 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
dfaAMPLCytosol aminopeptidase36299.1097.89ND0.320.561.3MammalianProteasePresumably involved in the processing and regular turnover of intracellular proteins. Catalyzes the removal of unsubstituted N-terminal amino acids from various peptides.16.04
dfaAMPNAminopeptidase N569295.9395.51ND0.750.770.5MammalianExpressed 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.ProteaseCoronaviruses 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
dfaAMYPPancreatic alpha-amylase351100.0099.67ND0.940.900.4MammalianHydrolaseHypoglycemia
Pancreatic disease
Pancreatic alpha-amylase inhibitor: Acarbose
Pancreatic alpha-amylase unknown: Miglitol
15.11
dfaANDRAndrogen receptor4167889.2485.30ND0.660.660.6Nature11159
VirtualToxLab
MammalianIsoform 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 receptorAndrogen 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
dfaANKK1Ankyrin repeat and protein kinase domain-containing protein 136484.7893.34ND0.480.980.4MammalianHighly expressed in brain and weakly expressed in placenta and spinal cord. {ECO:0000269|PubMed:14741327, ECO:0000269|PubMed:15146457}.Kinase16.04
dfaANM1Protein arginine N-methyltransferase 155699.2393.26ND0.260.730.4MammalianWidely expressed. {ECO:0000269|PubMed:11097842}.WriterArginine 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
dfaANM3Protein arginine N-methyltransferase 314899.89100.00ND0.480.820.4MammalianWriterMethylates (mono and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in some proteins.15.11
dfaAOC1Amiloride-sensitive amine oxidase [copper-containing]54099.0388.13ND0.620.670.4MammalianPlacenta and kidney.EnzymeCatalyzes 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: Amiloride15.11
dfaAOC3Membrane primary amine oxidase414692.0286.74ND0.560.640.7MammalianStrongly 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}.EnzymeInflammation 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, Phenelzine16.04
dfaAOFBAmine oxidase [flavin-containing] B2195194.6882.97ND0.480.660.8MammalianMania
Psychotic disorder
OxidoreductaseMajor 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
dfaAPEX1DNA-(apurinic or apyrimidinic site) lyase444684.7283.62ND0.590.690.4MammalianEnzymeOvarian 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: Lucanthone16.04
dfaARBK1Beta-adrenergic receptor kinase 148185.8988.53ND0.620.770.4MammalianExpressed in peripheral blood leukocytes. {ECO:0000269|PubMed:10085131}.KinaseCongestive 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
dfaARGI1Arginase-115499.9099.90ND0.760.430.2MammalianEnzymeArgininemia (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-Ornithine15.11
dfaARGI2Arginase-2, mitochondrial14199.9399.96ND0.510.480.5MammalianExpressed 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.EnzymeErectile 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-Ornithine16.04
dfaARY2Arylamine N-acetyltransferase 225999.6497.03ND0.360.520.3MammalianEnzymeParticipates 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
dfaASIC3Acid-sensing ion channel 324590.2782.31ND0.710.710.4MammalianExpressed 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 channelAnalgesics
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
dfaAT1A1Sodium/potassium-transporting ATPase subunit alpha-114499.8099.97ND0.550.980.7MammalianThis 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
dfaATRSerine/threonine-protein kinase ATR28896.4694.12ND0.650.740.7MammalianUbiquitous, 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}.KinaseSeckel 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
dfaATS4A disintegrin and metalloproteinase with thrombospondin motifs 4419693.6295.68ND0.670.790.8MammalianExpressed 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}.ProteaseOsteoarthritis 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: Tinzaparin15.11
dfaATS5A disintegrin and metalloproteinase with thrombospondin motifs 5637893.2585.81ND0.580.690.5MammalianExpressed 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.ProteaseOsteoarthritis 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
dfaAURKAAurora kinase A6191493.9693.35ND0.720.750.6MammalianHighly 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.KinaseColorectal 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
dfaAURKBAurora kinase B4147691.3788.42ND0.540.691.0MammalianHigh 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}.KinaseNote=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
dfaAURKCAurora kinase C610494.6189.93ND0.810.910.6MammalianIsoform 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}.KinaseSpermatogenic 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
dfaB2CL1Bcl-2-like protein 1126698.6893.74ND0.740.830.8MammalianBcl-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 channelAnaplastic 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
dfaB2LA1Bcl-2-related protein A1212785.2690.51ND0.050.570.4MammalianSeems 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
dfaBACE1Beta-secretase 12266998.0694.95ND0.640.580.7MammalianExpressed 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}.ProteaseAlzheimer'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
dfaBACE2Beta-secretase 2141798.0597.68ND0.430.680.5MammalianBrain. 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}.ProteaseResponsible 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
dfaBADBcl2-associated agonist of cell death45499.5799.77ND0.810.700.4MammalianExpressed in a wide variety of tissues.Other cytosolic proteinPromotes 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
dfaBCL2Apoptosis regulator Bcl-2138897.7594.66ND0.790.880.6MammalianExpressed in a variety of tissues.Other ion channelNote=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: Ibuprofen15.11
dfaBGALBeta-galactosidase16598.8798.23ND0.490.710.5MammalianEnzymeGM1-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
dfaBIRC2Baculoviral IAP repeat-containing protein 2119099.8799.47ND0.550.710.7MammalianPresent 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.EnzymeMulti-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
dfaBKRB1B1 bradykinin receptor558498.1898.96ND0.530.720.7Nature11159MammalianFamily A G protein-coupled receptorDiabetic 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
dfaBKRB2B2 bradykinin receptor334497.5797.99ND0.820.820.7Nature11159MammalianUbiquitous. Widespread in normal smooth muscle tissue and neurons. {ECO:0000269|PubMed:7835885}.Family A G protein-coupled receptorAlzheimer'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: Icatibant16.04
dfaBLKTyrosine-protein kinase Blk526091.4292.56ND0.320.720.6MammalianExpressed in lymphatic organs, pancreatic islets, Leydig cells, striate ducts of salivary glands and hair follicles. {ECO:0000269|PubMed:19667185}.KinaseMaturity-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
dfaBLMBloom syndrome protein653786.0388.22ND0.220.350.3MammalianEnzymeBloom 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
dfaBMP1Bone morphogenetic protein 1426997.5299.79ND0.770.710.4MammalianUbiquitous.ProteaseOsteogenesis 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
dfaBMP2KBMP-2-inducible protein kinase26580.8187.06ND0.810.940.5MammalianKinaseMay be involved in osteoblast differentiation.16.04
dfaBMPR2Bone morphogenetic protein receptor type-237199.6695.38ND0.860.970.2MammalianHighly expressed in heart and liver.KinasePulmonary 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
dfaBMR1ABone morphogenetic protein receptor type-1A47499.9796.92ND0.910.760.3MammalianHighly expressed in skeletal muscle.KinaseJuvenile 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
dfaBMR1BBone morphogenetic protein receptor type-1B57090.4993.25ND0.930.730.3MammalianKinaseAcromesomelic 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
dfaBMXCytoplasmic tyrosine-protein kinase BMX78499.4698.79ND0.730.780.4MammalianHighly expressed in cells with great migratory potential, including endothelial cells and metastatic carcinoma cell lines.KinaseNon-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
dfaBRAFSerine/threonine-protein kinase B-raf261096.7796.59ND0.810.810.6MammalianBrain and testis.KinaseNote=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: Sorafenib15.11
dfaBRD2Bromodomain-containing protein 217599.6996.56ND0.340.430.3MammalianReaderMay 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
dfaBRD3Bromodomain-containing protein 346996.0497.67ND0.440.500.4MammalianUbiquitous.ReaderNote=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
dfaBRD4Bromodomain-containing protein 4521295.4997.09ND0.570.530.4MammalianUbiquitously expressed. {ECO:0000269|PubMed:12543779}.ReaderNote=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
dfaBRS3Bombesin receptor subtype-3422595.2392.31ND0.730.490.6MammalianIn germ cells in testis. Lung carcinoma cells.Family A G protein-coupled receptorCancer, 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
dfaBRSK1Serine/threonine-protein kinase BRSK1523290.3189.78ND0.580.480.4MammalianWidely expressed, with highest levels in brain and testis. Protein levels remain constant throughout the cell cycle. {ECO:0000269|PubMed:15150265}.KinaseSerine/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
dfaBRSK2Serine/threonine-protein kinase BRSK236899.9696.61ND0.750.870.4MammalianDetected in pancreas islets (at protein level). {ECO:0000269|PubMed:22798068}.KinaseSerine/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
dfaBTKTyrosine-protein kinase BTK734191.0293.22ND0.630.720.7MammalianPredominantly expressed in B-lymphocytes.KinaseX-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: Ibrutinib15.11
dfaC11B1Cytochrome P450 11B1, mitochondrial544794.1795.19ND0.640.660.5MammalianCytochrome P450Adrenal 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
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dfaC11B2Cytochrome P450 11B2, mitochondrial345697.3691.22ND0.630.640.6MammalianCytochrome P450Corticosterone 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
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dfaC1RComplement C1r subcomponent17799.7499.76ND0.390.400.3MammalianProteaseC1r 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, Trastuzumab16.04
dfaC1SComplement C1s subcomponent18399.9399.86ND0.570.700.4MammalianProteaseComplement 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, Trastuzumab16.04
dfaC3ARC3a anaphylatoxin chemotactic receptor25699.5591.13ND0.320.510.6MammalianWidely 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 receptorReceptor for the chemotactic and inflammatory peptide anaphylatoxin C3a. This receptor stimulates chemotaxis, granule enzyme release and superoxide anion production.16.04
dfaC5AR1C5a anaphylatoxin chemotactic receptor 1518897.0797.27ND0.450.360.6MammalianFamily A G protein-coupled receptorReceptor 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
dfaCA2D1Voltage-dependent calcium channel subunit alpha-2/delta-1517797.9198.26ND0.510.540.5MammalianIsoform 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 familyThe 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
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dfaCAC1BVoltage-dependent N-type calcium channel subunit alpha-1B726496.4497.55ND0.740.680.4Nature11159MammalianIsoform 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 channelDystonia 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, Verapamil16.04
dfaCAC1CVoltage-dependent L-type calcium channel subunit alpha-1C345296.3395.39ND0.800.780.6Nature11159MammalianExpressed 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 channelTimothy 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
dfaCAC1DVoltage-dependent L-type calcium channel subunit alpha-1D223995.6194.57ND0.620.720.7MammalianExpressed 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 channelSinoatrial 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
dfaCAC1GVoltage-dependent T-type calcium channel subunit alpha-1G422293.3197.74ND0.240.400.4MammalianHighly 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 channelVoltage-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, Zonisamide16.04
dfaCAC1SVoltage-dependent L-type calcium channel subunit alpha-1S47899.1599.85ND0.330.340.4MammalianSkeletal muscle specific.Voltage-gated ion channelPeriodic 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
dfaCAH1Carbonic anhydrase 13285194.2588.24ND0.640.640.6MammalianAplastic anaemia
Decreased appetite
Electrolyte imbalance
Glycosuria
Gout
Haemolysis
Haemolytic anaemia
Haemorrhagic diathesis
Hyperuricaemia
Hypokalaemia
Hyponatraemia
Pancreatic disorder
Pancreatitis
Purine metabolism disorder
Thrombocytopenia
Xanthopsia
LyaseGlaucoma
Hypertension
Pancreatic cancer
Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea. {ECO:0000269|PubMed:10550681}.Carbonic anhydrase 1 inhibitor: Methyclothiazide15.11
dfaCAH12Carbonic anhydrase 121115694.1881.48ND0.710.580.6MammalianHighly 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
LyaseHyperchlorhidrosis, 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: Benzthiazide15.11
dfaCAH13Carbonic anhydrase 13322286.8889.71ND0.740.720.7MammalianExpressed in thymus, small intestine, spleen, prostate, ovary, colon and testis. {ECO:0000269|PubMed:14600151}.Electrolyte imbalance
Haemorrhagic diathesis
Hypokalaemia
Paraesthesia
LyaseReversible hydration of carbon dioxide.Carbonic anhydrase 13 inhibitor: Zonisamide15.11
dfaCAH14Carbonic anhydrase 14238491.2080.95ND0.650.630.6MammalianHigh 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
LyaseRenal failure Reversible hydration of carbon dioxide.Carbonic anhydrase 14 inhibitor: Acetazolamide15.11
dfaCAH15Carbonic anhydrase 1527783.9685.83ND0.740.840.4MammalianEnzymeReversible hydration of carbon dioxide. {ECO:0000250}.16.04
dfaCAH2Carbonic anhydrase 21343196.3490.24ND0.660.440.6MammalianAplastic 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
LyaseOsteopetrosis, 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: Methyclothiazide15.11
dfaCAH4Carbonic anhydrase 44118793.5393.12ND0.710.020.5MammalianExpressed 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
LyaseRetinitis 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: Methyclothiazide15.11
dfaCAH7Carbonic anhydrase 7136492.0582.36ND0.710.510.6MammalianLyaseReversible hydration of carbon dioxide.Carbonic anhydrase 7 inhibitor: Methazolamide15.11
dfaCAH9Carbonic anhydrase 91151993.2081.88ND0.600.470.7MammalianExpressed 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
LyaseBladder 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, Zonisamide16.04
dfaCALRLCalcitonin gene-related peptide type 1 receptor149899.6299.80ND0.740.780.8MammalianPredominantly expressed in the lung and heart.Family B G protein-coupled receptorCluster 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
dfaCAN1Calpain-1 catalytic subunit453996.4396.89ND0.720.690.7MammalianUbiquitous.ProteaseCalcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.15.11
dfaCAN2Calpain-2 catalytic subunit310584.5284.36ND0.840.700.5MammalianUbiquitous.ProteaseCalcium-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
dfaCARM1Histone-arginine methyltransferase CARM129699.1197.97ND0.720.760.6MammalianOverexpressed in prostate adenocarcinomas and high-grade prostatic intraepithelial neoplasia. {ECO:0000269|PubMed:15221992}.WriterMethylates (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
dfaCASP1Caspase-1164996.8694.65ND0.700.730.8MammalianExpressed 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}.ProteaseBrain 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: Minocycline15.11
dfaCASP3Caspase-36136490.8188.12ND0.760.830.6MammalianHighly 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.ProteaseChronic 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: Minocycline16.04
dfaCASP6Caspase-6416097.6696.24ND0.690.720.4MammalianProteaseNot 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
dfaCASP7Caspase-7334896.4696.08ND0.660.780.7MammalianHighly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain.ProteaseInvolved 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
dfaCASP8Caspase-8232895.9795.76ND0.800.820.6MammalianIsoform 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.ProteaseCaspase-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
dfaCASRExtracellular calcium-sensing receptor742495.0597.26ND0.550.640.7MammalianExpressed 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 receptorHypocalciuric 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: Cinacalcet16.04
dfaCATBCathepsin B2126294.5291.26ND0.650.680.7MammalianProteaseThiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis.15.11
dfaCATCDipeptidyl peptidase 148594.8884.60ND0.530.670.8MammalianUbiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas. {ECO:0000269|PubMed:9092576}.ProteasePapillon-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
dfaCATDCathepsin D673396.1697.52ND0.670.700.5MammalianExpressed in the aorta extrcellular space (at protein level). {ECO:0000269|PubMed:20551380}.ProteaseCeroid 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, porcine16.04
dfaCATFCathepsin F24799.8487.59ND0.810.570.6MammalianHigh 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.ProteaseCeroid 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
dfaCATGCathepsin G320896.8192.24ND0.720.700.7MammalianProteaseAlpha 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
dfaCATKCathepsin K1156997.0387.45ND0.670.530.8MammalianPredominantly expressed in osteoclasts (bones).ProteasePycnodysostosis (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
dfaCATL1Cathepsin L16135092.4791.24ND0.520.650.8MammalianProteaseAutoimmune diseases
Melanoma
Important for the overall degradation of proteins in lysosomes.15.11
dfaCATL2Cathepsin L2711497.4998.10ND0.750.760.5MammalianPredominantly 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}.ProteaseCysteine protease. May have an important role in corneal physiology. {ECO:0000269|PubMed:10029531, ECO:0000269|PubMed:9727401}.16.04
dfaCATSCathepsin S5141293.0795.55ND0.610.050.6MammalianProteaseAutoimmune 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
dfaCBPCREB-binding protein413589.3088.85ND0.700.030.3MammalianWriterNote=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
dfaCBPA1Carboxypeptidase A1213696.1993.71ND0.580.540.5MammalianPancreas. {ECO:0000269|PubMed:7556081}.ProteaseCarboxypeptidase 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
dfaCBPB1Carboxypeptidase B37792.4181.32ND0.710.640.8MammalianProtease15.11
dfaCBPB2Carboxypeptidase B228799.0598.12ND0.840.710.5MammalianPlasma; synthesized in the liver.ProteaseThrombosis 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
dfaCBX7Chromobox protein homolog 7112099.8199.88ND0.370.670.2MammalianReaderComponent 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
dfaCCKARCholecystokinin receptor type A5118897.8698.74ND0.640.660.7Nature11159MammalianFamily A G protein-coupled receptorAcid-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: Ceruletide16.04
dfaCCR1C-C chemokine receptor type 1356895.2893.72ND0.560.650.7MammalianWidely expressed in different hematopoietic cells.Family A G protein-coupled receptorAutoimmune 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
dfaCCR2C-C chemokine receptor type 21120497.4187.03ND0.630.520.6MammalianFamily A G protein-coupled receptorInflammatory 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
dfaCCR3C-C chemokine receptor type 3386597.7097.69ND0.770.810.6MammalianIn eosinophils as well as trace amounts in neutrophils and monocytes.Family A G protein-coupled receptorAllergic 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
dfaCCR4C-C chemokine receptor type 4631195.7997.82ND0.620.720.6MammalianPredominantly 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 receptorAsthma 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
dfaCCR5C-C chemokine receptor type 51164898.5896.22ND0.670.570.6MammalianHighly 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 receptorDiabetes 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: Maraviroc15.11
dfaCCR6C-C chemokine receptor type 645399.2484.35ND0.070.600.1MammalianSpleen, 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 receptorReceptor 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
dfaCCR8C-C chemokine receptor type 8316398.6495.26ND0.620.570.6MammalianFamily A G protein-coupled receptorAllergic 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
dfaCD11ACyclin-dependent kinase 11A46499.8293.84ND0.620.930.3MammalianExpressed ubiquitously. Some evidence of isoform-specific tissue distribution. {ECO:0000269|PubMed:8195233, ECO:0000269|PubMed:9750192}.KinaseAppears 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
dfaCD11BCyclin-dependent kinase 11B46493.3892.33ND0.020.930.8MammalianExpressed ubiquitously. Some evidence of isoform-specific tissue distribution. {ECO:0000269|PubMed:8195233, ECO:0000269|PubMed:9750192}.KinasePlays 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
dfaCDC7Cell division cycle 7-related protein kinase845895.3596.97ND0.710.700.5MammalianKinaseSeems 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
dfaCDK1Cyclin-dependent kinase 16114993.0990.58ND0.650.690.6MammalianIsoform 2 is found in breast cancer tissues.KinaseCancer, 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
dfaCDK14Cyclin-dependent kinase 1476497.0293.18ND0.060.940.6MammalianHighly 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}.KinaseSerine/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
dfaCDK15Cyclin-dependent kinase 1536195.7089.88ND0.080.950.4MammalianKinaseSerine/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
dfaCDK16Cyclin-dependent kinase 1656688.3187.14ND0.670.940.4MammalianDetected in pancreas islets (at protein level). Detected in brain and pancreas. {ECO:0000269|PubMed:22798068}.KinaseProtein 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
dfaCDK18Cyclin-dependent kinase 1846499.4298.29ND0.420.950.5MammalianIsoform 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}.KinaseMay play a role in signal transduction cascades in terminally differentiated cells.16.04
dfaCDK19Cyclin-dependent kinase 1949792.5895.66ND0.150.790.8MammalianKinase16.04
dfaCDK2Cyclin-dependent kinase 26191693.4091.02ND0.650.700.7MammalianKinaseAcute 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: Bosutinib15.11
dfaCDK3Cyclin-dependent kinase 326899.1299.85ND0.030.430.6MammalianExpressed in cancer cell lines and glioblastoma tissue. {ECO:0000269|PubMed:18794154}.KinaseSerine/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
dfaCDK4Cyclin-dependent kinase 4652896.9897.30ND0.610.700.6MammalianKinaseMelanoma, 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: Palbociclib16.04
dfaCDK5Cyclin-dependent-like kinase 5762589.2187.90ND0.620.660.6MammalianIsoform 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}.KinaseLissencephaly 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
dfaCDK7Cyclin-dependent kinase 7329385.4987.07ND0.580.760.5MammalianUbiquitous.KinaseB-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
dfaCDK8Cyclin-dependent kinase 8826487.7289.03ND0.660.690.6MammalianKinaseCancer, 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
dfaCDK9Cyclin-dependent kinase 9626485.8386.83ND0.400.720.7MammalianUbiquitous.KinaseNote=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
dfaCDKL2Cyclin-dependent kinase-like 225986.1197.45ND0.780.980.2MammalianExpressed in testis and kidney, and at lower level in brain and lung. {ECO:0000269|PubMed:9000130}.Kinase15.11
dfaCDKL5Cyclin-dependent kinase-like 546099.0899.54ND0.900.990.2MammalianExpressed in brain, lung, kidney, prostate, ovary, placenta, pancreas and testis.KinaseNote=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
dfaCEGTCeramide glucosyltransferase411297.5294.26ND0.890.780.4MammalianFound in all tissues examined. {ECO:0000269|PubMed:8643456}.TransferaseSphingolipid 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
dfaCELBile salt-activated lipase26392.1686.51ND0.260.800.8MammalianEnzymeCatalyzes fat and vitamin absorption. Acts in concert with pancreatic lipase and colipase for the complete digestion of dietary triglycerides.15.11
dfaCEL2AChymotrypsin-like elastase family member 2A75082.1682.20ND0.810.800.5MammalianPancreas. Not detected in keratinocytes. {ECO:0000269|PubMed:10620133}.Acts upon elastin.16.04
dfaCETPCholesteryl ester transfer protein {ECO:0000303|PubMed:3600759}767696.8797.81ND0.650.610.6MammalianExpressed by the liver and secreted in plasma.Other ion channelHyperalphalipoproteinemia 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
dfaCFTRCystic fibrosis transmembrane conductance regulator613197.2299.79ND0.830.880.4MammalianExpressed in the respiratory airway, including bronchial epithelium, and in the female reproductive tract, including oviduct (at protein level). {ECO:0000269|PubMed:22207244}.Other ion channelCystic 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
dfaCHK1Serine/threonine-protein kinase Chk17172295.4796.05ND0.650.000.7MammalianExpressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon. {ECO:0000269|PubMed:9278511, ECO:0000269|PubMed:9382850}.KinaseSolid 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
dfaCHK2Serine/threonine-protein kinase Chk2552894.8194.25ND0.710.730.6MammalianHigh expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues.KinaseLi-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
dfaCHKACholine kinase alpha37799.4099.23ND0.270.580.4MammalianEnzymeCancer, 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: Choline15.11
dfaCHLECholinesterase4266291.9885.13ND0.710.750.7MammalianDetected in blood plasma (at protein level). Present in most cells except erythrocytes. {ECO:0000269|PubMed:19368529, ECO:0000269|PubMed:19542320}.Bradycardia
Salivary hypersecretion
HydrolaseButyrylcholinesterase 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: Pegvisomant15.11
dfaCLATCholine O-acetyltransferase14499.7399.96ND0.100.290.8MammalianEnzymeMyasthenic 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: Choline16.04
dfaCLK1Dual specificity protein kinase CLK1540289.8089.94ND0.530.580.7MammalianEndothelial cells. {ECO:0000269|PubMed:19168442}.KinaseDual 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
dfaCLK2Dual specificity protein kinase CLK2148389.4388.30ND0.520.690.5MammalianEndothelial cells. {ECO:0000269|PubMed:19168442}.KinaseDual 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
dfaCLK3Dual specificity protein kinase CLK3113892.6098.46ND0.430.580.3MammalianEndothelial cells. {ECO:0000269|PubMed:19168442}.KinaseDual 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
dfaCLK4Dual specificity protein kinase CLK44119587.8089.14ND0.520.710.7MammalianExpressed in liver, kidney, heart, muscle, brain and endothelial cells. {ECO:0000269|PubMed:11170754, ECO:0000269|PubMed:19168442}.KinaseDual 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
dfaCLTR1Cysteinyl leukotriene receptor 1138599.0799.26ND0.810.750.5MammalianWidely 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 receptorAsthma 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
dfaCMA1Chymase529795.5798.64ND0.640.510.5MammalianMast cells in lung, heart, skin and placenta. Expressed in both normal skin and in urticaria pigmentosa lesions. {ECO:0000269|PubMed:8144971}.ProteaseAsthma
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
dfaCNR1Cannabinoid receptor 11432896.7490.92ND0.590.000.8Nature11159MammalianWidely expressed. {ECO:0000269|PubMed:15620723}.Family A G protein-coupled receptorAnalgesics
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
dfaCNR2Cannabinoid receptor 25362495.0189.27ND0.590.000.7MammalianPreferentially 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 receptorAnalgesics
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
dfaCOMTCatechol O-methyltransferase38294.7392.89ND0.950.830.3MammalianBrain, liver, placenta, lymphocytes and erythrocytes.TransferaseParkinson'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-Adenosylmethionine15.11
dfaCP17ASteroid 17-alpha-hydroxylase/17,20 lyase342094.5387.43ND0.650.570.5MammalianCytochrome P450Adrenal 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: Progesterone15.11
dfaCP1A1Cytochrome P450 1A1520296.0693.19ND0.840.760.4MammalianLung, lymphocytes and placenta.Cytochrome P450Cytochromes 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
dfaCP1B1Cytochrome P450 1B1310697.4198.39ND0.600.500.3MammalianExpressed in many tissues. {ECO:0000269|PubMed:8175734}.Cytochrome P450Peters 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: Biotin15.11
dfaCP24A1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial44198.7899.46ND0.890.890.3MammalianCytochrome P450Has 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
dfaCP26ACytochrome P450 26A139799.7099.90ND0.390.480.4MammalianHighest levels in adult liver, heart, pituitary gland, adrenal gland, placenta and regions of the brain. {ECO:0000269|PubMed:9826557}.Cytochrome P450Cardiovascular 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
dfaCP2C8Cytochrome P450 2C8132887.8686.94ND0.650.680.5MammalianCytochrome P450Cytochromes 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: Cyclosporine15.11
dfaCP51ALanosterol 14-alpha demethylase65280.3185.30ND0.490.690.3MammalianUbiquitously expressed with highest levels in testis, ovary, adrenal, prostate, liver, kidney and lung. {ECO:0000269|PubMed:8619637}.Cytochrome P450Catalyzes 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
dfaCRFR1Corticotropin-releasing factor receptor 12175599.4198.37ND0.530.510.6Nature11159MammalianPredominantly expressed in the cerebellum, pituitary, cerebral cortex and olfactory lobe. {ECO:0000269|PubMed:8243652}.Family B G protein-coupled receptorAnxiety 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
dfaCSF1RMacrophage colony-stimulating factor 1 receptor787594.7394.61ND0.650.720.7MammalianExpressed in bone marrow and in differentiated blood mononuclear cells.KinaseNote=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: Imatinib15.11
dfaCSKTyrosine-protein kinase CSK216087.1286.17ND0.260.810.5MammalianExpressed in lung and macrophages. {ECO:0000269|PubMed:1371489}.KinaseNon-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
dfaCSK21Casein kinase II subunit alpha640086.1784.06ND0.770.740.6MammalianExpressed in gastric carcinoma tissue and the expression gradually increases with the progression of the carcinoma (at protein level). {ECO:0000269|PubMed:24962073}.KinaseBreast 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
dfaCSK22Casein kinase II subunit alpha'510194.2993.08ND0.900.810.3MammalianKinaseCatalytic 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
dfaCTRAChymotrypsinogen A420691.4689.02ND0.630.740.7MammalianProtease15.11
dfaCTRB1Chymotrypsinogen B58499.1596.66ND0.410.850.9MammalianProtease16.04
dfaCTRCChymotrypsin-C59096.6885.58ND0.710.530.5MammalianPancreas.ProteasePancreatitis, 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
dfaCTROCitron Rho-interacting kinase46589.4892.73ND0.240.990.2MammalianKinasePlays 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
dfaCX3C1CX3C chemokine receptor 114199.97100.00ND0.310.580.4MammalianExpressed in lymphoid and neural tissues.Family A G protein-coupled receptorMacular 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
dfaCXCR1C-X-C chemokine receptor type 1418498.3897.69ND0.720.730.5MammalianFamily A G protein-coupled receptorAcute 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: Ketoprofen16.04
dfaCXCR2C-X-C chemokine receptor type 2444298.0795.33ND0.650.750.6MammalianFamily A G protein-coupled receptorAcute 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
dfaCXCR3C-X-C chemokine receptor type 3769796.7594.63ND0.590.630.7MammalianIsoform 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 receptorAutoimmune 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
dfaCXCR4C-X-C chemokine receptor type 4516898.8899.62ND0.470.720.7MammalianExpressed 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 receptorWHIM 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, Plerixafor16.04
dfaDAPK1Death-associated protein kinase 177299.0196.60ND0.680.820.7MammalianIsoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas. {ECO:0000269|PubMed:18422656}.KinaseCalcium/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
dfaDAPK3Death-associated protein kinase 3436489.5489.44ND0.430.580.6MammalianWidely expressed. Isoform 1 and isoform 2 are expressed in the bladder smooth muscle. {ECO:0000269|PubMed:15292222, ECO:0000269|PubMed:17126281}.KinaseSerine/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
dfaDCAMS-adenosylmethionine decarboxylase proenzyme35399.5699.76ND0.450.620.8MammalianEnzymeCancer, 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-Adenosylmethionine15.11
dfaDCKDeoxycytidine kinase39499.2899.53ND0.860.880.4MammalianEnzymeRequired 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: Cladribine15.11
dfaDCLK1Serine/threonine-protein kinase DCLK1410682.7789.11ND0.190.870.4MammalianIn 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}.KinaseProbable 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
dfaDCLK3Serine/threonine-protein kinase DCLK326586.3280.92ND0.150.620.6MammalianKinase16.04
dfaDCMCMalonyl-CoA decarboxylase, mitochondrial120999.5896.87ND0.600.710.6MammalianExpressed 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}.EnzymeMalonyl-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
dfaDDR1Epithelial discoidin domain-containing receptor 1410191.4894.64ND0.640.800.6MammalianDetected 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}.KinaseTyrosine 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: Imatinib15.11
dfaDDR2Discoidin domain-containing receptor 2412195.3698.53ND0.620.560.6MammalianDetected 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}.KinaseSpondyloepimetaphyseal 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: Regorafenib16.04
dfaDEFMPeptide deformylase, mitochondrial14599.7084.52ND0.730.290.7MammalianUbiquitous.EnzymeRemoves the formyl group from the N-terminal Met of newly synthesized proteins. {ECO:0000250}.15.11
dfaDGAT1Diacylglycerol O-acyltransferase 1557198.3099.14ND0.500.590.6MammalianEnzymeDiarrhea 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
dfaDHB1Estradiol 17-beta-dehydrogenase 1129897.6997.13ND0.640.670.5MammalianEnzymeBreast cancer (hormone-sensitive) Favors the reduction of estrogens and androgens. Also has 20-alpha-HSD activity. Uses preferentially NADH.15.11
dfaDHB2Estradiol 17-beta-dehydrogenase 2227398.4297.54ND0.430.540.4MammalianEnzymeCapable 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
dfaDHB3Testosterone 17-beta-dehydrogenase 3414696.2484.22ND0.500.560.7MammalianTestis.EnzymeMale 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
dfaDHI1Corticosteroid 11-beta-dehydrogenase isozyme 15175791.4687.89ND0.670.690.6MammalianWidely 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
dfaDHI2Corticosteroid 11-beta-dehydrogenase isozyme 2734892.8192.75ND0.600.680.5MammalianExpressed 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}.EnzymeApparent 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
dfaDHSOSorbitol dehydrogenase16699.8299.88ND0.420.630.6MammalianExpressed 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}.EnzymeDiabetic 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
dfaDMPKMyotonin-protein kinase27396.7494.56ND0.030.630.8MammalianMost 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}.KinaseDystrophia 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
dfaDOPODopamine beta-hydroxylase17792.8484.15ND0.430.330.5MammalianEnzymeDopamine 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
dfaDOT1LHistone-lysine N-methyltransferase, H3 lysine-79 specific26199.9399.92ND0.850.600.6MammalianWriterHistone methyltransferase. Methylates 'Lys-79' of histone H3. Nucleosomes are preferred as substrate compared to free histones. Binds to DNA.15.11
dfaDPEP1Dipeptidase 1213297.9799.85ND0.730.810.4MammalianProteaseBacterial 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: Cilastatin15.11
dfaDPOLADNA polymerase alpha catalytic subunit38280.5182.78ND0.210.830.5MammalianTransferasePlays 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: Cladribine15.11
dfaDPP2Dipeptidyl peptidase 25120095.4596.22ND0.730.490.6MammalianDetected in seminal plasma (at protein level). {ECO:0000269|PubMed:15487984}.ProteasePlays an important role in the degradation of some oligopeptides. {ECO:0000269|PubMed:15487984}.15.11
dfaDPP4Dipeptidyl peptidase 46305197.3197.57ND0.700.000.6MammalianExpressed 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}.ProteaseAutoimmune 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: Atorvastatin15.11
dfaDPP8Dipeptidyl peptidase 85122996.2895.87ND0.770.810.6MammalianUbiquitously expressed, with highest levels in testis, placenta, prostate, muscle and brain. {ECO:0000269|PubMed:11012666, ECO:0000269|PubMed:12662155}.ProteaseDipeptidyl 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
dfaDPP9Dipeptidyl peptidase 9490097.4191.12ND0.670.830.8MammalianUbiquitously 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}.ProteaseDipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2.16.04
dfaDRD1D(1A) dopamine receptor5198587.1084.55ND0.680.670.6Nature11159MammalianDetected 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 receptorParkinson'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
dfaDRD2D(2) dopamine receptor6769587.8585.86ND0.500.450.6Nature11159MammalianAkathisia
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 receptorAnxiety 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
dfaDRD3D(3) dopamine receptor2279289.0589.55ND0.550.560.8Nature11159MammalianBrain.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 receptorTremor, 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: Ziprasidone15.11
dfaDRD4D(4) dopamine receptor3169396.1790.90ND0.540.010.7Nature11159MammalianAkathisia
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 receptorParkinson'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
dfaDRD5D(1B) dopamine receptor430993.8594.95ND0.700.750.7MammalianNeuron-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 receptorBenign 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
dfaDUS22Dual specificity protein phosphatase 2234099.97100.00ND0.500.730.3MammalianUbiquitous. Highest expression seen in heart, placenta, lung, liver, kidney and pancreas. {ECO:0000269|PubMed:11717427}.PhosphataseActivates 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
dfaDUSTYDual serine/threonine and tyrosine protein kinase25899.5599.22ND0.310.700.4MammalianPredominantly 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}.EnzymeCongenital 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
dfaDUTDeoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial411799.7098.94ND0.900.890.3MammalianFound 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}.EnzymeThis 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
dfaDYN1Dynamin-1511299.7799.11ND0.760.740.2MammalianEnzymeEpileptic 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
dfaDYRDihydrofolate reductase1150098.3395.30ND0.550.000.9MammalianWidely 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}.OxidoreductaseMegaloblastic 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: Pyrimethamine15.11
dfaDYR1ADual specificity tyrosine-phosphorylation-regulated kinase 1A5192884.5783.11ND0.610.600.5MammalianUbiquitous. 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}.KinaseMental 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
dfaDYR1BDual specificity tyrosine-phosphorylation-regulated kinase 1B332482.7988.24ND0.750.800.5MammalianHighest 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}.KinaseAbdominal 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
dfaDYRK2Dual specificity tyrosine-phosphorylation-regulated kinase 2514188.4890.82ND0.550.740.4MammalianTestis, after the onset of spermatogenesis. {ECO:0000269|PubMed:9748265}.KinaseSerine/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
dfaDYRK3Dual specificity tyrosine-phosphorylation-regulated kinase 3618288.3786.43ND0.410.730.5MammalianIsoform 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}.KinaseNegative 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
dfaDYRK4Dual specificity tyrosine-phosphorylation-regulated kinase 487392.2287.34ND0.710.880.3MammalianEnzymePossible non-essential role in spermiogenesis. {ECO:0000250}.16.04
dfaE2AK1Eukaryotic translation initiation factor 2-alpha kinase 138891.8594.63ND0.710.790.5MammalianExpressed predominantly in erythroid cells. At much lower levels, expressed in hepatocytes (at protein level). {ECO:0000269|PubMed:20071449}.KinaseInhibits 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
dfaE2AK2Interferon-induced, double-stranded RNA-activated protein kinase613694.3792.57ND0.560.640.5MammalianHighly 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}.KinaseIFN-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
dfaE2AK3Eukaryotic translation initiation factor 2-alpha kinase 326498.7389.49ND0.690.780.9MammalianUbiquitous. A high level expression is seen in secretory tissues.KinaseWolcott-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
dfaE2AK4eIF-2-alpha kinase GCN2 {ECO:0000250|UniProtKB:Q9QZ05}76898.4297.45ND0.830.970.4MammalianWidely expressed (PubMed:10504407). Expressed in lung, smooth muscle cells and macrophages (PubMed:24292273). {ECO:0000269|PubMed:10504407, ECO:0000269|PubMed:24292273}.KinasePulmonary 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
dfaEAA1Excitatory amino acid transporter 126699.5885.06ND0.010.741.2MammalianHighly expressed in cerebellum, but also found in frontal cortex, hippocampus and basal ganglia.Electrochemical transporterEpisodic 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
dfaEAA2Excitatory amino acid transporter 216393.1789.04ND0.890.710.4MammalianElectrochemical transporterTransports 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
dfaEAA3Excitatory amino acid transporter 326799.8199.96ND0.910.530.3MammalianExpressed 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 transporterDicarboxylic 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
dfaEBP3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase212993.1292.01ND0.730.800.6MammalianEnzymeChondrodysplasia 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
dfaECE1Endothelin-converting enzyme 1531693.7193.60ND0.500.460.7MammalianAll 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}.ProteaseHirschsprung 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
dfaEDNRAEndothelin-1 receptor6170296.7897.85ND0.660.650.7Nature11159MammalianIsoform 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 receptorMandibulofacial 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
dfaEDNRBEndothelin B receptor2124898.0897.31ND0.730.770.6Nature11159MammalianExpressed in placental stem villi vessels, but not in cultured placental villi smooth muscle cells. {ECO:0000269|PubMed:9284755}.Family A G protein-coupled receptorWaardenburg 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, Sitaxentan16.04
dfaEF2KEukaryotic elongation factor 2 kinase36084.5980.97ND0.210.600.5MammalianKinaseThreonine 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
dfaEGFREpidermal growth factor receptor4409895.8892.89ND0.620.560.8MammalianUbiquitously expressed. Isoform 2 is also expressed in ovarian cancers. {ECO:0000269|PubMed:17671655}.Decreased appetiteKinaseLung 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: Cetuximab15.11
dfaEGLN1Egl nine homolog 1424594.2893.04ND0.780.870.8MammalianAccording 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}.EnzymeErythrocytosis, 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
dfaEGLN2Egl nine homolog 2153100.00100.00ND0.930.560.4MammalianExpressed 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}.EnzymeAnemia
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
dfaEGLN3Egl nine homolog 356793.2898.71ND0.100.810.6MammalianWidely 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}.EnzymeCellular 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
dfaELNENeutrophil elastase5119394.9593.06ND0.650.770.8MammalianBone marrow cells.ProteaseCyclic 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
dfaELOV6Elongation of very long chain fatty acids protein 6 {ECO:0000255|HAMAP-Rule:MF_03206, ECO:0000305}310099.5499.95ND0.390.440.5MammalianUbiquitous. {ECO:0000269|PubMed:20937905}.EnzymeCatalyzes 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
dfaENPLEndoplasmin65599.6098.93ND0.810.950.4MammalianMolecular 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: Rifabutin15.11
dfaENPP2Ectonucleotide pyrophosphatase/phosphodiesterase family member 2614098.2998.58ND0.600.570.5MammalianExpressed 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
dfaEPHA2Ephrin type-A receptor 2422193.4794.61ND0.700.790.6MammalianExpressed 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}.KinaseCataract 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
dfaEPHA3Ephrin type-A receptor 368684.5288.40ND0.540.910.5MammalianWidely expressed. Highest level in placenta.KinaseColorectal 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
dfaEPHA6Ephrin type-A receptor 636591.3494.96ND0.690.930.4MammalianExpressed in brain and testis. {ECO:0000269|PubMed:14726470}.KinaseReceptor 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
dfaEPHA7Ephrin type-A receptor 746999.7499.74ND0.820.870.2MammalianWidely expressed.KinaseReceptor 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
dfaEPHA8Ephrin type-A receptor 856687.2885.62ND0.470.920.5MammalianKinaseReceptor 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
dfaEPHB1Ephrin type-B receptor 127283.1581.73ND0.280.900.4MammalianPreferentially expressed in brain.KinaseReceptor 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
dfaEPHB2Ephrin type-B receptor 2410297.1996.36ND0.340.850.5MammalianBrain, heart, lung, kidney, placenta, pancreas, liver and skeletal muscle. Preferentially expressed in fetal brain.KinaseProstate 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
dfaEPHB3Ephrin type-B receptor 339799.3799.47ND0.530.530.5MammalianUbiquitous.KinaseReceptor 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
dfaEPHB4Ephrin type-B receptor 4642196.9898.19ND0.710.700.5MammalianAbundantly 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}.KinaseLung 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
dfaERBB2Receptor tyrosine-protein kinase erbB-21145894.4989.45ND0.690.490.7MammalianExpressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth. {ECO:0000269|PubMed:15380516}.KinaseHereditary 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
dfaERBB4Receptor tyrosine-protein kinase erbB-4418694.1395.56ND0.590.790.8MammalianExpressed 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}.KinaseAmyotrophic 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: Afatinib15.11
dfaERCC5DNA repair protein complementing XP-G cells25292.8593.87ND0.900.960.6MammalianOther nuclear proteinXeroderma 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
dfaERG1Squalene monooxygenase27299.8399.75ND0.200.430.5MammalianEnzymeCatalyzes 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, Terbinafine16.04
dfaERG7Lanosterol synthase414491.2293.39ND0.530.690.8MammalianEnzymeHypercholesterolemia Catalyzes the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus. {ECO:0000269|PubMed:7639730}.15.11
dfaERN1Serine/threonine-protein kinase/endoribonuclease IRE139388.9387.02ND0.520.750.6MammalianUbiquitously expressed. High levels observed in pancreatic tissue. {ECO:0000269|PubMed:9637683}.EnzymeSenses 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
dfaERR1Steroid hormone receptor ERR159891.7797.80ND0.670.690.4MammalianNuclear receptorBreast 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
dfaESR1Estrogen receptor1191195.1092.42ND0.600.580.8Nature11159
VirtualToxLab
MammalianWidely 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 receptorEstrogen 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: Diethylstilbestrol15.11
dfaESR2Estrogen receptor beta3145993.9893.89ND0.600.580.6Nature11159
VirtualToxLab
MammalianIsoform 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 receptorBreast 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: Diethylstilbestrol15.11
dfaEST1Liver carboxylesterase 1437383.3282.95ND0.650.700.9MammalianExpressed predominantly in liver with lower levels in heart and lung. {ECO:0000269|PubMed:10562416}.EnzymeAlzheimer'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: Oseltamivir15.11
dfaEST2Cocaine esterase312294.6084.22ND0.800.730.5MammalianPreferentially 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}.EnzymeInvolved 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
dfaEZH2Histone-lysine N-methyltransferase EZH224399.28100.00ND0.740.700.4MammalianExpressed in many tissues. Overexpressed in numerous tumor types including carcinomas of the breast, colon, larynx, lymphoma and testis. {ECO:0000269|PubMed:14532106}.WriterWeaver 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
dfaF13ACoagulation factor XIII A chain37899.9399.92ND0.490.150.5MammalianAminoacyltransferaseFactor 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-Glutamine16.04
dfaF16P1Fructose-1,6-bisphosphatase 1339598.0598.04ND0.800.780.5MammalianExpressed in pancreatic islets. {ECO:0000269|PubMed:18375435}.EnzymeFructose-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
dfaFA10Coagulation factor X4433397.9995.20ND0.700.000.7MammalianPlasma; synthesized in the liver. {ECO:0000269|PubMed:6587384}.ProteaseFactor 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 Factor15.11
dfaFA11Coagulation factor XI315399.3298.58ND0.660.790.8MammalianIsoform 2 is produced by platelets and megakaryocytes but absent from other blood cells.ProteaseFactor 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 IX15.11
dfaFA12Coagulation factor XII215885.9386.97ND0.340.510.5MammalianProteaseFactor 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 Oleate16.04
dfaFA7Coagulation factor VII129898.9999.65ND0.590.470.6MammalianPlasma.ProteaseFactor 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
dfaFA9Coagulation factor IX {ECO:0000303|PubMed:3857619}116899.9699.71ND0.720.690.5MammalianDetected 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}.ProteaseHemophilia 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 Factor15.11
dfaFAAH1Fatty-acid amide hydrolase 14160994.3388.36ND0.620.620.8MammalianHighly 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}.EnzymeAnalgesics
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
dfaFABP4Fatty acid-binding protein, adipocyte712296.5495.57ND0.780.840.6MammalianFatty acid binding protein familyAtherosclerosis 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
dfaFABPHFatty acid-binding protein, heart35688.0787.81ND0.690.620.3MammalianFatty acid binding protein familyFABP are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters.15.11
dfaFAK1Focal adhesion kinase 1357993.6295.60ND0.460.680.7MammalianDetected 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}.KinaseNote=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
dfaFAK2Protein-tyrosine kinase 2-beta425789.8285.79ND0.660.700.5MammalianMost 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}.KinaseNote=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: Leflunomide15.11
dfaFASFatty acid synthase593387.0685.61ND0.460.530.4MammalianUbiquitous. Prominent expression in brain, lung, and liver. {ECO:0000269|PubMed:7567999, ECO:0000269|PubMed:7595075}.TransferaseEndometrial 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: Cerulenin15.11
dfaFCER2Low affinity immunoglobulin epsilon Fc receptor25699.9499.93ND0.670.450.4MammalianMembrane receptorLow-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
dfaFDFTSqualene synthase359793.7192.62ND0.600.670.8MammalianEnzymeHypercholesterolemia
Hyperlipidemia
Hypocholesterolemia
15.11
dfaFEN1Flap endonuclease 1 {ECO:0000255|HAMAP-Rule:MF_03140}5105990.8590.11ND0.860.850.4MammalianEnzymeStructure-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
dfaFERTyrosine-protein kinase Fer316986.7093.73ND0.490.660.5MammalianIsoform 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}.KinaseTyrosine-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
dfaFESTyrosine-protein kinase Fes/Fps812690.8490.70ND0.690.900.4MammalianWidely expressed. Detected in adult colon epithelium. {ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:19051325}.KinaseNote=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
dfaFFAR1Free fatty acid receptor 1242999.3899.06ND0.580.560.4MammalianDetected in brain and pancreas. Detected in pancreatic beta cells. {ECO:0000269|PubMed:12496284, ECO:0000269|PubMed:16289108}.Family A G protein-coupled receptorG-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: Icosapent15.11
dfaFFAR2Free fatty acid receptor 216899.5399.95ND0.350.570.5MammalianExpressed 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 receptorG 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
dfaFFAR4Free fatty acid receptor 415599.3297.54ND0.540.780.6MammalianAbundant 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 receptorReceptor 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
dfaFGF1Fibroblast growth factor 122699.9699.03ND0.650.490.8MammalianPredominantly expressed in kidney and brain. Detected at much lower levels in heart and skeletal muscle. {ECO:0000269|PubMed:11964394, ECO:0000269|PubMed:7504343}.Secreted proteinHepatic 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 Polysulfate15.11
dfaFGFR1Fibroblast growth factor receptor 13109193.1393.31ND0.590.640.6MammalianDetected 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}.KinasePfeiffer 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
dfaFGFR2Fibroblast growth factor receptor 2512594.0492.97ND0.300.780.7MammalianKinaseCrouzon 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: Palifermin15.11
dfaFGFR3Fibroblast growth factor receptor 3520889.9692.11ND0.680.090.4MammalianExpressed 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}.KinaseAchondroplasia (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
dfaFGFR4Fibroblast growth factor receptor 438299.3093.84ND0.030.880.4MammalianExpressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. {ECO:0000269|PubMed:10631118}.KinaseObesity 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
dfaFGRTyrosine-protein kinase Fgr78888.1690.63ND0.740.910.4MammalianDetected 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}.KinaseNote=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
dfaFKB1APeptidyl-prolyl cis-trans isomerase FKBP1A247496.4198.25ND0.680.640.8MammalianIsomeraseKeeps 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: Pimecrolimus15.11
dfaFKBP4Peptidyl-prolyl cis-trans isomerase FKBP436099.7799.96ND0.360.610.4MammalianWidely expressed. {ECO:0000269|PubMed:1279700}.EnzymeNeurological 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
dfaFKBP5Peptidyl-prolyl cis-trans isomerase FKBP527699.5599.81ND0.120.650.7MammalianWidely expressed, enriched in testis compared to other tissues.EnzymeImmunophilin 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
dfaFLT3Receptor-type tyrosine-protein kinase FLT34122493.4393.58ND0.660.670.6MammalianDetected 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}.KinaseLeukemia, 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: Sorafenib15.11
dfaFOLH1Glutamate carboxypeptidase 2117496.0690.15ND0.560.401.1MammalianHighly 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}.ProteaseAmyotrophic 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: Capromab15.11
dfaFPPSFarnesyl pyrophosphate synthase121299.6999.73ND0.490.531.0MammalianTransferaseKey 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: Pamidronate15.11
dfaFPR1fMet-Leu-Phe receptor314096.2097.12ND0.350.800.6MammalianNeutrophils.Family A G protein-coupled receptorGastric 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: Nedocromil16.04
dfaFPR2N-formyl peptide receptor 249499.4799.39ND0.680.340.4MammalianExpressed abundantly in the lung and neutrophils. Also found in the spleen and testis. {ECO:0000269|PubMed:9151906}.Family A G protein-coupled receptorAlzheimer'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
dfaFRKTyrosine-protein kinase FRK421688.8394.56ND0.160.511.5MammalianPredominantly expressed in epithelial derived cell lines and tissues, especially normal liver, kidney, breast and colon. {ECO:0000269|PubMed:7696183}.KinaseNon-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: Regorafenib16.04
dfaFSHRFollicle-stimulating hormone receptor34499.7999.88ND0.690.720.6MammalianSertoli cells and ovarian granulosa cells.Family A G protein-coupled receptorOvarian 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
dfaFUCOTissue alpha-L-fucosidase110097.3796.10ND0.220.651.0MammalianEnzymeFucosidosis (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
dfaFYNTyrosine-protein kinase Fyn544084.4584.50ND0.700.720.5MammalianIsoform 1 is highly expressed in the brain. Isoform 2 is expressed in cells of hemopoietic lineages, especially T-lymphocytes. {ECO:0000269|PubMed:10196263}.KinasePhiladelphia-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: Dasatinib15.11
dfaG6PDGlucose-6-phosphate 1-dehydrogenase59999.4495.20ND0.470.090.4MammalianIsoform Long is found in lymphoblasts, granulocytes and sperm.EnzymeAnemia, 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
dfaGABR1Gamma-aminobutyric acid type B receptor subunit 116999.1499.11ND0.350.600.4MammalianHighly 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 receptorComponent 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: Baclofen15.11
dfaGABT4-aminobutyrate aminotransferase, mitochondrial35097.4397.71ND0.830.910.4MammalianLiver > pancreas > brain > kidney > heart > placenta.TransferaseGABA 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, Vigabatrin16.04
dfaGAKCyclin-G-associated kinase66997.6293.45ND0.840.970.5MammalianUbiquitous. Highest in testis.KinaseAssociates 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
dfaGALK1Galactokinase510999.6395.74ND0.390.660.4MammalianEnzymeGalactosemia 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
dfaGALR2Galanin receptor type 224199.9899.70ND0.240.370.4MammalianExpressed 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 receptorAlzheimer'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
dfaGASRGastrin/cholecystokinin type B receptor3116498.7598.98ND0.770.010.7Nature11159MammalianIsoform 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 receptorAcid-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: Pentagastrin16.04
dfaGBA2Non-lysosomal glucosylceramidase14499.6099.84ND0.730.840.6MammalianWidely expressed. Highly expressed in brain, heart, skeletal muscle, kidney and placenta and expressed at lower level in liver. {ECO:0000269|PubMed:11489889}.EnzymeSpastic 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
dfaGBRA1Gamma-aminobutyric acid receptor subunit alpha-1516295.7392.56ND0.030.690.8Nature11159MammalianAgitation
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 channelEpilepsy, 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
dfaGBRA2Gamma-aminobutyric acid receptor subunit alpha-2310699.3895.92ND0.340.560.4MammalianAgitation
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 channelAnxiety 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
dfaGBRA3Gamma-aminobutyric acid receptor subunit alpha-367199.67100.00ND0.790.780.2MammalianAgitation
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 channelAnxiety 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
dfaGBRA5Gamma-aminobutyric acid receptor subunit alpha-5410292.7193.67ND0.710.670.4MammalianAgitation
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 channelAlzheimer'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
dfaGCKRGlucokinase regulatory protein25099.9299.99ND0.730.640.4MammalianFound 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
dfaGCRGlucocorticoid receptor5181994.8288.50ND0.650.610.6Nature11159
VirtualToxLab
MammalianWidely 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 receptorGlucocorticoid 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: Flunisolide15.11
dfaGGPPSGeranylgeranyl pyrophosphate synthase17291.9094.59ND0.710.550.5MammalianAbundantly expressed in testis. Found in other tissues to a lower extent.EnzymeCatalyzes 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: Zoledronate16.04
dfaGHRLAppetite-regulating hormone14199.9999.98ND0.580.730.5MammalianHighest 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
dfaGHSRGrowth hormone secretagogue receptor type 1492396.7595.95ND0.480.580.6Nature11159MammalianPituitary and hypothalamus.Family A G protein-coupled receptorGrowth 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
dfaGIPRGastric inhibitory polypeptide receptor19899.9899.88ND0.400.440.4MammalianFamily B G protein-coupled receptorThis is a receptor for GIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.16.04
dfaGLCMGlucosylceramidase651086.6080.90ND0.500.530.6MammalianEnzymeGaucher 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
dfaGLRGlucagon receptor461797.8199.42ND0.660.670.5MammalianFamily B G protein-coupled receptorHyperglycemia
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 recombinant16.04
dfaGLRA1Glycine receptor subunit alpha-137887.6083.85ND0.670.770.6MammalianRespiratory depressionLigand-gated ion channelHyperekplexia 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
dfaGNRHRGonadotropin-releasing hormone receptor4103998.6298.92ND0.580.680.7MammalianPituitary, ovary, testis, breast and prostate but not in liver and spleen.FlushingFamily A G protein-coupled receptorHypogonadotropic 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
dfaGP119Glucose-dependent insulinotropic receptor454298.9498.06ND0.430.520.5MammalianPredominantly expressed in the pancreas, especially in the islets. {ECO:0000269|PubMed:15607732}.Family A G protein-coupled receptorDiabetes 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
dfaGP142Probable G-protein coupled receptor 14228599.94100.00ND0.520.620.5MammalianExclusively 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 receptorOrphan receptor.16.04
dfaGPBARG-protein coupled bile acid receptor 1837395.9194.38ND0.700.710.6MammalianUbiquitously 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 receptorType 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
dfaGPR35G-protein coupled receptor 35722888.4582.61ND0.830.870.4MammalianPredominantly expressed in immune and gastrointestinal tissues. {ECO:0000269|PubMed:16754668}.Family A G protein-coupled receptorActs 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
dfaGPR55G-protein coupled receptor 55444580.6281.75ND0.370.530.4MammalianExpressed 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 receptorMay 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
dfaGRB2Growth factor receptor-bound protein 2118399.8599.76ND0.510.670.8MammalianOther cytosolic proteinAdapter 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 bovine15.11
dfaGRIA1Glutamate receptor 129699.0791.15ND0.680.780.7MammalianWidely expressed in brain.Ligand-gated ion channelSchizophrenia 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
dfaGRIA2Glutamate receptor 2525695.9895.24ND0.570.650.6MammalianLigand-gated ion channelReceptor 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
dfaGRIA4Glutamate receptor 4612199.6499.27ND0.500.720.8MammalianDetected in cerebellum (at protein level).Ligand-gated ion channelReceptor 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
dfaGRIK1Glutamate receptor ionotropic, kainate 1325795.0094.16ND0.510.650.7MammalianMost abundant in the cerebellum and the suprachiasmatic nuclei (SCN) of the hypothalamus.Ligand-gated ion channelAnalgesics
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: Topiramate15.11
dfaGRIK2Glutamate receptor ionotropic, kainate 2216998.6495.82ND0.620.730.8MammalianExpression is higher in cerebellum than in cerebral cortex.Ligand-gated ion channelMental 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, Thiopental16.04
dfaGRIK3Glutamate receptor ionotropic, kainate 326699.3199.54ND0.620.770.6MammalianExpressed in the deep cortical layers, dentate gyrus, reticular thalamic nucleus, mammillary bodies, pons, and cerebellum of the adult.Ligand-gated ion channelReceptor 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
dfaGRK4G protein-coupled receptor kinase 446086.6990.50ND0.460.930.5MammalianIsoform 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}.KinaseSpecifically 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
dfaGRK5G protein-coupled receptor kinase 5713686.4783.47ND0.220.480.3MammalianHighest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney. {ECO:0000269|PubMed:7685906}.KinaseSerine/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
dfaGRM1Metabotropic glutamate receptor 1870196.9689.83ND0.760.720.6MammalianDetected in brain.Family C G protein-coupled receptorSpinocerebellar 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
dfaGRM2Metabotropic glutamate receptor 2681295.5489.79ND0.700.670.6MammalianDetected 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 receptorAlzheimer'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
dfaGRM3Metabotropic glutamate receptor 3619298.7999.65ND0.670.710.6MammalianDetected 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 receptorAlzheimer'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
dfaGRM4Metabotropic glutamate receptor 4630597.8392.25ND0.640.630.4MammalianStrongly 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 receptorParkinson'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
dfaGRM5Metabotropic glutamate receptor 53223695.2786.97ND0.510.540.7MammalianFamily C G protein-coupled receptorAnalgesics
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
dfaGRM7Metabotropic glutamate receptor 725899.7197.28ND0.980.750.2MammalianExpressed 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 receptorConvulsions 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
dfaGRM8Metabotropic glutamate receptor 828299.1299.92ND0.670.410.6MammalianFamily C G protein-coupled receptorAnalgesics
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
dfaGRP7878 kDa glucose-regulated protein272100.0099.95ND0.830.900.4MammalianNote=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
dfaGSHRGlutathione reductase, mitochondrial1211887.3991.60ND0.880.830.2MammalianOxidoreductaseMaintains high levels of reduced glutathione in the cytosol.Glutathione reductase, mitochondrial : Flavin adenine dinucleotide, Glutathione
Glutathione reductase, mitochondrial inhibitor: Carmustine
15.11
dfaGSK3AGlycogen synthase kinase-3 alpha566493.4391.62ND0.610.370.6MammalianKinaseNot 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
dfaGSK3BGlycogen synthase kinase-3 beta7233793.4590.22ND0.610.660.6MammalianExpressed 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}.KinaseAlzheimer'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: Lithium15.11
dfaGSTP1Glutathione S-transferase P28399.8598.92ND0.540.700.6MammalianEnzymeConjugation 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
dfaHCAR2Hydroxycarboxylic acid receptor 2746695.9097.62ND0.560.620.6MammalianExpression 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 receptorActs 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: Niacin16.04
dfaHCAR3Hydroxycarboxylic acid receptor 334395.5799.08ND0.370.660.6MammalianExpression largely restricted to adipose tissue and spleen. {ECO:0000269|PubMed:12522134}.Family A G protein-coupled receptorReceptor 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: Niacin16.04
dfaHCKTyrosine-protein kinase HCK532698.3699.12ND0.590.630.6MammalianDetected 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}.KinaseNote=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: Bosutinib15.11
dfaHDA10Histone deacetylase 10413699.4799.10ND0.640.880.7MammalianUbiquitous. High expression in liver, spleen, pancreas and kidney.EraserResponsible 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: Panobinostat16.04
dfaHDA11Histone deacetylase 11410997.8896.73ND0.700.950.7MammalianWeakly expressed in most tissues. Strongly expressed in brain, heart, skeletal muscle, kidney and testis.EraserResponsible 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
dfaHDAC1Histone deacetylase 15166894.9593.84ND0.620.640.6MammalianUbiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain.EraserCancer, 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, Vorinostat16.04
dfaHDAC2Histone deacetylase 2446196.9495.92ND0.590.670.7MammalianWidely expressed; lower levels in brain and lung.EraserColon 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
dfaHDAC3Histone deacetylase 3437197.0394.09ND0.680.760.7MammalianWidely expressed.EraserResponsible 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, Vorinostat16.04
dfaHDAC4Histone deacetylase 4736394.6996.49ND0.750.890.6MammalianUbiquitous.EraserBrachydactyly-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: Panobinostat15.11
dfaHDAC5Histone deacetylase 5616290.9993.51ND0.900.860.4MammalianUbiquitous.EraserResponsible 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: Panobinostat16.04
dfaHDAC6Histone deacetylase 6487894.7289.26ND0.730.780.6MammalianEraserChondrodysplasia 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, Vorinostat16.04
dfaHDAC7Histone deacetylase 7516897.4996.41ND0.690.800.6MammalianEraserResponsible 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: Panobinostat15.11
dfaHDAC8Histone deacetylase 8466991.0390.42ND0.800.770.4MammalianWeakly 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}.EraserCornelia 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
dfaHDAC9Histone deacetylase 9512494.5096.24ND0.900.910.5MammalianBroadly 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}.EraserNote=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 Acid16.04
dfaHIPK2Homeodomain-interacting protein kinase 2528693.4188.81ND0.410.751.2MammalianHighly 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}.KinaseSerine/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
dfaHIPK4Homeodomain-interacting protein kinase 4227290.8694.17ND0.540.660.5MammalianKinaseProtein 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
dfaHMDH3-hydroxy-3-methylglutaryl-coenzyme A reductase273898.7598.60ND0.560.690.7MammalianMyalgiaOxidoreductaseAtherosclerosis
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, Simvastatin15.11
dfaHMOX1Heme oxygenase 1510698.3699.26ND0.580.620.5MammalianExpressed at higher levels in renal cancer tissue than in normal tissue (at protein level). {ECO:0000269|PubMed:20855888}.EnzymeHeme 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 E15.11
dfaHMOX2Heme oxygenase 228999.6599.80ND0.420.530.3MammalianEnzymeHeme 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
dfaHPGDSHematopoietic prostaglandin D synthase25791.1289.82ND0.720.780.6MammalianExpressed 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}.EnzymeBifunctional 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, Tranilast15.11
dfaHPPD4-hydroxyphenylpyruvate dioxygenase25197.8396.58ND0.710.800.4MammalianOxidoreductaseTyrosinemia 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: Nitisinone16.04
dfaHPRTHypoxanthine-guanine phosphoribosyltransferase28799.5899.51ND0.350.270.4MammalianEnzymeLesch-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
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dfaHPSEHeparanase113399.8299.90ND0.420.520.3MammalianHighly 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}.EnzymeHepatocellular 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, Heparin16.04
dfaHRH1Histamine H1 receptor4148691.3388.13ND0.700.620.6Nature11159MammalianAgranulocytosis
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 receptorAcute 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:
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dfaHRH2Histamine H2 receptor547984.1184.19ND0.530.660.6Nature11159MammalianAnticholinergic syndrome
Cycloplegia
Family A G protein-coupled receptorEpidermal 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
dfaHRH3Histamine H3 receptor5312093.3388.79ND0.530.590.7Nature11159MammalianExpressed 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 receptorAcid-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
dfaHRH4Histamine H4 receptor583496.1696.79ND0.600.620.6MammalianExpressed 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 syndromeFamily A G protein-coupled receptorAllergic 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
dfaHS90BHeat shock protein HSP 90-beta437996.4692.06ND0.790.810.5MammalianOther cytosolic proteinMolecular 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
dfaHXK4Glucokinase556498.3698.88ND0.430.560.5MammalianIsoform 1 is expressed in pancreas. Isoform 2 and isoform 3 is expressed in liver.EnzymeMaturity-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
dfaHYEPEpoxide hydrolase 138298.6296.93ND0.490.830.5MammalianFound in liver. {ECO:0000269|PubMed:12878321}.ProteaseNote=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
dfaHYESBifunctional epoxide hydrolase 23118697.8998.31ND0.540.670.7MammalianProteaseCardiovascular 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
dfaI23O1Indoleamine 2,3-dioxygenase 1426390.8285.09ND0.750.700.4MammalianExpressed 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}.EnzymeDepression 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, Melatonin16.04
dfaICMTTransmembrane protein 106A218796.3597.15ND0.650.750.5Mammalian16.04
dfaIF4EEukaryotic translation initiation factor 4E112390.7691.19ND0.380.480.5MammalianOther nuclear proteinAutism 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
dfaIF4HEukaryotic translation initiation factor 4H88699.8799.44ND0.810.860.2MammalianThe 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
dfaIGF1RInsulin-like growth factor 1 receptor4117695.2191.51ND0.800.800.6MammalianFound 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}.KinaseInsulin-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
dfaIKBANF-kappa-B inhibitor alpha14199.8599.79ND0.750.430.3MammalianOther cytosolic proteinEctodermal 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
dfaIKKAInhibitor of nuclear factor kappa-B kinase subunit alpha339091.6395.33ND0.610.680.6MammalianWidely expressed.KinaseCocoon 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, Sulfasalazine16.04
dfaIKKBInhibitor of nuclear factor kappa-B kinase subunit beta789795.3095.95ND0.670.770.6MammalianHighly expressed in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis and peripheral blood.KinaseImmunodeficiency 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
dfaIKKEInhibitor of nuclear factor kappa-B kinase subunit epsilon124088.2793.97ND0.610.580.6MammalianHighly expressed in spleen followed by thymus, peripheral blood leukocytes, pancreas, placenta. Weakly expressed in lung, kidney, prostate, ovary and colon.KinaseSerine/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
dfaIMDH1Inosine-5'-monophosphate dehydrogenase 1 {ECO:0000255|HAMAP-Rule:MF_03156}311099.7099.53ND0.640.430.7MammalianIMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor.OxidoreductaseRetinitis 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
dfaIMDH2Inosine-5'-monophosphate dehydrogenase 2 {ECO:0000255|HAMAP-Rule:MF_03156}361797.3788.90ND0.640.490.5MammalianIMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor.OxidoreductaseLeukemia, 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 acid15.11
dfaINSRInsulin receptor488494.9393.65ND0.680.720.6MammalianIsoform 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}.KinaseRabson-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
dfaINSRRInsulin receptor-related protein46699.7792.81ND0.360.940.4MammalianKinaseReceptor 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
dfaIRAK1Interleukin-1 receptor-associated kinase 1424380.4087.99ND0.510.730.4MammalianIsoform 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}.KinaseSerine/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
dfaIRAK3Interleukin-1 receptor-associated kinase 336586.2992.55ND0.320.890.5MammalianExpressed predominantly in peripheral blood lymphocytes. {ECO:0000269|PubMed:10383454}.KinaseAsthma-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
dfaIRAK4Interleukin-1 receptor-associated kinase 4537592.8791.94ND0.600.710.5MammalianKinaseRecurrent 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
dfaITA2BIntegrin alpha-IIb24199.9797.23ND0.750.500.3MammalianIsoform 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 receptorGlanzmann 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, Tirofiban15.11
dfaITA4Integrin alpha-4214796.6498.34ND0.570.830.7MammalianMembrane receptorNot 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
dfaITALIntegrin alpha-L413999.7898.72ND0.580.730.6MammalianLeukocytes.AdhesionIntegrin 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
dfaITAVIntegrin alpha-V34499.6099.80ND0.810.820.6MammalianMembrane receptorBrain 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
dfaITKTyrosine-protein kinase ITK/TSK668395.9797.47ND0.640.680.6MammalianT-cell lines and natural killer cell lines.KinaseLymphoproliferative 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: Pazopanib15.11
dfaJAK1Tyrosine-protein kinase JAK1548296.1594.85ND0.830.800.5MammalianExpressed 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}.KinaseTyrosine 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, Tofacitinib15.11
dfaJAK2Tyrosine-protein kinase JAK26128492.8090.23ND0.640.710.7MammalianUbiquitously expressed throughout most tissues. {ECO:0000269|PubMed:16424865}.KinaseNote=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, Tofacitinib15.11
dfaJAK3Tyrosine-protein kinase JAK3687794.5893.63ND0.570.690.6MammalianIn 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}.KinaseSevere 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: Tofacitinib15.11
dfaJUNTranscription factor AP-168389.1981.99ND0.730.800.4MammalianTranscription factorAllergic 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
dfaKAPCAcAMP-dependent protein kinase catalytic subunit alpha549789.7189.70ND0.460.500.6MammalianIsoform 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}.KinasePrimary 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
dfaKC1ACasein kinase I isoform alpha540789.7189.49ND0.670.620.4MammalianKinaseCasein 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
dfaKC1ALCasein kinase I isoform alpha-like36399.9485.59ND0.460.970.3MammalianKinaseCasein 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
dfaKC1DCasein kinase I isoform delta646391.3290.70ND0.740.800.5MammalianExpressed 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}.KinaseAdvanced 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
dfaKC1ECasein kinase I isoform epsilon610491.7786.87ND0.950.930.2MammalianExpressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. Expressed in monocytes and lymphocytes but not in granulocytes.KinaseCasein 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
dfaKC1G1Casein kinase I isoform gamma-1623184.5384.43ND0.680.710.4MammalianKinaseSerine/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
dfaKC1G2Casein kinase I isoform gamma-2627088.3690.66ND0.650.800.4MammalianTestis.KinaseSerine/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
dfaKC1G3Casein kinase I isoform gamma-3619386.3991.55ND0.650.710.4MammalianKinaseSerine/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
dfaKCC1ACalcium/calmodulin-dependent protein kinase type 1512485.6786.19ND0.480.820.5MammalianWidely expressed. Expressed in cells of the zona glomerulosa of the adrenal cortex. {ECO:0000269|PubMed:12193581, ECO:0000269|PubMed:17056143}.KinaseCalcium/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
dfaKCC1DCalcium/calmodulin-dependent protein kinase type 1D814087.9683.79ND0.370.910.5MammalianWidely 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}.KinaseCalcium/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
dfaKCC1GCalcium/calmodulin-dependent protein kinase type 1G36595.2398.54ND0.460.750.8MammalianMainly 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}.KinaseCalcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade. In vitro phosphorylates transcription factor CREB1 (By similarity). {ECO:0000250}.15.11
dfaKCC2ACalcium/calmodulin-dependent protein kinase type II subunit alpha514181.3883.14ND0.740.880.3MammalianKinaseCaM-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
dfaKCC2BCalcium/calmodulin-dependent protein kinase type II subunit beta222284.2489.72ND0.460.560.4MammalianWidely expressed. Expressed in adult and fetal brain. Expression is slightly lower in fetal brain. Expressed in skeletal muscle. {ECO:0000269|PubMed:16690701}.KinaseCalcium/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
dfaKCC2DCalcium/calmodulin-dependent protein kinase type II subunit delta233889.1294.12ND0.360.380.7MammalianExpressed 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}.KinaseCalcium/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
dfaKCC2GCalcium/calmodulin-dependent protein kinase type II subunit gamma123388.2890.97ND0.730.790.5MammalianExpressed in skeletal muscle. {ECO:0000269|PubMed:16690701}.KinaseCalcium/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: Bosutinib15.11
dfaKCJ11ATP-sensitive inward rectifier potassium channel 1114998.4199.97ND0.000.340.6MammalianVoltage-gated ion channelFamilial 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
dfaKCMA1Calcium-activated potassium channel subunit alpha-128597.6487.57ND0.080.511.2MammalianWidely expressed. Except in myocytes, it is almost ubiquitously expressed. {ECO:0000269|PubMed:11880513}.Voltage-gated ion channelGeneralized 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
dfaKCNA3Potassium voltage-gated channel subfamily A member 3733091.3893.94ND0.360.430.5MammalianVoltage-gated ion channelAutoimmune 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: Dalfampridine16.04
dfaKCNA5Potassium voltage-gated channel subfamily A member 5847892.4492.92ND0.650.570.4MammalianPancreatic islets and insulinoma.Voltage-gated ion channelAtrial 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: Dalfampridine16.04
dfaKCNJ1ATP-sensitive inward rectifier potassium channel 116897.8599.93ND0.420.320.3MammalianIn the kidney and pancreatic islets. Lower levels in skeletal muscle, pancreas, spleen, brain, heart and liver. {ECO:0000269|PubMed:7635463}.Voltage-gated ion channelBartter 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
dfaKCNN3Small conductance calcium-activated potassium channel protein 3311499.3298.13ND0.850.680.5MammalianVoltage-gated ion channelForms 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: Miconazole16.04
dfaKCNN4Intermediate conductance calcium-activated potassium channel protein 425098.9698.47ND0.970.940.2MammalianWidely expressed in non-excitable tissues.Voltage-gated ion channelDehydrated 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, Quinine16.04
dfaKCNQ1Potassium voltage-gated channel subfamily KQT member 1 {ECO:0000305}49498.1590.35ND0.510.670.7MammalianAbundantly 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 channelLong 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, Indapamide16.04
dfaKCNQ2Potassium voltage-gated channel subfamily KQT member 2517490.9889.30ND0.060.500.9MammalianIn 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 channelSeizures, 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
dfaKDM1ALysine-specific histone demethylase 1A714595.8597.60ND0.770.720.4MammalianUbiquitously expressed. {ECO:0000269|PubMed:16079795}.EraserHistone 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
dfaKGP1cGMP-dependent protein kinase 1218892.0995.67ND0.600.570.5MammalianPrimarily expressed in lung and placenta. {ECO:0000269|PubMed:9192852}.KinaseAortic 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
dfaKGP2cGMP-dependent protein kinase 2213196.7794.32ND0.470.680.6MammalianHighly concentrated in brain, lung and intestinal mucosa.Kinase16.04
dfaKHKKetohexokinase {ECO:0000312|HGNC:HGNC:6315}28599.9099.93ND0.480.460.5MammalianMost abundant in liver, kidney, gut, spleen and pancreas. Low levels also found in adrenal, muscle, brain and eye. {ECO:0000269|PubMed:9799106}.EnzymeFructosuria (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
dfaKIF11Kinesin-like protein KIF11475896.5095.34ND0.550.640.6MammalianOther cytosolic proteinMicrocephaly 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
dfaKISSRKiSS-1 receptor15299.91100.00ND0.510.650.8MammalianMost 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 receptorHypogonadotropic 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
dfaKITMast/stem cell growth factor receptor Kit580796.2696.40ND0.580.660.6MammalianIsoform 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}.KinasePiebald 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
dfaKITHThymidine kinase, cytosolic39099.6999.46ND0.470.580.5MammalianEnzymeThymidine kinase, cytosolic substrate: Trifluridine, Zidovudine16.04
dfaKKCC1Calcium/calmodulin-dependent protein kinase kinase 156697.6395.97ND0.660.820.3MammalianKinaseCalcium/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
dfaKKCC2Calcium/calmodulin-dependent protein kinase kinase 277791.7185.91ND0.710.850.6MammalianUbiquitously 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}.KinaseCalcium/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
dfaKLKKallikrein-1015899.8199.79ND0.570.270.3MammalianExpressed in breast, ovary and prostate.Has a tumor-suppressor role for NES1 in breast and prostate cancer.16.04
dfaKLK1Kallikrein-137799.1699.79ND0.850.870.4MammalianIsoform 2 is expressed in pancreas, salivary glands, kidney, colon, prostate gland, testis, spleen and the colon adenocarcinoma cell line T84. {ECO:0000269|PubMed:7749372}.ProteaseGlandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.16.04
dfaKLKB1Plasma kallikrein311295.2088.99ND0.850.960.5MammalianProteasePrekallikrein 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: Ecallantide16.04
dfaKMOKynurenine 3-monooxygenase {ECO:0000255|HAMAP-Rule:MF_03018}25499.5692.20ND0.190.820.3MammalianHighest levels in placenta and liver. Detectable in kidney. {ECO:0000269|PubMed:9237672}.EnzymeCatalyzes 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
dfaKPCAProtein kinase C alpha type494593.3592.34ND0.620.690.8MammalianKinaseLeukemia, 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
dfaKPCBProtein kinase C beta type335197.2996.28ND0.680.740.6MammalianKinaseB-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
dfaKPCDProtein kinase C delta type478589.7787.21ND0.620.000.7MammalianKinaseAutoimmune 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 Mebutate15.11
dfaKPCD1Serine/threonine-protein kinase D1315498.9098.70ND0.800.840.6MammalianKinaseSerine/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
dfaKPCD2Serine/threonine-protein kinase D2734188.6691.26ND0.370.560.5MammalianWidely expressed.KinaseSerine/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
dfaKPCD3Serine/threonine-protein kinase D3541188.5189.90ND0.650.700.5MammalianUbiquitous.KinaseConverts transient diacylglycerol (DAG) signals into prolonged physiological effects, downstream of PKC. Involved in resistance to oxidative stress (By similarity). {ECO:0000250}.16.04
dfaKPCEProtein kinase C epsilon type634895.1097.39ND0.570.540.8MammalianKinaseNot 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
dfaKPCGProtein kinase C gamma type637189.7391.12ND0.440.610.8MammalianExpressed in Purkinje cells of the cerebellar cortex. {ECO:0000269|PubMed:12644968}.KinaseSpinocerebellar 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
dfaKPCIProtein kinase C iota type710788.4886.81ND0.840.610.4MammalianPredominantly 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}.KinaseCalcium- 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
dfaKPCLProtein kinase C eta type424997.9195.02ND0.500.661.0MammalianMost abundant in lung, less in heart and skin. {ECO:0000269|PubMed:1986216}.KinaseIschemic 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
dfaKPCTProtein kinase C theta type357690.9792.04ND0.640.660.6MammalianExpressed in skeletal muscle, T-cells, megakaryoblastic cells and platelets. {ECO:0000269|PubMed:7686153}.KinaseNot 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
dfaKPCZProtein kinase C zeta type516887.4691.53ND0.360.680.9MammalianExpressed in brain, and to a lesser extent in lung, kidney and testis.KinaseNot 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
dfaKPYMPyruvate kinase PKM7113185.2483.60ND0.610.580.4MammalianSpecifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. {ECO:0000269|PubMed:18191611}.EnzymeGlycolytic 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
dfaKS6A1Ribosomal protein S6 kinase alpha-1712994.5893.82ND0.760.820.4MammalianKinaseSerine/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
dfaKS6A3Ribosomal protein S6 kinase alpha-3559485.7988.66ND0.580.560.5MammalianExpressed in many tissues, highest levels in skeletal muscle.KinaseCoffin-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
dfaKS6A4Ribosomal protein S6 kinase alpha-458592.8394.28ND0.310.890.8MammalianKinaseSerine/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
dfaKS6A5Ribosomal protein S6 kinase alpha-5724891.3391.06ND0.470.730.8MammalianWidely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver. {ECO:0000269|PubMed:9687510, ECO:0000269|PubMed:9873047}.KinaseSerine/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
dfaKS6A6Ribosomal protein S6 kinase alpha-696589.1987.53ND0.800.860.4MammalianKinaseConstitutively 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
dfaKS6B1Ribosomal protein S6 kinase beta-1644286.6586.64ND0.490.610.6MammalianWidely expressed. {ECO:0000269|PubMed:9804755}.KinaseCancer, 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
dfaKSYKTyrosine-protein kinase SYK158292.1187.61ND0.650.560.6MammalianWidely 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}.KinaseAllergic 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
dfaLATS1Serine/threonine-protein kinase LATS126499.8296.84ND0.960.930.1MammalianExpressed in all adult tissues examined except for lung and kidney. {ECO:0000269|PubMed:10518011}.KinaseNegative 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
dfaLCAPLeucyl-cystinyl aminopeptidase36897.1099.58ND0.850.800.5MammalianHighly 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}.ProteaseRelease 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
dfaLCKTyrosine-protein kinase Lck6176794.0293.67ND0.590.680.7MammalianExpressed specifically in lymphoid cells.KinaseNote=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
dfaLDHAL-lactate dehydrogenase A chain59799.5890.76ND0.530.790.6MammalianEnzymeGlycogen 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
dfaLDHBL-lactate dehydrogenase B chain64899.1699.52ND0.650.730.5MammalianEnzymeLactate 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
dfaLGULLactoylglutathione lyase36392.8590.22ND0.700.750.5MammalianEnzymeTumors 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
dfaLIMK1LIM domain kinase 1743787.2782.90ND0.520.720.5MammalianHighest 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.KinaseNote=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: Dabrafenib15.11
dfaLIMK2LIM domain kinase 2212089.4792.75ND0.890.830.4MammalianHighest 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}.KinaseDisplays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro. {ECO:0000269|PubMed:10436159, ECO:0000269|PubMed:11018042}.15.11
dfaLIPLLipoprotein lipase25699.6385.95ND0.370.750.8MammalianEnzymeLipoprotein 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
dfaLIPSHormone-sensitive lipase315992.8990.04ND0.480.580.8MammalianEnzymeLipodystrophy, 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
dfaLKHA4Leukotriene A-4 hydrolase348097.8796.63ND0.560.550.6MammalianIsoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.ProteaseInflammation
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
dfaLMBL3Lethal(3)malignant brain tumor-like protein 319396.3497.29ND0.830.740.4MammalianReaderPutative 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
dfaLOX12Arachidonate 12-lipoxygenase, 12S-type742290.7089.45ND0.550.630.4MammalianExpressed in vascular smooth muscle cells. {ECO:0000269|PubMed:23578768}.EnzymeEsophageal 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
dfaLOX5Arachidonate 5-lipoxygenase3238792.8182.52ND0.460.570.6MammalianOxidoreductaseNot 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
dfaLPAR1Lysophosphatidic acid receptor 1413296.5197.92ND0.780.590.4MammalianExpressed 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 receptorMultiple 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