Available 3D Atomic Property Field (dfz)

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model	name	nof_cluster	nof_ligand	auc	tag	Tissue	category	ADR	Disease	Function	Drug_Mechanism
dfzADA17	Disintegrin and metalloproteinase domain-containing protein 17	5	1713	98.08		Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney.			Inflammatory bowel disease Inflammatory diseases Neuroimmunological diseases	Cleaves the membrane-bound precursor of tnf-alpha to its mature soluble form. Responsible for the proteolytic release of several other cell-surface proteins, including p75 tnf-receptor, interleukin 1 receptor type II and p55 tnf-receptor.
dfzATS4	A disintegrin and metalloproteinase with thrombospondin motifs 4	1	205	92.49		Expressed in brain, lung and heart. Expressed at very low level in placenta and skeletal muscles.			Osteoarthritis	Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. Could also be a critical factor in the exacerbation of neurodegeneration in alzheimer's disease.
dfzATS5	A disintegrin and metalloproteinase with thrombospondin motifs 5	1	379	84.57		Expressed at low level in placenta primarily but also detected in heart and brain, cervix, uterus, bladder, esophagus, rib cartilage, chondroblastoma, fibrous tissue and a joint capsule from an arthritic patient.			Osteoarthritis	Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. May play a role in proteolytic processing mostly during the peri-implantation period.
dfzBRD2	Bromodomain-containing protein 2	1	74	99.65						May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.
dfzBRD3	Bromodomain-containing protein 3	2	74	84.35		Ubiquitous.			Note=A chromosomal aberration involving BRD3 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with NUT which produces a BRD3-NUT fusion protein.	Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors. Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets (By similarity). Regulates transcription of the CCND1 gene.
dfzBRD4	Bromodomain-containing protein 4	2	153	98.93		Ubiquitously expressed.			Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.	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. 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.
dfzCPNS1	Calpain small subunit 1	1	102	81.53						Regulatory subunit of the calcium-regulated non- lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.
dfzEGLN1	Egl nine homolog 1	3	211	97.57		According to PubMed:11056053, widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to PubMed:12351678 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. According to PubMed:12788921; expressed in adult and fetal heart, brain, liver, lung, skeletal muscle and kidney. Also expressed in placenta. Highest levels in adult heart, brain, lung and liver and fetal brain, heart spleen and skeletal muscle.			Erythrocytosis, familial, 3 (ECYT3) [MIM:609820]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels. 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 preferencially recognized via a LXXLAP motif.
dfzLMBL1	Lethal(3)malignant brain tumor-like protein 1	1	56	99.99		Widely expressed. Expression is reduced in colorectal cancer cell line SW480 and promyelocytic leukemia cell line HL-60.				Polycomb group (PcG) protein that specifically recognizes and binds mono- and dimethyllysine residues on target proteins, therey acting as a 'reader' of a network of post- translational modifications. PcG proteins maintain the transcriptionally repressive state of genes: acts as a chromatin compaction factor by recognizing and binding mono- and dimethylated histone H1b/HIST1H1E at 'Lys-26' (H1bK26me1 and H1bK26me2) and histone H4 at 'Lys-20' (H4K20me1 and H4K20me2), leading to condense chromatin and repress transcription. Recognizes and binds p53/TP53 monomethylated at 'Lys-382', leading to repress p53/TP53-target genes. Also recognizes and binds RB1/RB monomethylated at 'Lys-860'. Participates in the ETV6-mediated repression. Probably plays a role in cell proliferation. Overexpression induces multinucleated cells, suggesting that it is required to accomplish normal mitosis.
dfzLMBL3	Lethal(3)malignant brain tumor-like protein 3	1	60	99.3						Putative Polycomb group (PcG) protein. PcG proteins maintain the transcriptionally repressive state of genes, probably via a modification of chromatin, rendering it heritably changed in its expressibility. Required for normal maturation of myeloid progenitor cells (By similarity).
dfzPARP1	Poly [ADP-ribose] polymerase 1	2	1350	96.4					Asthma Cancer, unspecific Chronic obstructive pulmonary disease Diabetic cardiovascular dysfunction Diabetic endothelial dysfunction Multiple sclerosis Traumatic brain injury Tumors	Involved in the base excision repair (ber) pathway, by catalysing the poly(adp-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in dna metabolism. This modification follows DNA damages.
dfzPARP2	Poly [ADP-ribose] polymerase 2	1	72	92.41		Widely expressed, mainly in actively dividing tissues. The highest levels are in the brain, heart, pancreas, skeletal muscle and testis; also detected in kidney, liver, lung, placenta, ovary and spleen; levels are low in leukocytes, colon, small intestine, prostate and thymus.				Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks.
dfzPIN1	Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1	1	80	96.04		The phosphorylated form at Ser-71 is expressed in normal breast tissue cells but not in breast cancer cells. <a class="attribution" href="Q13526#ref11" onclick="ensureReferenceVisible('ref11')">Ref.11</a> <a class="attribution" href="Q13526#ref18" onclick="ensureReferenceVisible('ref18')">Ref.18</a>			Alzheimer's disease Cancer, unspecific Hepatocellular carcinoma	Essential ppiase that regulates mitosis presumably by interacting with nima and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue n-terminal to the isomerized proline bond. Catalyzing pser/thr-pro cis/trans isomerization.
dfzPUR2	Trifunctional purine biosynthetic protein adenosine-3	2	80	99.93					Solid tumor		GAR transformylase inhibitor: Pemetrexed
dfzSHBG	Sex hormone-binding globulin	2	90	93.67		Isoform 1 and isoform 2 are present in liver and testis.				Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol. Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentration.
dfzSPHK1	Sphingosine kinase 1	3	152	98.43		Widely expressed with highest levels in adult liver, kidney, heart and skeletal muscle. <a class="attribution" href="Q9NYA1#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a>			Late-Stage Ovarian cancer Prostate cancer
dfzTNKS1	Tankyrase-1	2	94	84.59		Ubiquitous; highest levels in testis.				Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1. Stimulates 26S proteasome activity.
dfzTNKS2	Tankyrase-2	4	140	86.29		Highly expressed in placenta, skeletal muscle, liver, brain, kidney, heart, thymus, spinal cord, lung, peripheral blood leukocytes, pancreas, lymph nodes, spleen, prostate, testis, ovary, small intestine, colon, mammary gland, breast and breast carcinoma, and in common-type meningioma. Highly expressed in fetal liver, heart and brain.				Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP- ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. Stimulates 26S proteasome activity.
dfzTP53B	Tumor suppressor p53-binding protein 1	1	55	98.52					Note=A chromosomal aberration involving TP53BP1 is found in a form of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;15)(q33;q22) with PDGFRB creating a TP53BP1-PDGFRB fusion protein.	Plays a key role in the response to DNA damage. May have a role in checkpoint signaling during mitosis. Enhances TP53- mediated transcriptional activation.
dfzAAKB1	5'-AMP-activated protein kinase subunit beta-1	1	95	87.66			5'-AMP-activated protein kinase beta subunit			Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).
dfzHYES	Bifunctional epoxide hydrolase 2	3	1252	97.01			AB hydrolase		Cardiovascular disease, unspecified Hypertension Renal diseases	This enzyme acts on epoxides (alkene oxides, oxiranes) and arene oxides. plays a role in xenobiotic metabolism by degrading potential toxic epoxides. also determines steady- state levels of physiological mediators.
dfzCETP	Cholesteryl ester transfer protein	2	628	90.86		Expressed by the liver and secreted in plasma.	BPI/LBP/Plunc		Atherosclerosis Coronary atherosclerosis Hypercholesterolemia Hyperlipidemia Peripheral Vascular Disease	Involved in the transfer of insoluble cholesteryl esters in the reverse transport of cholesterol.
dfzB2CL1	Bcl-2-like protein 1	2	189	94.48		Bcl-X(S) is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, Bcl-X(L) is found in tissues containing long-lived postmitotic cells, such as adult brain.	Bcl-2		Anaplastic Large Cell Lymphomas Colorectal cancer Mesothelioma	Potent inhibitor of cell death. Isoform bcl-x(l) anti- apoptotic activity is inhibited by association with siva isoform 1. Inhibits activation of caspases (by similarity). Appears to regulate cell death by blocking the voltage-dependent anion channnel.
dfzBCL2	Apoptosis regulator Bcl-2	1	230	90.23		Expressed in a variety of tissues.	Bcl-2		Chronic lymphocytic leukemia Prostate cancer (hormone refractory) Waldenstrom's macroglobulinemia	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.
dfzOXDA	D-amino-acid oxidase	2	126	90.29			DAMOX/DASOX			Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D- amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids.
dfzDCK	Deoxycytidine kinase	1	98	97.5			DCK/DGK			Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.
dfzF16P1	Fructose-1,6-bisphosphatase 1	3	331	97.79			FBPase class 1		Diabetes Mellitus Type 2
dfzFKB1A	Peptidyl-prolyl cis-trans isomerase FKBP1A	2	346	97.05			FKBP-type PPIase
dfzFPPS	Farnesyl pyrophosphate synthase	1	159	99.84			FPP/GGPP synthase		Cancer, unspecific Chagas' disease Hypercholesterolemia Leishmania infections Myeloma disease Osteoporosis, unspecified Skeletal disorders Toxoplasma infections Trypanosomatid infections	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.
dfz5HT2B	5-hydroxytryptamine receptor 2B	1	2659	65.74	Nature11159	Ubiquitous. Detected in liver, kidney, heart, pulmonary artery, and intestine. Detected at lower levels in blood, placenta and brain, especially in cerebellum, occipital cortex and frontal cortex. <a class="attribution" href="P41595#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a> <a class="attribution" href="P41595#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a> <a class="attribution" href="P41595#ref3" onclick="ensureReferenceVisible('ref3')">Ref.3</a> <a class="attribution" href="P41595#ref10" onclick="ensureReferenceVisible('ref10')">Ref.10</a> <a class="attribution" href="P41595#ref15" onclick="ensureReferenceVisible('ref15')">Ref.15</a>	G-protein coupled receptor 1	Dry mouth Dyskinesia Extrapyramidal disorder Insomnia Nasal congestion Orthostatic hypotension	Anxiety disorder, unspecified Migraine P-chloroamphetamine-induced hyperglycemia	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 mediates its action by association with G proteins.	Serotonin 2b (5-HT2b) receptor antagonist: Methysergide Serotonin 2b (5-HT2b) receptor partial agonist: Methylergonovine
dfzAA2AR	Adenosine receptor A2a	2	5907	92.25	Nature11159		G-protein coupled receptor 1	Angina pectoris Flushing Palpitations	Analgesics Brain injury Depression Dyskinesia Inflammation Ischemia reperfusion injuries Neurodegenerative diseases Neuropsychiatric disorders Oxygen-induced retinopathy Pain Parkinson's disease Renal diseases	Receptor for adenosine, and the activity of this receptor is mediated by G proteins which activate adenylyl cyclase.	Adenosine A2 receptor antagonist: Pentoxifylline Adenosine A2a receptor agonist: Regadenoson
dfzACM2	Muscarinic acetylcholine receptor M2	1	2700	72.26	Nature11159		G-protein coupled receptor 1	Anticholinergic syndrome Constipation Cycloplegia Diabetic eye disease Dry mouth Dry skin Extrapyramidal disorder Gastric hypomotility Hyperpyrexia Intraocular pressure increased Mydriasis Salivary hypersecretion Tachycardia Urinary incontinence Urinary retention Vision blurred	Alzheimer's disease Analgesics Autoimmune cardiomyopathy Bronchoconstriction (cold air-induced) Chronic obstructive pulmonary disease, unspecified Hypothermia Neurogenic bladder Pain, unspecified Tremor, unspecified	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.	Muscarinic acetylcholine receptor M2 agonist: Bethanechol Muscarinic acetylcholine receptor M2 antagonist: Atropine, Darifenacin, Fesoterodine, Oxybutynin, Propantheline, Solifenacin, Tolterodine, Trospium
dfzACM3	Muscarinic acetylcholine receptor M3	1	2459	70.12	Nature11159		G-protein coupled receptor 1	Anticholinergic syndrome Constipation Cycloplegia Diabetic eye disease Dry mouth Dry skin Dysphagia Extrapyramidal disorder Hyperpyrexia Intraocular pressure increased Mydriasis Salivary hypersecretion Tachycardia Urinary retention Vision blurred	Airway hyperreactivity Urge incontinence	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.	Muscarinic acetylcholine receptor M3 agonist: Acetylcholine, Bethanechol, Carbachol, Cevimeline, Methacholine, Pilocarpine Muscarinic acetylcholine receptor M3 antagonist: Aclidinium, Anisotropine, Atropine, Clidinium, Cyclopentolate, Darifenacin, Dicyclomine, Diphemanil, Fesoterodine, Glycopyrrolate, Hexocyclium, Ipratropium, Isopropamide, Mepenzolate, Methscopolamine, Oxybutynin, Oxyphencyclimine, Oxyphenonium, Propantheline, Solifenacin, Tiotropium, Tolterodine, Tridihexethyl, Tropicamide, Trospium
dfzADRB2	Beta-2 adrenergic receptor	3	1960	90.91	Nature11159		G-protein coupled receptor 1	Angina pectoris Anxiety Arrhythmia Atrioventricular block Bradycardia Bronchospasm Cardiac arrest Cardiac failure Cardiac failure congestive Dry eye Fear Myocardial infarction Neurotoxicity Palpitations Peripheral coldness Raynaud's phenomenon Sleep disorder Tachycardia Tension Tremor Vasodilatation Ventricular arrhythmia	Anxiety disorder, unspecified Asthma Cardiac arrhythmias Chronic obstructive pulmonary disease, unspecified Depression Glaucoma Hypertension Inflammation Multiple sclerosis Obstructive airway disease Respiratory distress syndrome Skeletal muscle wasting Skeletal muscle weakness	Beta-adrenergic receptors mediate the catecholamine- induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine.	Beta-2 adrenergic receptor agonist: Albuterol, Arformoterol, Bitolterol, Dobutamine, Formoterol, Indacaterol, Isoetharine, Levosalbutamol, Metaproterenol, Pirbuterol, Protokylol, Ritodrine, Salmeterol, Terbutaline, Vilanterol Beta-2 adrenergic receptor antagonist: Esmolol, Levobunolol, Metipranolol, Nadolol, Nebivolol, Oxprenolol, Penbutolol, Propafenone, Propranolol, Sotalol, Timolol Beta-2 adrenergic receptor partial agonist: Pindolol
dfzCCKAR	Cholecystokinin receptor type A	0	2272	69.6	Nature11159		G-protein coupled receptor 1		Acid-related diseases Alcoholism Gastroesophageal Reflux Disease (GERD) Gastrointestinal Diseases and Disorders, miscellaneous Gastrointestinal motility disorders Irritable Bowel Syndrome (IBS) Obesity Pancreatic Cancer	Receptor for cholecystokinin. 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 protein.	Cholecystokinin A receptor agonist: Ceruletide
dfzCCR5	C-C chemokine receptor type 5	1	1856	96		Highly expressed in spleen, thymus, in the myeloid cell line THP-1, in the promyeloblastic cell line KG-1a and on CD4+ and CD8+ T-cells. Medium levels in peripheral blood leukocytes and in small intestine. Low levels in ovary and lung. <a class="attribution" href="P51681#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a> <a class="attribution" href="P51681#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a>	G-protein coupled receptor 1		Human immunodeficiency virus [HIV] disease	Receptor for a c-c type chemokine. Binds to MIP-1-alpha, MIP-1-beta and rantes and subsequently transduces a signal by increasing the intracellular calcium ions level. May play a role in the control of granulocytic lineage proliferation or differentiation.	C-C chemokine receptor type 5 antagonist: Maraviroc
dfzCXCR4	C-X-C chemokine receptor type 4	1	177	85.91			G-protein coupled receptor 1		Breast cancer HIV Infection Human immunodeficiency virus [HIV] disease Late-stage Solid tumors Multiple Myeloma Non-Hodgkin's Lymphoma Ovarian cancer Prostate cancer (metastatic)	Receptor for the c-x-c chemokine sdf-1. Transduces a signal by increasing the intracellular calcium ions level. Involved in haematopoiesis and in cardiac ventricular septum formation. Plays also an essential role in vascularization of the gastrointestinal tract.
dfzDRD3	D(3) dopamine receptor	1	3682	76.75	Nature11159	Brain.	G-protein coupled receptor 1	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	Drug dependence Neurological diseases Psychiatric illness Respiratory diseases Schizophrenia	This is one of the five types (D1 to D5) of receptors for dopamine, and the activity of this receptor is mediated by g proteins which activate adenylyl cyclase.	Dopamine D3 receptor agonist: Levodopa Dopamine D3 receptor antagonist: Chlorprothixene
dfzGASR	Gastrin/cholecystokinin type B receptor	0	2373	81.59	Nature11159	Isoform <a href="#P32239" onclick="ensureIsoformSequenceVisible('P32239'); return true;">1</a> 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 <a href="#P32239-2" onclick="ensureIsoformSequenceVisible('P32239-2'); return true;">2</a> is present in pancreatic cancer cells and colorectal cancer cells, but not in normal pancreas or colonic mucosa. Isoform <a href="#P32239-3" onclick="ensureIsoformSequenceVisible('P32239-3'); return true;">3</a> is expressed in brain, pancreas, stomach, the stomach cancer cell line AGS and the colon cancer cell line LoVo. <a class="attribution" href="P32239#ref3" onclick="ensureReferenceVisible('ref3')">Ref.3</a> <a class="attribution" href="P32239#ref5" onclick="ensureReferenceVisible('ref5')">Ref.5</a> <a class="attribution" href="P32239#ref6" onclick="ensureReferenceVisible('ref6')">Ref.6</a> <a class="attribution" href="P32239#ref7" onclick="ensureReferenceVisible('ref7')">Ref.7</a> <a class="attribution" href="P32239#ref8" onclick="ensureReferenceVisible('ref8')">Ref.8</a> <a class="attribution" href="P32239#ref10" onclick="ensureReferenceVisible('ref10')">Ref.10</a>	G-protein coupled receptor 1		Acid-related diseases Anxiety disorder, unspecified Cocaine dependence Gastrin sensitive tumours Gastrointestinal adenocarcinomas Gastrointestinal motility disorders Malignant gliomas Medullary thyroid cancer Neuroendocrine tumors Small cell lung cancer Stromal ovarian tumors	Receptor for gastrin and cholecystokinin, and 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.
dfzHRH1	Histamine H1 receptor	1	1583	85.77	Nature11159		G-protein coupled receptor 1	Agranulocytosis Akathisia Anticholinergic syndrome Ataxia Bladder disorder Bone marrow disorder Central nervous system stimulation Chest discomfort Conduction disorder Constipation Convulsion Cycloplegia Dermatitis allergic Diabetic eye disease Dry mouth Dystonia Dysuria Euphoric mood Extrapyramidal disorder Galactorrhoea Haemolytic anaemia Hypercholesterolaemia Hyperthermia Hyporeflexia Increased appetite Increased viscosity of bronchial secretion Insomnia Muscular weakness Myopathy Nervousness Parkinsonism Photosensitivity reaction Sedation Skin sensitisation Somnolence Tachycardia Tardive dyskinesia Tinnitus Tremor Urinary retention Urinary tract disorder Vision blurred Weight increased	Acute lymphoblastic leukaemia (therapy-refractory) Allergic diseases Allergic rhinitis, unspecified Anxiety disorder, unspecified Chronic rhinitis Chronic urticaria Epidermal hyperplasia Epilepsy Hypotension Intimal hyperplasia Ischemia Motion sickness Nausea and vomiting Seasonal allergic rhinitis Systemic arterial vasodilation	In peripheral tissues, the h1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neuro.	Histamine H1 receptor agonist: Histamine, Tolazoline Histamine H1 receptor antagonist: Acrivastine, Alcaftadine, Antazoline, Azatadine, Azelastine, Bepotastine, Bromodiphenhydramine, Brompheniramine, Buclizine, Carbinoxamine, Cetirizine, Chlorpheniramine, Chlorpheniramine Polistirex, Clemastine, Cyclizine, Cyproheptadine, Desloratadine, Dexbrompheniramine, Dexchlorpheniramine, Dimenhydrinate, Diphenhydramine, Diphenylpyraline, Doxylamine, Emedastine, Epinastine, Fexofenadine, Hydroxyzine, Ketotifen, Levocabastine, Levocetirizine, Loratadine, Meclizine, Methdilazine, Methylpromazine, Olopatadine, Orphenadrine, Pheniramine, Promethazine, Propiomazine, Pyrilamine, Trimipramine, Tripelennamine, Triprolidine
dfzOPRD	Delta-type opioid receptor	1	5131	88.1	Nature11159		G-protein coupled receptor 1	Biliary colic Bladder disorder Bradycardia Cerebrovascular disorder Constipation Death Dependence Dermatitis contact Drug tolerance Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Restlessness Shock Somnolence Ureteral spasm Urticaria Withdrawal syndrome	Analgesics Cough Dyspnea Ischemia Pain, unspecified Parkinson's disease	Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Highly stereoselective and receptor for enkephalins.	Opioid receptors; mu/kappa/delta agonist: Codeine, Codeine Polistirex, Hydrocodone, Hydrocodone Polistirex, Nalbuphine, Oxymorphone Opioid receptors; mu/kappa/delta antagonist: Nalmefene, Naloxone, Naltrexone
dfzOPRK	Kappa-type opioid receptor	1	5440	81.86	Nature11159	Detected in brain and placenta. <a class="attribution" href="P41145#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a> <a class="attribution" href="P41145#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a>	G-protein coupled receptor 1	Biliary colic Bladder disorder Bradycardia Cerebrovascular disorder Coma Constipation Death Dependence Dermatitis contact Drug tolerance Dysphoria Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Respiratory disorder Restlessness Shock Somnolence Ureteral spasm Withdrawal syndrome	Alcohol dependence Analgesics Behcet's disease Diarrhea Dyspnea Focal ischemia Immune disease Neurodegenerative diseases Pain, unspecified	Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. The receptor for dynorphins and may play a role in arousal and regulation of autonomic and neuroendocrine functions.	Kappa opioid receptor agonist: Anileridine, Buprenorphine Kappa opioid receptor antagonist: Dezocine Kappa opioid receptor partial agonist: Butorphanol, Levallorphan
dfzOPRM	Mu-type opioid receptor	2	6374	83.87	Nature11159	Expressed in brain. Isoform <a href="#P35372-16" onclick="ensureIsoformSequenceVisible('P35372-16'); return true;">16</a> and isoform <a href="#P35372-17" onclick="ensureIsoformSequenceVisible('P35372-17'); return true;">17</a> are detected in brain. <a class="attribution" href="P35372#ref32" onclick="ensureReferenceVisible('ref32')">Ref.32</a>	G-protein coupled receptor 1	Biliary colic Biliary tract disorder Bladder disorder Bradycardia Cerebrovascular disorder Coma Constipation Death Dependence Dermatitis contact Disorientation Drug tolerance Dry mouth Dysphoria Dysuria Euphoric mood Hyperhidrosis Hypothermia Injection site irritation Injection site pain Intracranial pressure increased Mental disorder Miosis Mood altered Muscle rigidity Muscle spasms Oliguria Orthostatic hypotension Pruritus Respiratory depression Respiratory disorder Restlessness Shock Somnolence Ureteral spasm Urticaria Withdrawal syndrome	Analgesics Cough Diarrhea Dyspnea Opioid-induced bowel dysfunction Pain, unspecified	Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. The receptor for beta-endorphin.	Mu opioid receptor agonist: Alfentanil, Anileridine, Buprenorphine, Difenoxin, Dihydrocodeine, Diphenoxylate, Fentanyl, Hydromorphone, Levomethadyl Acetate, Levorphanol, Loperamide, Meperidine, Methadone, Morphine, Oxycodone, Propoxyphene, Remifentanil, Sufentanil, Tapentadol, Tramadol Mu opioid receptor antagonist: Alvimopan, Levallorphan, Methylnaltrexone Mu opioid receptor partial agonist: Butorphanol, Dezocine
dfzOPRX	Nociceptin receptor	1	1314	85.56			G-protein coupled receptor 1	Hyperhidrosis	Analgesics Anorexia nervosa Anxiety disorder, unspecified Cerebral ischemia Depression Drug dependence Epilepsy Erectile dysfunction Hypertension Neurogenic bladder Neuropathic pain Pain, unspecified	Receptor for the neuropeptide nocipeptin/orphanin fq. Has a potential role in modulating a number of brain functions, including instinctive behaviors and emotions. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase.
dfzP2Y12	P2Y purinoceptor 12	1	848	88.05		Highly expressed in the platelets, lower levels in the brain. Lowest levels in the lung, appendix, pituitary and adrenal gland. Expressed in the spinal cord and in the fetal brain.	G-protein coupled receptor 1		Aggregation and activation of platelets Cardiovascular disease, unspecified Thrombosis	Receptor for adp and atp coupled to g-proteins that inhibit the adenylyl cyclase second messenger system, which is not activated by udp and utp. Involved in platelets aggregation.	Purinergic receptor P2Y12 antagonist: Clopidogrel, Prasugrel, Ticlopidine Purinergic receptor P2Y12 negative allosteric modulator: Ticagrelor
dfzCALRL	Calcitonin gene-related peptide type 1 receptor	1	537	98.76		Predominantly expressed in the lung and heart.	G-protein coupled receptor 2		Cluster Headaches Diabetes mellitus Migraine Opioid dependence	This is a receptor for calcitonin gene-related peptide type 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
dfzCRFR1	Corticotropin-releasing factor receptor 1	1	2220	94.15	Nature11159	Predominantly expressed in the cerebellum, pituitary, cerebral cortex and olfactory lobe. <a class="attribution" href="P34998#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a>	G-protein coupled receptor 2		Anxiety Disorders Depression Innate anxiety Irritable Bowel Syndrome (IBS) Obesity Stress-related disorders	This is a receptor for corticotropin releasing factor. Shows high-affinity crf binding. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
dfzGABR1	Gamma-aminobutyric acid type B receptor subunit 1	1	80	98.21		Highly expressed in brain and weakly in heart, small intestine and uterus. Isoform 1A is mostly expressed in granular cell and molecular layer. Isoform 1B is mostly expressed in Purkinje cells. Isoform 1E is predominantly expressed in peripheral tissues as kidney, lung, trachea, colon, small intestine, stomach, bone marrow, thymus and mammary gland.	G-protein coupled receptor 3			Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Calcium is required for high affinity binding to GABA. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception. Activated by (-)-baclofen, cgp27492 and blocked by phaclofen. Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites.
dfzSMO	Smoothened homolog	2	448	95.15			G-protein coupled receptor Fz/Smo		Cancers	G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia.	Smoothened homolog inhibitor: Vismodegib
dfzGRB2	Growth factor receptor-bound protein 2	1	57	98.9			GRB2/sem-5/DRK			Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.
dfzHMDH	3-hydroxy-3-methylglutaryl-coenzyme A reductase	1	819	96.28			HMG-CoA reductase	Myalgia	Atherosclerosis Cardiovascular disease, unspecified Cervical cancer Coronary heart disease Dyslipidemia Head and neck squamous cell carcinomas Hypercholesterolemia Hypertriglyceridemia Myocardial infarction	This transmembrane glycoprotein is involved in the control of cholesterol biosynthesis. It is the rate-limiting enzyme of sterol biosynthesis.	HMG-CoA reductase inhibitor: Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin
dfzBIRC2	Baculoviral IAP repeat-containing protein 2	1	95	98.78		Present in many fetal and adult tissues. Mainly expressed in adult skeletal muscle, thymus, testis, ovary, and pancreas, low or absent in brain and peripheral blood leukocytes.	IAP			Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin- protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin- protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO, IKBKE and MXD1/MAD1. Can also function as an E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs), collectively referred to as pattern recognition receptors (PRRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase- dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle.
dfzXIAP	E3 ubiquitin-protein ligase XIAP	1	392	98.6		Ubiquitous, except peripheral blood leukocytes.	IAP		Hepatocellular carcinoma Neoplasms Ovarian cancer	Apoptotic suppressor. Inhibitor of caspase-3, -7 and -9.
dfzPTGES	Prostaglandin E synthase	1	459	83.32			MAPEG		Inflammation Rheumatoid arthritis, unspecified
dfzMDM2	E3 ubiquitin-protein ligase Mdm2	1	534	93.21		Ubiquitous. Isoform <a href="#Q00987" onclick="ensureIsoformSequenceVisible('Q00987'); return true;">Mdm2</a>-A, isoform <a href="#Q00987" onclick="ensureIsoformSequenceVisible('Q00987'); return true;">Mdm2</a>-B, isoform <a href="#Q00987" onclick="ensureIsoformSequenceVisible('Q00987'); return true;">Mdm2</a>-C, isoform <a href="#Q00987" onclick="ensureIsoformSequenceVisible('Q00987'); return true;">Mdm2</a>-D, isoform <a href="#Q00987" onclick="ensureIsoformSequenceVisible('Q00987'); return true;">Mdm2</a>-E, isoform <a href="#Q00987" onclick="ensureIsoformSequenceVisible('Q00987'); return true;">Mdm2</a>-F and isoform <a href="#Q00987" onclick="ensureIsoformSequenceVisible('Q00987'); return true;">Mdm2</a>-G are observed in a range of cancers but absent in normal tissues.	MDM2/MDM4		Not Available
dfzMIF	Macrophage migration inhibitory factor	1	110	85.97			MIF		Cancer, unspecific Glomerulonephritis Inflammation Inflammatory lung disease Inflammatory neurological disease Inflammatory response in alcoholic liver disease Rheumatoid arthritis, unspecified Sepsis Septic shock Systemic lupus erythematosus Ulcerative colitis	The expression of mif at sites of inflammation suggest a role for the mediator in regulating the function of macrophage in host defense. Also acts as a phenylpyruvate tautomerase.
dfzNQO1	NAD(P)H dehydrogenase [quinone] 1	2	79	94.87			NAD		Cancer, unspecific Nonsmall cell lung cancer	The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin k-dependent gamma-carboxylation of glutamate residues.
dfzNQO2	Ribosyldihydronicotinamide dehydrogenase [quinone]	3	220	92.03			NAD		Cancer, unspecific Malaria Tumors	The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin k-dependent gamma-carboxylation of glutamate residues.
dfzNAMPT	Nicotinamide phosphoribosyltransferase	1	237	99.76		Expressed in large amounts in bone marrow, liver tissue, and muscle. Also present in heart, placenta, lung, and kidney tissues.	NAPRTase			Catalyzes the condensation of nicotinamide with 5- phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway. The secreted form behaves both as a cytokine with immunomodulating properties and an adipokine with anti-diabetic properties, it has no enzymatic activity, partly because of lack of activation by ATP, which has a low level in extracellular space and plasma. Plays a role in the modulation of circadian clock function.
dfzNMT1	Glycylpeptide N-tetradecanoyltransferase 1	1	97	98.55		Heart, gut, kidney, liver and placenta.	NMT			Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins.
dfzNOS1	Nitric oxide synthase, brain	1	881	84.62		Isoform <a href="#P29475" onclick="ensureIsoformSequenceVisible('P29475'); return true;">1</a> is ubiquitously expressed: detected in skeletal muscle and brain, also in testis, lung and kidney, and at low levels in heart, adrenal gland and retina. Not detected in the platelets. Isoform <a href="#P29475-3" onclick="ensureIsoformSequenceVisible('P29475-3'); return true;">3</a> is expressed only in testis. Isoform <a href="#P29475-4" onclick="ensureIsoformSequenceVisible('P29475-4'); return true;">4</a> is detected in testis, skeletal muscle, lung, and kidney, at low levels in the brain, but not in the heart and adrenal gland.	NOS		Helminth infection Migraine and Cluster Headaches Schizophrenia	Produces nitric oxide (no) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, no displays many properties of a neurotransmitter.
dfzNOS2	Nitric oxide synthase, inducible	3	806	86.22		Expressed in the liver, retina, bone cells and airway epithelial cells of the lung. Not expressed in the platelets.	NOS		Ischemia reperfusion injuries	Produces nitric oxide (no) which is a messenger molecule with diverse functions throughout the body. In macrophages, no mediates tumoricidal and bactericidal actions.
dfzNOS3	Nitric oxide synthase, endothelial	2	297	91.74		Platelets, placenta, liver and kidney. <a class="attribution" href="P29474#ref19" onclick="ensureReferenceVisible('ref19')">Ref.19</a>	NOS		Angina Cardiovascular disease, unspecified Colon cancer Coronary Artery Disease Helminth infection Hypertension, Angina Inflammation Schizophrenia Sepsis	Produces nitric oxide (no) which is implicated in vascular smooth muscle relaxation through a cgmp-mediated signal transduction pathway. No mediates vascular endothelial growth factor (vegf)-induced angiogenesis in coronary vessels and promotes blood clot.
dfzPDK1	[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial	1	180	87.21		Expressed predominantly in the heart. Detected at lower levels in liver, skeletal muscle and pancreas.	PDK/BCKDK protein kinase			Serine/threonine kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.
dfzPDK2	[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial	1	125	94.46		Expressed in many tissues, with the highest level in heart and skeletal muscle, intermediate levels in brain, kidney, pancreas and liver, and low levels in placenta and lung.	PDK/BCKDK protein kinase			Serine/threonine kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.
dfzMTOR	Serine/threonine-protein kinase mTOR	2	1513	89.95		Expressed in numerous tissues, with highest levels in testis. <a class="attribution" href="P42345#ref7" onclick="ensureReferenceVisible('ref7')">Ref.7</a> <a class="attribution" href="P42345#ref14" onclick="ensureReferenceVisible('ref14')">Ref.14</a>	PI3/PI4-kinase		Cancer, unspecific Immunosuppression	Acts as the target for the cell-cycle arrest and immunosuppressive effects of the fkbp12-rapamycin complex.
dfzPK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	1	2407	90.05			PI3/PI4-kinase		Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The gene represented in this entry may be involved in disease pathogenesis. 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. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Note=The gene represented in this entry may be involved in disease pathogenesis. Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis. 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. Note=The disease is caused by mutations affecting the gene represented in this entry. Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) [MIM:602501]: A syndrome characterized by a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria. Note=The disease is caused by mutations affecting the gene represented in this entry. Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) [MIM:603387]: 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. Note=The disease is caused by mutations affecting the gene represented in this entry. Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:612918]: A sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth. Note=The disease is caused by mutations affecting the gene represented in this entry. Cowden syndrome 5 (CWS5) [MIM:615108]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. Note=The disease is caused by mutations affecting the gene represented in this entry.	Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1- AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.
dfzPK3CB	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform	2	981	81.47			PI3/PI4-kinase			Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.
dfzPK3CD	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	3	1129	90.35		Isoform 1 is expressed in spleen and lung (at protein level). Isoform 1 is expressed predominantly in leukocytes.	PI3/PI4-kinase			Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function.
dfzPK3CG	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	2	1180	90.35		Pancreas, skeletal muscle, liver and heart. <a class="attribution" href="P48736#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a>	PI3/PI4-kinase		Angioedema Cancer, unspecific Heart failure Myocardial infarction Solid tumors	3-phosphorylates the cellular phosphoinositide ptdins-4,5-biphosphate (ptdins(4,5)p2).
dfzMTAP	S-methyl-5'-thioadenosine phosphorylase	1	72	99.82		Ubiquitously expressed.	PNP/MTAP phosphorylase		T cell leukemias	Plays a major role in polyamine metabolism and is important for the salvage of both adenine and methionine.
dfzPNPH	Purine nucleoside phosphorylase	2	222	98.72			PNP/MTAP phosphorylase		B cell acute lymphoblastic leukemia (B-ALL) Cutaneous T-cell Lymphoma Malaria Moderate to Severe Plaque Psoriasis Psoriasis Refractory Cutaneous T-cell Lymphoma (CTCL) Schistosomiasis [bilharziasis] T-cell proliferation Trypanosomatid infections Tumors
dfzKIF11	Kinesin-like protein KIF11	1	727	88.99			TRAFAC class myosin-kinesin ATPase		Liver cancers	Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.
dfzAT1B1	Sodium/potassium-transporting ATPase subunit beta-1	1	137	91.69			X			This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane. The beta subunit regulates, through assembly of alpha/beta heterodimers, the number of sodium pumps transported to the plasma membrane. Involved in cell adhesion and establishing epithelial cell polarity (By similarity).
dfzADA	Disintegrin and metalloproteinase domain-containing protein 17	5	1713	98.08		Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney.	adenosine and AMP deaminases		Inflammatory bowel disease Inflammatory diseases Neuroimmunological diseases	Cleaves the membrane-bound precursor of tnf-alpha to its mature soluble form. Responsible for the proteolytic release of several other cell-surface proteins, including p75 tnf-receptor, interleukin 1 receptor type II and p55 tnf-receptor.
dfzSAHH	Adenosylhomocysteinase	1	92	99.47			adenosylhomocysteinase		Viral infection, unspecified	Adenosylhomocysteine is a competitive inhibitor of s-adenosyl-l-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration.
dfzAK1BA	Aldo-keto reductase family 1 member B10	4	69	89.27		Found in many tissues. Highly expressed in small intestine, colon and adrenal gland.	aldo/keto reductase			Acts as all-trans-retinaldehyde reductase. Can efficiently reduce aliphatic and aromatic aldehydes, and is less active on hexoses (in vitro). May be responsible for detoxification of reactive aldehydes in the digested food before the nutrients are passed on to other organs.
dfzAK1C2	Aldo-keto reductase family 1 member C2	1	91	96.69		Expressed in fetal testes. Expressed in fetal and adult adrenal glands.	aldo/keto reductase		46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. 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.
dfzAK1C3	Aldo-keto reductase family 1 member C3	3	302	90.69		Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. The dominant HSD in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate. <a class="attribution" href="P42330#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a> <a class="attribution" href="P42330#ref4" onclick="ensureReferenceVisible('ref4')">Ref.4</a> <a class="attribution" href="P42330#ref5" onclick="ensureReferenceVisible('ref5')">Ref.5</a> <a class="attribution" href="P42330#ref6" onclick="ensureReferenceVisible('ref6')">Ref.6</a> <a class="attribution" href="P42330#ref8" onclick="ensureReferenceVisible('ref8')">Ref.8</a> <a class="attribution" href="P42330#ref14" onclick="ensureReferenceVisible('ref14')">Ref.14</a>	aldo/keto reductase		Cancer, unspecific Head and neck cancer	Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (pg) d2, pgh2 and phenanthrenequinone (pq) and the oxidation of 9alpha,11beta- pgf2 to pgd2.
dfzALDR	Aldose reductase	4	920	87.27		Highly expressed in embryonic epithelial cells (EUE) in response to osmotic stress. <a class="attribution" href="P15121#ref15" onclick="ensureReferenceVisible('ref15')">Ref.15</a>	aldo/keto reductase	Gastrointestinal disorder	Analgesics Diabetic complications Diabetic neuropathy Diabetic retinopathy Neuropathic pain Noninsulin-dependent diabetes mellitus	Catalyzes the nadph-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
dfzCAH1	Carbonic anhydrase 1	2	2681	88.92			alpha-carbonic anhydrase	Aplastic anaemia Decreased appetite Electrolyte imbalance Glycosuria Gout Haemolysis Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Hyponatraemia Pancreatic disorder Pancreatitis Purine metabolism disorder Thrombocytopenia Xanthopsia	Glaucoma Hypertension Pancreatic cancer	Reversible hydration of carbon dioxide.	Carbonic anhydrase I inhibitor: Acetazolamide, Dichlorphenamide, Methazolamide, Methocarbamol
dfzCAH13	Carbonic anhydrase 13	1	272	82.27			alpha-carbonic anhydrase	Electrolyte imbalance Haemorrhagic diathesis Hypokalaemia Paraesthesia
dfzCAH14	Carbonic anhydrase 14	1	408	80.14		Most abundant in the kidney and heart, followed by the skeletal muscle, brain, lung and liver.	alpha-carbonic anhydrase			Reversible hydration of carbon dioxide.
dfzCAH2	Carbonic anhydrase 2	1	3468	89.32			alpha-carbonic anhydrase	Aplastic anaemia Decreased appetite Electrolyte imbalance Glycosuria Gout Haemolysis Haemolytic anaemia Haemorrhagic diathesis Hyperuricaemia Hypokalaemia Pancreatic disorder Pancreatitis Photosensitivity reaction Pulmonary oedema Purine metabolism disorder Purpura Thrombocytopenia Xanthopsia	Glaucoma Pancreatic cancer Renal failure	Reversible hydration of carbon dioxide.	Carbonic anhydrase II inhibitor: Acetazolamide, Brinzolamide, Dichlorphenamide, Dorzolamide, Methazolamide, Topiramate
dfzCAH7	Carbonic anhydrase 7	1	450	83.53			alpha-carbonic anhydrase			Reversible hydration of carbon dioxide.
dfzFAAH1	Fatty-acid amide hydrolase 1	2	1638	87.6		Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate. <a class="attribution" href="O00519#ref8" onclick="ensureReferenceVisible('ref8')">Ref.8</a>	amidase		Analgesics Anesthetic Anxiety disorder, unspecified Pain Sedation	Degrades bioactive fatty acid amides like oleamide, the endogenous cannabinoid, anandamide and myristic amide to their corresponding acids, thereby serving to terminate the signaling functions of these molecules.	Anandamide amidohydrolase inhibitor: Acetaminophen
dfzFABP4	Fatty acid-binding protein, adipocyte	3	102	94.48			calycin			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.
dfzFABPH	Fatty acid-binding protein, heart	1	55	96.3			calycin			FABP are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters.
dfzADK	Adenosine kinase	2	476	94.73		Widely expressed. Highest level in placenta, liver, muscle and kidney.	carbohydrate kinase PfkB		Analgesics Central and peripheral nervous system diseases Epilepsy Inflammation Inflammatory bowel disease Pain, unspecified Toxoplasmosis	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.
dfzAT1A1	Sodium/potassium-transporting ATPase subunit alpha-1	1	139	95.27			cation transport ATPase	Purine metabolism disorder	Atrial fibrillation and flutter Heart failure	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of atp coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions.
dfzCARM1	Histone-arginine methyltransferase CARM1	2	83	99.42		Overexpressed in prostate adenocarcinomas and high-grade prostatic intraepithelial neoplasia.	class I-like SAM-binding methyltransferase			Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg- 2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA- stabilizing properties and the half-life of their target mRNAs.
dfzCOMT	Catechol O-methyltransferase	1	54	99.68		Brain, liver, placenta, lymphocytes and erythrocytes.	class I-like SAM-binding methyltransferase		Parkinson's disease	Catalyzes the o-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like l-dopa, alpha-methyl dopa and isoproterenol.	Catechol O-methyltransferase inhibitor: Entacapone, Tolcapone
dfzPNMT	Phenylethanolamine N-methyltransferase	1	140	95.44			class I-like SAM-binding methyltransferase			Converts noradrenaline to adrenaline.
dfzEHMT2	Histone-lysine N-methyltransferase EHMT2	2	53	87.27		Expressed in all tissues examined, with high levels in fetal liver, thymus, lymph node, spleen and peripheral blood leukocytes and lower level in bone marrow.	class V-like SAM-binding methyltransferase			Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys- 373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself.
dfzPDE10	cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A	2	904	92.42		Abundant in the putamen and caudate nucleus regions of brain and testis, moderately expressed in the thyroid gland, pituitary gland, thalamus and cerebellum.	cyclic nucleotide phosphodiesterase			Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.
dfzPDE2A	cGMP-dependent 3',5'-cyclic phosphodiesterase	2	190	88.54		Expressed in brain and to a lesser extent in heart, placenta, lung, skeletal muscle, kidney and pancreas.	cyclic nucleotide phosphodiesterase	Dyspepsia Flushing Headache	Colorectal cancer Erectile dysfunction	Hydrolyzes both cyclic amp (camp) and cyclic gmp (cgmp).
dfzPDE4A	cAMP-specific 3',5'-cyclic phosphodiesterase 4A	1	1498	85.62		Isoform <a href="#P27815" onclick="ensureIsoformSequenceVisible('P27815'); return true;">1</a> is widely expressed. Isoform <a href="#P27815-2" onclick="ensureIsoformSequenceVisible('P27815-2'); return true;">2</a> is abundant in liver, stomach, testis, thyroid and adrenal glands. It is also found in placenta, kidney, pancreas, ovary, uterus, skin, monocytes, mast cells, macrophages, as well as in bronchial smooth muscle. Isoform <a href="#P27815-6" onclick="ensureIsoformSequenceVisible('P27815-6'); return true;">6</a> is expressed at high levels in the heart and small intestine. It is also found in the brain, kidney, spleen, colon, salivary gland, ovary and peripheral blood lymphocytes. Isoform <a href="#P27815-7" onclick="ensureIsoformSequenceVisible('P27815-7'); return true;">7</a> is expressed predominantly in skeletal muscle and brain and at lower levels in the testis. Isoform <a href="#P27815-7" onclick="ensureIsoformSequenceVisible('P27815-7'); return true;">7</a> is expressed in the brain. Found in specific neuronal subpopulations in cortex, spinal cord and cerebellum (at protein level). <a class="attribution" href="P27815#ref5" onclick="ensureReferenceVisible('ref5')">Ref.5</a> <a class="attribution" href="P27815#ref6" onclick="ensureReferenceVisible('ref6')">Ref.6</a> <a class="attribution" href="P27815#ref7" onclick="ensureReferenceVisible('ref7')">Ref.7</a>	cyclic nucleotide phosphodiesterase	Diarrhoea Dyspepsia Flushing Palpitations	Chronic lymphocytic leukemia		Phosphodiesterase 4A inhibitor: Theophylline
dfzPDE4B	cAMP-specific 3',5'-cyclic phosphodiesterase 4B	1	1699	91.64		Expressed in brain, heart, lung and skeletal muscle.	cyclic nucleotide phosphodiesterase	Diarrhoea Dyspepsia Flushing Palpitations	Asthma Chronic lymphocytic leukemia	May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.	Phosphodiesterase 4 inhibitor: Amlexanox, Dyphylline, Flavoxate, Roflumilast, Theophylline, Theophylline Glycinate
dfzPDE4D	cAMP-specific 3',5'-cyclic phosphodiesterase 4D	4	1391	91.94	Nature11159	Widespread; most abundant in skeletal muscle. Isoform <a href="#Q08499-8" onclick="ensureIsoformSequenceVisible('Q08499-8'); return true;">6</a> is detected in brain. Isoform <a href="#Q08499-9" onclick="ensureIsoformSequenceVisible('Q08499-9'); return true;">8</a> is detected in brain, placenta, lung and kidney. Isoform <a href="#Q08499-11" onclick="ensureIsoformSequenceVisible('Q08499-11'); return true;">7</a> is detected in heart and skeletal muscle. <a class="attribution" href="Q08499#ref6" onclick="ensureReferenceVisible('ref6')">Ref.6</a>	cyclic nucleotide phosphodiesterase	Dyspepsia Flushing	Asthma	Regulates the levels of camp in the cell.
dfzPDE5A	cGMP-specific 3',5'-cyclic phosphodiesterase	2	1340	91.96		Expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung.	cyclic nucleotide phosphodiesterase	Diarrhoea Dyspepsia Flushing Palpitations	Erectile dysfunction Injury to spine and spinal cord Pulmonary hypertension Vascular disease	Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides, and this phosphodiesterase catalyzes the specific hydrolysis of cgmp to 5'-GMP.	Phosphodiesterase 5A inhibitor: Avanafil, Dipyridamole, Sildenafil, Tadalafil, Vardenafil
dfzPDE9A	High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A	1	102	95.2		Expressed in all tissues examined (testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary and prostate) except blood. Highest levels in brain, heart, kidney, spleen, prostate and colon. Isoform PDE9A12 is found in prostate.	cyclic nucleotide phosphodiesterase			Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.
dfzPPIA	Peptidyl-prolyl cis-trans isomerase A	1	92	87.78			cyclophilin-type PPIase			PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
dfzCP1A1	Cytochrome P450 1A1	1	90	86.95		Lung, lymphocytes and placenta.	cytochrome P450			Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
dfzCP1B1	Cytochrome P450 1B1	1	68	88.65		Expressed in many tissues. <a class="attribution" href="Q16678#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a>	cytochrome P450		Breast cancer Colon adenocarcinoma Prostate cancer	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 and fatty acids.
dfzCP2C9	Cytochrome P450 2C9	2	1356	80.18			cytochrome P450
dfzCP2D6	Cytochrome P450 2D6	1	1717	72.97	VirtualToxLab		cytochrome P450		Insomnia	Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
dfzCP3A4	Cytochrome P450 3A4	1	2501	81.18	VirtualToxLab	Expressed in prostate and liver. According to some authors, it is not expressed in brain (<a class="attribution" href="#ref19" onclick="ensureReferenceVisible('ref19');">Ref.19</a>). According to others, weak levels of expression are measured in some brain locations (<a class="attribution" href="#ref22" onclick="ensureReferenceVisible('ref22');">Ref.22</a> and <a class="attribution" href="#ref20" onclick="ensureReferenceVisible('ref20');">Ref.20</a>). Also expressed in epithelium of the small intestine and large intestine, bile duct, nasal mucosa, kidney, adrenal cortex, epithelium of the gastric mucosa with intestinal metaplasia, gallbladder, intercalated ducts of the pancreas, chief cells of the parathyroid and the corpus luteum of the ovary (at protein level). <a class="attribution" href="P08684#ref12" onclick="ensureReferenceVisible('ref12')">Ref.12</a> <a class="attribution" href="P08684#ref13" onclick="ensureReferenceVisible('ref13')">Ref.13</a> <a class="attribution" href="P08684#ref14" onclick="ensureReferenceVisible('ref14')">Ref.14</a> <a class="attribution" href="P08684#ref19" onclick="ensureReferenceVisible('ref19')">Ref.19</a> <a class="attribution" href="P08684#ref20" onclick="ensureReferenceVisible('ref20')">Ref.20</a> <a class="attribution" href="P08684#ref22" onclick="ensureReferenceVisible('ref22')">Ref.22</a>	cytochrome P450	Abdominal pain upper Diabetes mellitus Headache Hyperlipidaemia Lipodystrophy acquired Oedema peripheral	Hypothalamic-pituitary ACTH function
dfzDUT	Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial	2	83	99.2		Found in a variety of tissues. Isoform 3 expression is constitutive, while isoform 2 expression correlates with the onset of DNA replication (at protein level). Isoform 2 degradation coincides with the cessation of nuclear DNA replication (at protein level).	dUTPase			This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.
dfzDYR	Dihydrofolate reductase	1	1180	99.05		Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain.	dihydrofolate reductase		Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]: An inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms. 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.
dfzPYRD	Dihydroorotate dehydrogenase (quinone), mitochondrial	4	381	97.41			dihydroorotate dehydrogenase		Postaxial acrofacial dysostosis (POADS) [MIM:263750]: POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases. Note=The disease is caused by mutations affecting the gene represented in this entry.	Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
dfzAOFA	Amine oxidase [flavin-containing] A	1	1166	63.68	Nature11159	Heart, liver, duodenum, blood vessels and kidney.	flavin monoamine oxidase	Dry mouth Hyperhidrosis Irritability Mania Psychotic disorder	Depression Mood [affective] disorders Social phobias	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. Mao-A preferentially oxidizes biogenic amines.
dfzGRIA2	Glutamate receptor 2	3	936	91.01			glutamate-gated ion channel			Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.
dfzGRIK1	Glutamate receptor ionotropic, kainate 1	1	318	80.39		Most abundant in the cerebellum and the suprachiasmatic nuclei (SCN) of the hypothalamus.	glutamate-gated ion channel		Analgesics Epilepsy Pain	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.
dfzQPCT	Glutaminyl-peptide cyclotransferase	2	160	96.94			glutaminyl-peptide cyclotransferase			Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue (By similarity).
dfzPYGL	Glycogen phosphorylase, liver form	3	476	97.67			glycogen phosphorylase		Glycogen storage disease 6 (GSD6) [MIM:232700]: A metabolic disorder characterized by mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent hepatomegaly. Heart and skeletal muscle are not affected. Note=The disease is caused by mutations affecting the gene represented in this entry.	Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
dfzPYGM	Glycogen phosphorylase, muscle form	7	189	89.98			glycogen phosphorylase		Diabetes Mellitus Type 2 Noninsulin-dependent diabetes mellitus	Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
dfzMGA	Maltase-glucoamylase, intestinal	1	72	97.56		Expressed in small intestine, granulocyte, and kidney but not in salivary gland or pancreas.	glycosyl hydrolase 31		Diabetes mellitus	May serve as an alternate pathway for starch digestion when luminal alpha-amylase activity is reduced because of immaturity or malnutrition. May play a unique role in the digestion of malted dietary oligosaccharides used in food manufacturing.	Maltase-glucoamylase inhibitor: Acarbose, Miglitol
dfzSUIS	Sucrase-isomaltase, intestinal	1	114	85.34		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.	glycosyl hydrolase 31		Congenital sucrase-isomaltase deficiency (CSID) [MIM:222900]: Autosomal recessive intestinal disorder that is clinically characterized by fermentative diarrhea, abdominal pain, and cramps upon ingestion of sugar. The symptoms are the consequence of absent or drastically reduced enzymatic activities of sucrase and isomaltase. The prevalence of CSID is 0.02 % in individuals of European descent and appears to be much higher in Greenland, Alaskan, and Canadian native people. CSID arises due to post-translational perturbations in the intracellular transport, polarized sorting, aberrant processing, and defective function of SI. Note=The disease is caused by mutations affecting the gene represented in this entry.	Plays an important role in the final stage of carbohydrate digestion. Isomaltase activity is specific for both alpha-1,4- and alpha-1,6-oligosaccharides.
dfzHS90A	Heat shock protein HSP 90-alpha	6	493	86.38			heat shock protein 90		Breast cancer Chronic Myelogenous Leukemia (CML) Gastrointestinal Stromal Tumors (GIST) Hematological Malignancies HER2-positive Metastatic Breast Cancer Melanoma Multiple Myeloma Non-small Cell Lung Cancer Ovarian cancer Prostate cancer Refractory Hematological Malignancies Solid tumors
dfzHS90B	Heat shock protein HSP 90-beta	1	426	85.13			heat shock protein 90			Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.
dfzHMOX1	Heme oxygenase 1	1	58	99.33		Expressed at higher levels in renal cancer tissue than in normal tissue (at protein level). <a class="attribution" href="P09601#ref10" onclick="ensureReferenceVisible('ref10')">Ref.10</a>	heme oxygenase		Atherosclerosis Cardiovascular disease, unspecified Cerebral vasospasm Chronic myeloid leukemia Crohn's Disease Ischemic injury of the liver Kaposi's sarcoma Neonatal Hyperbilirubinemia, jaundice Oxidative tissue injuries Ulcerative colitis Vascular disease	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.
dfzHXK4	Glucokinase	1	484	99.22		Isoform <a href="#P35557" onclick="ensureIsoformSequenceVisible('P35557'); return true;">1</a> is expressed in pancreas. Isoform <a href="#P35557-2" onclick="ensureIsoformSequenceVisible('P35557-2'); return true;">2</a> and isoform <a href="#P35557-3" onclick="ensureIsoformSequenceVisible('P35557-3'); return true;">3</a> is expressed in liver.	hexokinase		Benign prostatic hyperplasia Diabetes Mellitus Type 1 and 2 Noninsulin-dependent diabetes mellitus Prostate Disorders	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.
dfzHDAC2	Histone deacetylase 2	2	842	92.26		Widely expressed; lower levels in brain and lung.	histone deacetylase		Colon cancer	Responsible for the deacetylation of lysine residues on the n-terminal part of the core histones (h2a, h2b, h3 and h4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression.	Histone deacetylase 2 inhibitor: Vorinostat
dfzHDAC4	Histone deacetylase 4	2	619	86.44		Ubiquitous.	histone deacetylase		Acne Basal cell carcinoma Bladder cancer Colorectal Cancer Cutaneous T-Cell Lymphoma Leukemia, Lymphoid Leukemia, Myeloid Liver Cancer Lymphoma, Unspecified Melanoma; Prostate cancer Mesothelioma Multiple Myeloma Myelodysplastic Syndrome Ovarian cancer Pancreatic Cancer Prostate cancer Prostate cancer (hormone refractory) Renal Cell Carcinoma Sarcoma Skin cancer Solid tumors	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.
dfzHDAC7	Histone deacetylase 7	2	467	92.43			histone deacetylase			Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene.
dfzHDAC8	Histone deacetylase 8	2	824	94.74		Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney.	histone deacetylase		Cornelia de Lange syndrome 5 (CDLS5) [MIM:300882]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. 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. 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.
dfzIGF1	Insulin-like growth factor 1 receptor	1	1829	91.4		Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney. <a class="attribution" href="P08069#ref9" onclick="ensureReferenceVisible('ref9')">Ref.9</a> <a class="attribution" href="P08069#ref14" onclick="ensureReferenceVisible('ref14')">Ref.14</a> <a class="attribution" href="P08069#ref16" onclick="ensureReferenceVisible('ref16')">Ref.16</a> <a class="attribution" href="P08069#ref24" onclick="ensureReferenceVisible('ref24')">Ref.24</a>	insulin		Cancer, unspecific Colorectal cancer Ewing's sarcoma Medulloblastoma Peripheral neuroectodermal tumor Tumors	This receptor binds insulin-like growth factor I (IGF I) with a high affinity and igf ii with a lower affinity. It has a tyrosine-protein kinase activity.	Insulin-like growth factor I receptor agonist: Mecasermin, Mecasermin Rinfabate
dfzITA2B	Integrin alpha-IIb	1	1546	95.62		Isoform 1 and isoform 2 were identified in platelets and megakaryocytes, but not in reticulocytes or in Jurkat and U-937 white blood cell line. Isoform 3 is expressed by leukemia, prostate adenocarcinoma and melanoma cells but not by platelets or normal prostate or breast epithelial cells.	integrin alpha chain		Glanzmann thrombasthenia (GT) [MIM:273800]: A common inherited disease of platelet aggregation. It is characterized by mucocutaneous bleeding of mild-to-moderate severity. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb-IIIa complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the GPIIb-IIIa complex at reduced levels, have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. 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. 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.
dfzITAL	Integrin alpha-L	3	489	94.75			integrin alpha chain		Inflammatory diseases
dfzITB3	Integrin beta-3	1	2347	94.32		Isoform beta-3A and isoform beta-3C are widely expressed. Isoform beta-3A is specifically expressed in osteoblast cells; isoform beta-3C is specifically expressed in prostate and testis.	integrin beta chain		Platelet adhesion	Integrin alpha-v/beta-3 is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von willebrand factor. Integrin alpha-iib/beta-3 is a receptor for fibronectin.
dfzANDR	Androgen receptor	5	1964	82.18	Nature11159 VirtualToxLab	Isoform <a href="#P10275-2" onclick="ensureIsoformSequenceVisible('P10275-2'); return true;">2</a> is mainly expressed in heart and skeletal muscle. <a class="attribution" href="P10275#ref7" onclick="ensureReferenceVisible('ref7')">Ref.7</a>	nuclear hormone receptor	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	Prostate cancer Spinal and bulbar muscular atrophy	The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.	Androgen Receptor agonist: Danazol, Dromostanolone Propionate, Ethylestrenol, Fluoxymesterone, Methyltestosterone, Nandrolone Decanoate, Nandrolone Phenpropionate, Oxandrolone, Oxymetholone, Stanozolol, Testosterone, Testosterone Cypionate, Testosterone Enanthate, Testosterone Propionate Androgen Receptor antagonist: Bicalutamide, Enzalutamide, Flutamide, Nilutamide
dfzERR1	Steroid hormone receptor ERR1	1	114	83.24			nuclear hormone receptor		Breast cancer Diabetes mellitus Metabolic disorder, unspecified Obesity	Binds to an err-alpha response element (erre) containing a single consensus half-site, 5'-tnaaggtca-3'. Can bind to the medium-chain acyl coenzyme a dehydrogenase (mcad) response element nrre-1 and may act as an important regulator of mcad promoter.
dfzESR1	Estrogen receptor	2	2116	93	Nature11159 VirtualToxLab		nuclear hormone receptor	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	Brain injury Breast cancer Cardiovascular disease, unspecified Coronary atherosclerosis Endocrine independent cancer Neurodegenerative diseases Osteoporosis, unspecified Postmenopausal symptoms	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.
dfzESR2	Estrogen receptor beta	1	2049	90.04	Nature11159 VirtualToxLab	Isoform beta-1 is expressed in testis and ovary, and at a lower level in heart, brain, placenta, liver, skeletal muscle, spleen, thymus, prostate, colon, bone marrow, mammary gland and uterus. Also found in uterine bone, breast, and ovarian tumor cell lines, but not in colon and liver tumors. Isoform beta-2 is expressed in spleen, thymus, testis and ovary and at a lower level in skeletal muscle, prostate, colon, small intestine, leukocytes, bone marrow, mammary gland and uterus. Isoform beta-3 is found in testis. Isoform beta-4 is expressed in testis, and at a lower level in spleen, thymus, ovary, mammary gland and uterus. Isoform beta-5 is expressed in testis, placenta, skeletal muscle, spleen and leukocytes, and at a lower level in heart, lung, liver, kidney, pancreas, thymus, prostate, colon, small intestine, bone marrow, mammary gland and uterus. Not expressed in brain.	nuclear hormone receptor	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	Breast cancer Cardiovascular disease, unspecified ER beta-positive prostate tumors Neurodegenerative diseases Vascular injury response	Nuclear hormone receptor. binds estrogens with an affinity similar to that of esr1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner. Isoform beta-cx lacks ligand binding ability.	Estrogen receptor beta: Estramustine Phosphate Estrogen receptor beta modulator: Chlorotrianisene, Raloxifene
dfzGCR	Glucocorticoid receptor	2	1918	86.04	Nature11159 VirtualToxLab	Widely expressed. In the heart, detected in left and right atria, left and right ventricles, aorta, apex, intraventricular septum, and atrioventricular node as well as whole adult and fetal heart. <a class="attribution" href="P04150#ref21" onclick="ensureReferenceVisible('ref21')">Ref.21</a>	nuclear hormone receptor	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	Cocaine dependence Drug dependence Major depressive disorder	Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (gre) and as a modulator of other transcription factors. Affects inflammatory responses and cellular proliferation.	Glucocorticoid receptor agonist: Alclometasone Dipropionate, Amcinonide, Beclomethasone Dipropionate, Betamethasone, Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Phosphoric Acid, Betamethasone Valerate, Budesonide, Ciclesonide, Clobetasol Propionate, Clocortolone Pivalate, Cortisone Acetate, Desonide, Desoximetasone, Dexamethasone, Dexamethasone Acetate, Dexamethasone Phosphoric Acid, Diflorasone Diacetate, Difluprednate, Flumethasone Pivalate, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluorometholone, Fluorometholone Acetate, Fluprednisolone, Flurandrenolide, Fluticasone Furoate, Fluticasone Propionate, Halcinonide, Halobetasol Propionate, Hydrocortamate, Hydrocortisone, Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate, Hydrocortisone Phosphoric Acid, Hydrocortisone Probutate, Hydrocortisone Valerate, Loteprednol Etabonate, Medrysone, Meprednisone, Methylprednisolone, Methylprednisolone Hemisuccinate, Mometasone Furoate, Paramethasone Acetate, Prednicarbate, Prednisolone, Prednisolone Acetate, Prednisolone Phosphoric Acid, Prednisolone Tebutate, Prednisone, Rimexolone, Triamcinolone, Triamcinolone Acetonide, Triamcinolone Diacetate, Triamcinolone Hexacetonide Glucocorticoid receptor antagonist: Mifepristone
dfzMCR	Mineralocorticoid receptor	1	617	78.59	VirtualToxLab	Ubiquitous. Highly expressed in distal tubules, convoluted tubules and cortical collecting duct in kidney, and in sweat glands. Detected at lower levels in cardiomyocytes, in epidermis and in colon enterocytes. <a class="attribution" href="P08235#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a> <a class="attribution" href="P08235#ref10" onclick="ensureReferenceVisible('ref10')">Ref.10</a>	nuclear hormone receptor	Acne Adrenal insufficiency Amenorrhoea Cushingoid Depression Embolism arterial Endocrine disorder Euphoric mood Hyperglycaemia Hypokalaemia Menstrual disorder Muscular weakness Oedema Osteoporosis Peptic ulcer	Autoimmune and sudden sensorineural hearing loss Brain injury	Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion.	Mineralocorticoid receptor agonist: Desoxycorticosterone Acetate, Desoxycorticosterone Pivalate, Fludrocortisone Acetate Mineralocorticoid receptor antagonist: Drospirenone, Eplerenone, Felodipine, Nimodipine, Spironolactone
dfzNR1H2	Oxysterols receptor LXR-beta	3	607	95.94	VirtualToxLab	Ubiquitous.	nuclear hormone receptor		Atherosclerosis Dyslipidemia	Orphan receptor. Binds preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence 5'-aggtca-3' and 4-nt spacing (dr-4).
dfzNR1H3	Oxysterols receptor LXR-alpha	1	570	91.83	VirtualToxLab	Visceral organs specific expression. Strong expression was found in liver, kidney and intestine followed by spleen and to a lesser extent the adrenals.	nuclear hormone receptor		Atherosclerosis Cancer, unspecific	Orphan receptor. Interaction with rxr shifts rxr from its role as a silent dna-binding partner to an active ligand- binding subunit in mediating retinoid responses through target genes defined by lxres. Lxres are dr4-type response elements.
dfzNR1H4	Bile acid receptor	4	468	96.46			nuclear hormone receptor		Cancer, unspecific Hypercholesterolemia Intrahepatic cholestasis	Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. repress the transcription of the cholesterol 7-alpha-hydroxylase gene (cyp7a1) and activates the intestinal bile acid-binding protein (ibabp).	Bile acid receptor FXR agonist: Chenodiol, Ursodiol
dfzNR1I2	Nuclear receptor subfamily 1 group I member 2	1	98	87.58	Nature11159	Expressed in liver, colon and small intestine.	nuclear hormone receptor	Hepatitis	Anxiety disorder, unspecified Depression Eye inflammation Multiple Sclerosis	Orphan receptor; Its natural ligand is probably pregnane. Binds to a response element in the cyp3a4 gene promoter. activates its expression in response to a wide variety of endobiotics and xenobiotics.
dfzPPARA	Peroxisome proliferator-activated receptor alpha	1	2321	97.37		Skeletal muscle, liver, heart and kidney. <a class="attribution" href="Q07869#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a> <a class="attribution" href="Q07869#ref3" onclick="ensureReferenceVisible('ref3')">Ref.3</a>	nuclear hormone receptor	Myalgia	Hyperglycemia Hyperinsulinemia Insulin resistance Lipid metabolic disorders Obesity	Receptor that bind peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-coa oxidase and activates its transcription. It therefore controls the perox[UniProt]	Peroxisome proliferator-activated receptor alpha agonist: Clofibrate, Fenofibrate, Fenofibric Acid, Gemfibrozil
dfzPPARD	Peroxisome proliferator-activated receptor delta	1	1318	99.15		Ubiquitous with maximal levels in placenta and skeletal muscle.	nuclear hormone receptor		Atherosclerosis Hyperlipidemia Inflammation Metabolic Disease Metabolic syndrome X Noninsulin-dependent diabetes mellitus Obesity Skin diseases	Receptor that bind peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-coa oxidase and activates its transcription.
dfzPPARG	Peroxisome proliferator-activated receptor gamma	3	3248	94.36	VirtualToxLab	Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary. <a class="attribution" href="P37231#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a>	nuclear hormone receptor	Dyspepsia	Not Available		Peroxisome proliferator-activated receptor gamma agonist: Balsalazide, Mesalamine, Olsalazine, Pioglitazone, Rosiglitazone, Troglitazone
dfzPRGR	Progesterone receptor	1	1756	89.18	Nature11159 VirtualToxLab		nuclear hormone receptor	Acne Amenorrhoea Biliary tract disorder Breast pain Depression Fibrocystic breast disease Gynaecomastia Hirsutism Jaundice cholestatic Libido disorder Menstrual disorder Metrorrhagia Migraine Oedema Urticaria Weight increased	Breast cancer	The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.	Progesterone receptor agonist: Danazol, Desogestrel, Drospirenone, Dydrogesterone, Ethynodiol Diacetate, Etonogestrel, Fluticasone Propionate, Hydroxyprogesterone Caproate, Levonorgestrel, Medroxyprogesterone Acetate, Megestrol Acetate, Norelgestromin, Norethindrone, Norethindrone Acetate, Norethynodrel, Norgestimate, Norgestrel, Progesterone Progesterone receptor antagonist: Mifepristone Progesterone receptor modulator: Ulipristal Acetate
dfzRARA	Retinoic acid receptor alpha	1	268	98.84			nuclear hormone receptor		Acute promyelocytic leukemia	Nuclear receptor for retinoic acid. This metabolite has profound effects on vertebrate development. retinoic acid is a morphogen and is a powerful teratogen. This receptor controls cells functions by directly regulating gene expression.
dfzRARB	Retinoic acid receptor beta	1	281	99.27			nuclear hormone receptor		Pancreatic cancer	This is a receptor for retinoic acid. This metabolite has profound effects on vertebrate development. retinoic acid is a morphogen and is a powerful teratogen. This receptor controls cells functions by directly regulating gene expression.	Retinoic acid receptor beta agonist: Adapalene Retinoic acid receptor beta inhibitor: Isotretinoin
dfzRARG	Retinoic acid receptor gamma	1	268	99.02			nuclear hormone receptor		Acne Emphysema Photoaging Psoriasis		Retinoic acid receptor gamma agonist: Adapalene
dfzRXRA	Retinoic acid receptor RXR-alpha	2	454	98.67		Highly expressed in liver, also found in lung, kidney and heart.	nuclear hormone receptor	Arthralgia	Prostate cancer	Nuclear hormone receptor. Involved in retinoic acid response pathway. Binds 9-cis retinoic acid (9c-ra).
dfzRXRB	Retinoic acid receptor RXR-beta	1	195	99.23		Expressed in a variety of tumor cell lines.	nuclear hormone receptor			Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (By similarity). Specifically binds 9-cis retinoic acid (9C-RA).
dfzTHA	Thyroid hormone receptor alpha	1	300	92.88	VirtualToxLab		nuclear hormone receptor		Thyrotoxicosis [hyperthyroidism]	Nuclear hormone receptor. High affinity receptor for triiodothyronine.	Thyroid hormone receptor agonist: Dextrothyroxine, Levothyroxine, Liothyronine
dfzTHB	Thyroid hormone receptor beta	1	466	86.63	VirtualToxLab		nuclear hormone receptor		Hyperlipidemia Obesity Thyroid hormone resistance syndrome Thyrotoxicosis [hyperthyroidism]	High affinity receptor for triiodothyronine.
dfzVDR	Vitamin D3 receptor	1	280	95.57			nuclear hormone receptor		Breast cancer Colorectal cancer Kaposi's sarcoma Prostate cancer Vitamin D deficiency	Nuclear hormone receptor. Vdr mediates the action of vitamin d3 by controlling the expression of hormone sensitive genes.	Vitamin D receptor agonist: Calcifediol, Calcipotriene, Calcitriol, Cholecalciferol, Doxercalciferol, Ergocalciferol, Paricalcitol
dfzENPP2	Ectonucleotide pyrophosphatase/phosphodiesterase family member 2	3	125	93.61		Expressed in brain and adipose tissue.	nucleotide pyrophosphatase/phosphodiesterase		Note=May contribute to obesity.	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.
dfzP53	Cellular tumor antigen p53	1	266	86.56		Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform <a href="#P04637-2" onclick="ensureIsoformSequenceVisible('P04637-2'); return true;">2</a> is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform <a href="#P04637-3" onclick="ensureIsoformSequenceVisible('P04637-3'); return true;">3</a> is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform <a href="#P04637-7" onclick="ensureIsoformSequenceVisible('P04637-7'); return true;">7</a> is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform <a href="#P04637-8" onclick="ensureIsoformSequenceVisible('P04637-8'); return true;">8</a> is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform <a href="#P04637-9" onclick="ensureIsoformSequenceVisible('P04637-9'); return true;">9</a> is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine. <a class="attribution" href="P04637#ref9" onclick="ensureReferenceVisible('ref9')">Ref.9</a>	p53		Bladder cancer Cancer, unspecific Hepatocellular carcinoma Kidney Cancer Prostate cancer	Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division.
dfzBACE1	Beta-secretase 1	5	2387	96.75		Expressed at high levels in the brain and pancreas. In the brain, expression is highest in the substantia nigra, locus coruleus and medulla oblongata. <a class="attribution" href="P56817#ref15" onclick="ensureReferenceVisible('ref15')">Ref.15</a> <a class="attribution" href="P56817#ref16" onclick="ensureReferenceVisible('ref16')">Ref.16</a>	peptidase A1		Alzheimer's disease	Responsible for the proteolytic processing of the amyloid precursor protein (app). Cleaves at the amino 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 liquid.
dfzBACE2	Beta-secretase 2	2	457	94.97		Brain. Present in neurons within the hippocampus, frontal cortex and temporal cortex (at protein level). Expressed at low levels in most peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at low levels in the brain. Found in spinal cord, medulla oblongata, substantia nigra and locus coruleus. Expressed in the ductal epithelium of both normal and malignant prostate.	peptidase A1			Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C- terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672.
dfzCATD	Cathepsin D	2	835	92.57		Expressed in the aorta extrcellular space (at protein level). <a class="attribution" href="P07339#ref17" onclick="ensureReferenceVisible('ref17')">Ref.17</a>	peptidase A1		Alzheimer's disease Breast cancer	Acid protease active in intracellular protein breakdown. Involved in the pathogenesis of several diseases such as breast cancer and possibly alzheimer's disease.
dfzRENI	Renin	2	1716	98.16			peptidase A1		Cancer, unspecific Hypertension	Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin i from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.	Renin inhibitor: Aliskiren
dfzCATB	Cathepsin B	2	1038	81.09			peptidase C1		Acute otitis media Arthritis Ischemia Tumor angiogenesis	Thiol protease which is believed to participate in intracellular degradation and turnover of proteins. Has also been implicated in tumor invasion and metastasis.
dfzCATC	Dipeptidyl peptidase 1	2	79	83.6		Ubiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas. <a class="attribution" href="P53634#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a>	peptidase C1		Alzheimer's disease Sepsis	Thiol protease. Has dipeptidylpeptidase activity. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin g and granzymes a and b. Can also activate neuramindase and factor xiii.
dfzCATK	Cathepsin K	5	1681	92.76		Predominantly expressed in osteoclasts (bones).	peptidase C1		Bone Metastases Cancer, unspecific Osteoporosis Postmenopausal Women with Osteoporosis Rheumatoid arthritis	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.
dfzCATL1	Cathepsin L1	2	1268	82.37			peptidase C1		Autoimmune diseases Melanoma	Important for the overall degradation of proteins in lysosomes.
dfzCATS	Cathepsin S	3	1543	92.78			peptidase C1		Autoimmune diseases Psoriasis and Psoriatic Disorders	Thiol protease. The bond-specificity of this proteinase is in part similar to the specificities of cathepsin l and cathepsin n.
dfzCASP1	Caspase-1	1	635	94.62		Expressed in larger amounts in spleen and lung. Detected in liver, heart, small intestine, colon, thymus, prostate, skeletal muscle, peripheral blood leukocytes, kidney and testis. No expression in the brain. <a class="attribution" href="P29466#ref7" onclick="ensureReferenceVisible('ref7')">Ref.7</a>	peptidase C14A		Brain inflammation Cerebral ischemia Diabetic retinopathy Inflammation	Thiol protease that cleaves il-1 beta between an asp and an ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Specifically inhibited by the cowpox virus crma protein.
dfzCASP3	Caspase-3	3	1068	87.64		Highly expressed in lung, spleen, heart, liver and kidney. Moderate levels in brain and skeletal muscle, and low in testis. Also found in many cell lines, highest expression in cells of the immune system.	peptidase C14A		Chronic experimental allergic encephalomyelitis Dysregulation of apoptosis Multiple sclerosis Neurodegenerative diseases	Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(adp-ribose) polymerase (parp) at a 216-asp-\|-gly-217 bond. Cleaves and activates sterol regulatory element.
dfzCASP6	Caspase-6	2	156	88.45			peptidase C14A		Not Available
dfzCASP7	Caspase-7	2	351	82.09		Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain.	peptidase C14A			Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-\|-Gly- 217' bond. Overexpression promotes programmed cell death.
dfzCASP8	Caspase-8	1	275	97.07		Isoform <a href="#Q14790" onclick="ensureIsoformSequenceVisible('Q14790'); return true;">1</a>, isoform <a href="#Q14790-5" onclick="ensureIsoformSequenceVisible('Q14790-5'); return true;">5</a> and isoform <a href="#Q14790-7" onclick="ensureIsoformSequenceVisible('Q14790-7'); return true;">7</a> 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.	peptidase C14A		Not Available
dfzCAN1	Calpain-1 catalytic subunit	3	635	95.6		Ubiquitous.	peptidase C2			Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.
dfzAMPE	Glutamyl aminopeptidase	1	59	85.47		Expressed by epithelial cells of the proximal tubule cells and the glomerulus of the nephron. Also found in a variety of other tissues.	peptidase M1		Hypertension	Appears to have a role in the catabolic pathway of the renin-angiotensin system. Probably plays a role in regulating growth and differentiation of early b-lineage cells.
dfzAMPN	Aminopeptidase N	1	388	84.91			peptidase M1			Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. 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 and involved the cleavage of peptides bound to major histocompatibility complex class II molecules of antigen presenting cells. May have a role in angiogenesis (By similarity). It is able to degrade Leu-enkephalin and Met-enkephalin but not cholecystokinin CCK8, neuromedin C (GRP-10), somatostatin-14, substance P and vasoactive intestinal peptide. In case of porcine transmissible gastroenteritis coronavirus (TGEV) and porcine respiratory coronavirus (PRCoV) infections, serves as a receptor for TGEV and PRCoV spike glycoprotein in a species-specific manner.
dfzLKHA4	Leukotriene A-4 hydrolase	3	520	93.05		Isoform <a href="#P09960" onclick="ensureIsoformSequenceVisible('P09960'); return true;">1</a> and isoform <a href="#P09960-2" onclick="ensureIsoformSequenceVisible('P09960-2'); return true;">2</a> are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.	peptidase M1		Inflammation Leukemia, Myeloid Myocardial infarction Oesophageal cancer Solid tumors	Hydrolyzes an epoxide moiety of leukotriene a4 (lta-4) to form leukotriene b4 (ltb-4). The enzyme also has some peptidase activity.
dfzMMP12	Macrophage metalloelastase	3	384	95.87		Found in alveolar macrophages but not in peripheral blood monocytes.	peptidase M10A		Atherosclerosis Crohn's disease, unspecified Emphysema Gastro-intestinal ulcers Non-small Cell Lung Cancer (NSCLC) Prostate cancer Renal Cell Carcinoma Ulcerative colitis	May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the p1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the p1 site.
dfzMMP13	Collagenase 3	1	2368	94.79		Seems to be specific to breast carcinomas.	peptidase M10A		Brain Cancer Hormone-refractory Prostate cancer Kaposi's Sarcoma Lung Cancer Myocardial infarction (MI) Non-small Cell Lung Cancer Osteoarthritis Prostate cancer Squamous cell carcinoma	Degrades collagen type i. Does not act on gelatin or casein. Could have a role in tumoral process.	Matrix metalloproteinase 13 inhibitor: Doxycycline
dfzMMP3	Stromelysin-1	2	1776	96.84			peptidase M10A		Brain Cancer Cancer, unspecific Lung Cancer Myocardial infarction (MI) Osteoarthritis Osteoarthritis Ovarian cancer Pancreatic Cancer Prostate cancer	Can degrade fibronectin, laminin, gelatins of type i, iii, iv, and v; collagens iii, iv, x, and ix, and cartilage proteoglycans. Activates procollagenase.
dfzMMP7	Matrilysin	1	501	84.75			peptidase M10A		Cancer, unspecific Inflammation	Degrades casein, gelatins of types i, iii, iv, and v, and fibronectin. Activates procollagenase.	Matrix metalloproteinase 7 inhibitor: Doxycycline
dfzMMP8	Neutrophil collagenase	2	859	89.36		Neutrophils.	peptidase M10A		Inflammatory diseases Osteoarthritis Osteoporosis, unspecified Rheumatoid arthritis, unspecified Tumors	Can degrade fibrillar type i, ii, and iii collagens.	Matrix metalloproteinase 8 inhibitor: Doxycycline
dfzNEP	Neprilysin	1	995	97.47			peptidase M13		Congestive Heart Failure Hypertension Prostate cancer (early stage hormone sensitive)	Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as met- and leu-enkephalins by cleavage of a gly-phe bond.
dfzCBPB1	Carboxypeptidase B	2	61	84.36			peptidase M14
dfzCBPB2	Carboxypeptidase B2	1	79	98.55		Plasma; synthesized in the liver.	peptidase M14		Thrombosis
dfzDPEP1	Dipeptidase 1	1	134	99.81			peptidase M19		Bacterial infections	Hydrolyzes a wide range of dipeptides. Implicated in the renal metabolism of glutathione and its conjugates. converts leukotriene D4 to leukotriene E4; it may play an important role in the regulation of leukotriene activity.	Renal dipeptidase inhibitor: Cilastatin
dfzACE	Angiotensin-converting enzyme	2	1343	97.06			peptidase M2	Angioedema Cough Dysgeusia Palpitations Pancreatitis	Chronic obstructive pulmonary disease, unspecified Heart failure Hypertension Vascular disease	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 vasodilatator.
dfzACE2	Angiotensin-converting enzyme 2	1	164	95.16		Expressed in endothelial cells from small and large arteries, and in arterial smooth muscle cells. Expressed in lung alveolar epithelial cells, enterocytes of the small intestine, Leydig cells and Sertoli cells (at protein level). Expressed in heart, kidney, testis, and gastrointestinal system. <a class="attribution" href="Q9BYF1#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a> <a class="attribution" href="Q9BYF1#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a> <a class="attribution" href="Q9BYF1#ref3" onclick="ensureReferenceVisible('ref3')">Ref.3</a> <a class="attribution" href="Q9BYF1#ref14" onclick="ensureReferenceVisible('ref14')">Ref.14</a> <a class="attribution" href="Q9BYF1#ref18" onclick="ensureReferenceVisible('ref18')">Ref.18</a> <a class="attribution" href="Q9BYF1#ref21" onclick="ensureReferenceVisible('ref21')">Ref.21</a>	peptidase M2		Cardiovascular disease, unspecified
dfzMAP11	Methionine aminopeptidase 1	3	118	91.5			peptidase M24A			Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Required for normal progression through the cell cycle.
dfzMAP2	Methionine aminopeptidase 2	4	418	92.34			peptidase M24A		Bacterial infections Cancer, unspecific Mesothelioma	Removes the amino-terminal methionine from nascent proteins.
dfzFOLH1	Glutamate carboxypeptidase 2	2	222	95.69		Highly expressed in prostate epithelium. Detected in urinary bladder, kidney, testis, ovary, fallopian tube, breast, adrenal gland, liver, esophagus, stomach, small intestine, colon and brain (at protein level). Detected in the small intestine, brain, kidney, liver, spleen, colon, trachea, spinal cord and the capillary endothelium of a variety of tumors. Expressed specifically in jejunum brush border membranes. In the brain, highly expressed in the ventral striatum and brain stem. Also expressed in fetal liver and kidney. Isoform PSMA' is the most abundant form in normal prostate. Isoform PSMA-1 is the most abundant form in primary prostate tumors. Isoform PSMA-2 is also found in normal prostate as well as in brain and liver. Isoform PSMA-9 is specifically expressed in prostate cancer. <a class="attribution" href="Q04609#ref15" onclick="ensureReferenceVisible('ref15')">Ref.15</a> <a class="attribution" href="Q04609#ref24" onclick="ensureReferenceVisible('ref24')">Ref.24</a> <a class="attribution" href="Q04609#ref25" onclick="ensureReferenceVisible('ref25')">Ref.25</a> <a class="attribution" href="Q04609#ref26" onclick="ensureReferenceVisible('ref26')">Ref.26</a>	peptidase M28		Amyotrophic lateral sclerosis Prostate cancer Stroke	Has both folate hydrolase and n-acetylated-alpha-linked- acidic dipeptidase (naaladase) activity. Has a preference for tri- alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission.
dfzCATG	Cathepsin G	1	136	91.03			peptidase S1		Alpha 1 Antitrypsin Deficiency Atopic Dermatitis Chronic Obstructive Pulmonary Disease (COPD)
dfzCMA1	Chymase	1	368	92.78		Mast cells in lung, heart, skin and placenta. Expressed in both normal skin and in urticaria pigmentosa lesions. <a class="attribution" href="P23946#ref3" onclick="ensureReferenceVisible('ref3')">Ref.3</a>	peptidase S1		Asthma Atopic dermatitis Cardiovascular disease, unspecified Inflammation Myocardial infarction	Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion.
dfzFA10	Coagulation factor X	2	4587	98.7		Plasma; synthesized in the liver. <a class="attribution" href="P00742#ref8" onclick="ensureReferenceVisible('ref8')">Ref.8</a>	peptidase S1		Thrombosis Thrombotic disease	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 inhibitor: Apixaban, Rivaroxaban
dfzFA11	Coagulation factor XI	2	57	98.77		Isoform <a href="#P03951-2" onclick="ensureIsoformSequenceVisible('P03951-2'); return true;">2</a> is produced by platelets and megakaryocytes but absent from other blood cells.	peptidase S1		Clotting Disorders	Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.
dfzFA7	Coagulation factor VII	2	530	99.73		Plasma.	peptidase S1		Coagulative disorders	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.
dfzFA9	Coagulation factor IX	1	172	99.65		Synthesized primarily in the liver and secreted in plasma.	peptidase S1		Blood, Blood Forming Organ Disorders, Unspecified Cardiac Surgery Coronary Artery Disease Thrombosis Vascular Diseases Venous Thromboembolism	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.
dfzST14	Suppressor of tumorigenicity 14 protein	1	123	99.1			peptidase S1		Breast cancer	Degrades extracellular matrix. Proposed to play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with arg or lys as the p1 site.
dfzTHRB	Prothrombin	1	4314	95.53		Expressed by the liver and secreted in plasma.	peptidase S1		Coagulative disorders Coronary atherosclerosis Gliomas Heparin-induced thrombocytopenia type II Multiple organ failure Thromboembolic disorders Thrombosis Thrombotic disease	Thrombin, which cleaves bonds after arg and lys, converts fibrinogen to fibrin and activates factors v, vii, viii, xiii, and, in complex with thrombomodulin, protein c.	Thrombin inhibitor: Argatroban, Bivalirudin, Dabigatran Etexilate, Desirudin, Lepirudin
dfzTPA	Tissue-type plasminogen activator	2	248	93.91		Synthesized in numerous tissues (including tumors) and secreted into most extracellular body fluids, such as plasma, uterine fluid, saliva, gingival crevicular fluid, tears, seminal fluid, and milk.	peptidase S1		Neurological diseases	Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single arg-val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in tissue remodeling and degradation and in cell migration.	Tissue-type plasminogen activator inhibitor: Aminocaproic Acid
dfzTRY2	Anionic trypsin-2	2	550	90.49			peptidase S1
dfzTRYB1	Tryptase alpha/beta-1	2	359	97.77			peptidase S1			Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type (By similarity).
dfzUROK	Urokinase-type plasminogen activator	2	731	97.22		Expressed in the prostate gland and prostate cancers. <a class="attribution" href="P00749#ref23" onclick="ensureReferenceVisible('ref23')">Ref.23</a>	peptidase S1		Cancer, unspecific Melanoma	Potent plasminogen activator and is clinically used for therapy of thrombolytic disorders.
dfzDPP2	Dipeptidyl peptidase 2	1	564	93.68		Detected in seminal plasma (at protein level).	peptidase S28			Plays an important role in the degradation of some oligopeptides.
dfzPPCE	Prolyl endopeptidase	1	441	96.27			peptidase S9A		Dementia Neurological diseases	Cleaves peptide bonds on the c-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.
dfzDPP4	Dipeptidyl peptidase 4	4	3207	97.49		Expressed specifically in lymphatic vessels but not in blood vessels in the skin, small intestine, esophagus, ovary, breast and prostate glands. Not detected in lymphatic vessels in the lung, kidney, uterus, liver and stomach (at protein level). Expressed in the poorly differentiated crypt cells of the small intestine as well as in the mature villous cells. Expressed at very low levels in the colon. <a class="attribution" href="P27487#ref12" onclick="ensureReferenceVisible('ref12')">Ref.12</a> <a class="attribution" href="P27487#ref32" onclick="ensureReferenceVisible('ref32')">Ref.32</a>	peptidase S9B		Autoimmune diseases Diabetes mellitus Malignancies Noninsulin-dependent diabetes mellitus Obesity	Removes n-terminal dipeptides sequentially from polypeptides having unsubstituted n-termini provided that the penultimate residue is proline. It plays a role in t cell activation.	Dipeptidyl peptidase IV inhibitor: Alogliptin, Linagliptin, Saxagliptin, Sitagliptin
dfzPA2GA	Phospholipase A2, membrane associated	2	320	96.61			phospholipase A2		Atherosclerosis Coronary Artery Disease
dfzPA2GX	Group 10 secretory phospholipase A2	1	55	85.81		Found in spleen, thymus, peripheral blood leukocytes, pancreas, lung, and colon.	phospholipase A2			PA2 catalyzes the calcium-dependent hydrolysis of the 2- acyl groups in 3-sn-phosphoglycerides. Has a powerful potency for releasing arachidonic acid from cell membrane phospholipids. Prefers phosphatidylethanolamine and phosphatidylcholine liposomes to those of phosphatidylserine.
dfzFDFT	Squalene synthase	3	604	93.54			phytoene/squalene synthase		Hypercholesterolemia Hyperlipidemia Hypocholesterolemia
dfzKCNH2	HERG	0	5167	90.52	Nature11159 VirtualToxLab	Highly expressed in heart and brain. Isoforms USO are frequently overexpressed in cancer cells. <a class="attribution" href="Q12809#ref6" onclick="ensureReferenceVisible('ref6')">Ref.6</a>	potassium channel	Electrocardiogram QT prolonged	Cardiac arrhythmias	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. channel properties are modulated by camp and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (ikr).	HERG blocker: Amiodarone, Dofetilide, Dronedarone, Ibutilide, Sotalol
dfzPGH1	Prostaglandin G/H synthase 1	1	1704	79.75	Nature11159		prostaglandin G/H synthase	Abdominal pain upper Aplastic anaemia Asthma Dyspepsia Erythema multiforme Gastrointestinal haemorrhage Haematuria Haemorrhagic diathesis Hepatitis Nephropathy Oedema Peptic ulcer Pruritus Rash Renal failure Renal tubular disorder Thrombocytopenia Tinnitus Toxic epidermal necrolysis	Cardiovascular disease, unspecified Chronic inflammatory diseases	May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells.
dfzPGH2	Prostaglandin G/H synthase 2	1	3210	87.32	Nature11159		prostaglandin G/H synthase	Abdominal pain upper Aplastic anaemia Dyspepsia Erythema multiforme Flatulence Gastrointestinal haemorrhage Haematuria Haemorrhagic diathesis Hepatitis Nephropathy Oedema Oliguria Peptic ulcer Pruritus Renal failure Thrombocytopenia Tinnitus	Abdominal aortic aneurysm Adenomatous polyposis Alzheimer's disease Analgesics Arthritis Bladder cancer Breast cancer Cancer, unspecific Carcinoma in situ, unspecified Carpal tunnel syndrome Colorectal cancer Dysmenorrhea, unspecified Endometriosis Genitourinary tumors Gestational hypertension Inflammation Inflammatory diseases Lung cancer Malignant mesothelioma Meningioma Myocardial infarction Oropharyngeal squamous cell carcinoma Osteoarthritis Pain, unspecified Pathological angiogenesis Peutz-Jeghers syndrome Prostate cancer Pyresis Renal cell carcinoma Rheumatoid arthritis, unspecified Stroke Vascular lesion regression	May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity.	Cyclooxygenase inhibitor: Acetaminophen, Aminosalicylic Acid, Aspirin, Balsalazide, Bismuth Subsalicylate, Bromfenac, Diclofenac, Diflunisal, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamic Acid, Mefenamic Acid, Mesalamine, Naproxen, Nepafenac, Olsalazine, Oxaprozin, Oxyphenbutazone, Phenylbutazone, Piroxicam, Sulfasalazine, Sulindac, Suprofen, Tolmetin Cyclooxygenase-2 inhibitor: Carprofen, Celecoxib, Etodolac, Meloxicam, Nabumetone, Rofecoxib, Valdecoxib
dfzAAPK2	5'-AMP-activated protein kinase catalytic subunit alpha-2	1	158	85.18			protein kinase			Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.
dfzABL1	Tyrosine-protein kinase ABL1	4	1887	92.65			protein kinase		Myeloma disease
dfzABL2	Abelson tyrosine-protein kinase 2	2	183	91.26		Widely expressed.	protein kinase			Non-receptor tyrosine-protein kinase that plays an ABL1- overlapping role in key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion and receptor endocytosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like MYH10 (involved in movement); CTTN (involved in signaling); or TUBA1 and TUBB (microtubule subunits). Binds directly F-actin and regulates actin cytoskeletal structure through its F-actin- bundling activity. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as CRK, CRKL, DOK1 or ARHGAP35. Adhesion-dependent phosphorylation of ARHGAP35 promotes its association with RASA1, resulting in recruitment of ARHGAP35 to the cell periphery where it inhibits RHO. Phosphorylates multiple receptor tyrosine kinases like PDGFRB and other substrates which are involved in endocytosis regulation such as RIN1. In brain, may regulate neurotransmission by phosphorylating proteins at the synapse. ABL2 acts also as a regulator of multiple pathological signaling cascades during infection. Pathogens can highjack ABL2 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.
dfzACK1	Activated CDC42 kinase 1	1	502	90.66		The Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. It also shows a significant increase in expression in prostate cancers during the progressive stages.	protein kinase			Non-receptor tyrosine-protein and serine/threonine- protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr- 287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR.
dfzACVR1	Activin receptor type-1	2	376	87.02		Expressed in normal parenchymal cells, endothelial cells, fibroblasts and tumor-derived epithelial cells.	protein kinase		Fibrodysplasia ossificans progressiva (FOP) [MIM:135100]: A rare autosomal dominant connective tissue disorder resulting in skeletal malformations and progressive extraskeletal ossification. Heterotopic ossification begins in childhood and can be induced by trauma or may occur without warning. Bone formation is episodic and progressive, leading to a debilitating ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible. 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).
dfzAKT1	RAC-alpha serine/threonine-protein kinase	1	2009	87.04		Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. <a class="attribution" href="P31749#ref6" onclick="ensureReferenceVisible('ref6')">Ref.6</a> <a class="attribution" href="P31749#ref39" onclick="ensureReferenceVisible('ref39')">Ref.39</a> <a class="attribution" href="P31749#ref52" onclick="ensureReferenceVisible('ref52')">Ref.52</a>	protein kinase		Advanced, Relapsed/Refractory Multiple Myeloma Brain ischemic insult Breast cancer Cancer, unspecific Diabetes mellitus Glioblastoma Multiforme (GBM) Huntington's disease Non-Hodgkin's Lymphoma Non-small Cell Lung Cancer Parkinson's disease Recurrent Malignant Glioma Refractory, Rare Sarcoma's Seizure Solid tumors Stroke	General protein kinase capable of phosphorylating several known proteins.
dfzAKT2	RAC-beta serine/threonine-protein kinase	2	1234	84.56		Expressed in all cell types so far analyzed.	protein kinase		Note=Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, plays also a pivotal role in the biology of glioblastoma. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. 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. 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'.
dfzALK	ALK tyrosine kinase receptor	1	1199	87.89		Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells.	protein kinase		Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. 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.
dfzAURKA	Aurora kinase A	1	2503	94.95		Highly expressed in testis and weakly in skeletal muscle, thymus and spleen. Also highly expressed in colon, ovarian, prostate, neuroblastoma, breast and cervical cancer cell lines.	protein kinase		Colorectal Cancer Lymphoma, Unspecified Solid tumors
dfzAVR2A	Activin receptor type-2A	1	80	89.25			protein kinase			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 A, activin B and inhibin A.
dfzAVR2B	Activin receptor type-2B	1	82	80.88			protein kinase		Heterotaxy, visceral, 4, autosomal (HTX4) [MIM:613751]: A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can been associated with variety of congenital defects including cardiac malformations. HTX4 clinical features include dextrocardia, right aortic arch and a right-sided spleen, anomalies of the inferior and the superior vena cava, atrial ventricular canal defect with dextro-transposed great arteries, pulmonary stenosis, polysplenia and midline liver. Note=The disease is caused by mutations affecting the gene represented in this entry.	Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating 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, the type-2 receptors act as a primary activin receptors (binds activin-A/INHBA, activin-B/INHBB as well as inhibin-A/INHA-INHBA). 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. 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.
dfzBMP2K	BMP-2-inducible protein kinase	1	81	80.82			protein kinase			May be involved in osteoblast differentiation.
dfzBMR1B	Bone morphogenetic protein receptor type-1B	1	85	91.28			protein kinase		Acromesomelic chondrodysplasia, with genital anomalies (AMDGA) [MIM:609441]: A form of chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). 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. 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.
dfzBMX	Cytoplasmic tyrosine-protein kinase BMX	1	102	91.85		Highly expressed in cells with great migratory potential, including endothelial cells and metastatic carcinoma cell lines.	protein kinase			Non-receptor tyrosine kinase that plays central but diverse modulatory roles in various signaling processes involved in the regulation of actin reorganization, cell migration, cell proliferation and survival, cell adhesion, and apoptosis. Participates in signal transduction stimulated by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen receptors and integrins. Induces tyrosine phosphorylation of BCAR1 in response to integrin regulation. Activation of BMX by integrins is mediated by PTK2/FAK1, a key mediator of integrin signaling events leading to the regulation of actin cytoskeleton and cell motility. Plays a critical role in TNF-induced angiogenesis, and implicated in the signaling of TEK and FLT1 receptors, 2 important receptor families essential for angiogenesis. Required for the phosphorylation and activation of STAT3, a transcription factor involved in cell differentiation. Also involved in interleukin-6 (IL6) induced differentiation. Plays also a role in programming adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts. May be involved in regulation of endocytosis through its interaction with an endosomal protein RUFY1. May also play a role in the growth and differentiation of hematopoietic cells; as well as in signal transduction in endocardial and arterial endothelial cells.
dfzBRAF	Serine/threonine-protein kinase B-raf	2	676	96.17		Brain and testis.	protein kinase		Malignant melanoma Melanoma Pancreatic cancer	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.	Serine/threonine-protein kinase B-raf inhibitor: Dabrafenib, Regorafenib, Sorafenib, Vemurafenib
dfzBTK	Tyrosine-protein kinase BTK	1	857	90.04		Predominantly expressed in B-lymphocytes.	protein kinase		Acute lymphoblastic leukaemia B cell immunodeficiency	Plays a crucial role in b-cell ontogeny. Transiently phosphorylates gtf2i on tyrosine residues in response to b cell receptor crosslinking.
dfzCDC7	Cell division cycle 7-related protein kinase	1	967	89.59			protein kinase			Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3.
dfzCDK16	Cyclin-dependent kinase 16	1	81	86.56		Detected in pancreas islets (at protein level). Detected in brain and pancreas.	protein kinase			Protein kinase that plays a role in vesicle-mediated transport processes and exocytosis. Regulates GH1 release by brain neurons. Phosphorylates NSF, and thereby regulates NSF oligomerization. Required for normal spermatogenesis. Regulates neuron differentiation and dendrite development (By similarity). Plays a role in the regulation of insulin secretion in response to changes in blood glucose levels. Can phosphorylate CCNY at 'Ser- 336' (in vitro).
dfzCDK2	Cyclin-dependent kinase 2	1	3987	93			protein kinase		Acute lymphoblastic leukemia (ALL) Acute myeloid leukemia (AML) Advanced Solid tumors B-cell malignancies Cancer, unspecific Cardiovascular disease, unspecified Chronic lymphocytic leukemia (CLL) Hepatocellular Carcinoma (HCC) Nasopharyngeal Cancer (NPC) Non-Hodgkin's Lymphoma Non-small Cell Lung Cancer Solid tumors Viral infection, unspecified	Probably involved in the control of the cell cycle. Interacts with cyclins a, d, or e. Activity of cdk2 is maximal during s phase and g2.
dfzCDK5	Cyclin-dependent kinase 5	1	2276	89.64		Isoform <a href="#Q00535" onclick="ensureIsoformSequenceVisible('Q00535'); return true;">1</a> is ubiquitously expressed. Accumulates in cortical neurons (at protein level). Isoform <a href="#Q00535-2" onclick="ensureIsoformSequenceVisible('Q00535-2'); return true;">2</a> has only been detected in testis, skeletal muscle, colon, bone marrow and ovary. <a class="attribution" href="Q00535#ref3" onclick="ensureReferenceVisible('ref3')">Ref.3</a> <a class="attribution" href="Q00535#ref16" onclick="ensureReferenceVisible('ref16')">Ref.16</a>	protein kinase		Alzheimer's disease Bladder cancer	Probably involved in the control of the cell cycle. Interacts with d1 and d3-type g1 cyclins. Can phosphorylate histone h1, tau, map2 and nf-h and nf-m. Also interacts with p35 which activates the kinase.
dfzCDK8	Cyclin-dependent kinase 8	2	439	83.03			protein kinase		Cancer, unspecific	Probably involved in the control of the cell cycle. May play a role in transcriptional regulation. Binds to and is activated by cyclin c. Phosphorylates the ctd (carboxy-terminal domain) of the large subunit of rna polymerase ii (rnap ii).
dfzCDK9	Cyclin-dependent kinase 9	2	581	89.38		Ubiquitous.	protein kinase		Cancer, unspecific Heart disease, unspecified Leukemia, Unspecified Lymphoma, Unspecified Multiple Myeloma Solid tumors	Member of the cyclin-dependent kinase pair (cdk9/cyclin t) complex, also called positive transcription elongation factor b (p-tefb), which is proposed to facilitate the transition from abortive to production elongation by phosphorylating the ctd.
dfzCDKL1	Cyclin-dependent kinase-like 1	1	73	85		Highly expressed in kidney, and to a lower extent in ovary.	protein kinase
dfzCDKL2	Cyclin-dependent kinase-like 2	1	73	92.95		Expressed in testis and kidney, and at lower level in brain and lung.	protein kinase
dfzCHK1	Serine/threonine-protein kinase Chk1	1	2569	93.52		Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon. <a class="attribution" href="O14757#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a> <a class="attribution" href="O14757#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a>	protein kinase		Solid tumors
dfzCHK2	Serine/threonine-protein kinase Chk2	2	978	92.22		High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues.	protein kinase		Solid tumors
dfzCLK1	Dual specificity protein kinase CLK1	1	327	80.21		Endothelial cells.	protein kinase			Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA.
dfzCLK2	Dual specificity protein kinase CLK2	1	986	85.48		Endothelial cells.	protein kinase			Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.
dfzCLK3	Dual specificity protein kinase CLK3	1	165	94.04		Endothelial cells.	protein kinase			Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Phosphorylates SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.
dfzCSF1R	Macrophage colony-stimulating factor 1 receptor	3	1511	89.4			protein kinase		Bone marrow transplant Febrile neutropenia Non-myeloid cancer
dfzCSK	Casein kinase II subunit alpha	4	995	86.55			protein kinase		Breast cancer Cancer, unspecific	Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. The alpha and alpha' chains contain the catalytic site. Participates in wnt signaling.
dfzCSK21	Casein kinase II subunit alpha	4	995	86.55			protein kinase		Breast cancer Cancer, unspecific	Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. The alpha and alpha' chains contain the catalytic site. Participates in wnt signaling.
dfzDAPK1	Death-associated protein kinase 1	1	83	87.94		Isoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas.	protein kinase			Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript- selective translation inhibition. Isoform 2 cannot induce apoptosis but can induce membrane blebbing.
dfzDDR1	Epithelial discoidin domain-containing receptor 1	1	120	89.98		Detected in T-47D, MDA-MB-175 and HBL-100 breast carcinoma cells, A-431 epidermoid carcinoma cells, SW48 and SNU-C2B colon carcinoma cells and Hs 294T melanoma cells (at protein level). Expressed at low levels in most adult tissues and is highest in the brain, lung, placenta and kidney. Lower levels of expression are detected in melanocytes, heart, liver, skeletal muscle and pancreas. Abundant in breast carcinoma cell lines. In the colonic mucosa, expressed in epithelia but not in the connective tissue of the lamina propria. In the thyroid gland, expressed in the epithelium of the thyroid follicles. In pancreas, expressed in the islets of Langerhans cells, but not in the surrounding epithelial cells of the exocrine pancreas. In kidney, expressed in the epithelia of the distal tubules. Not expressed in connective tissue, endothelial cells, adipose tissue, muscle cells or cells of hematopoietic origin.	protein kinase			Tyrosine kinase that functions as cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11.
dfzDMPK	Myotonin-protein kinase	1	88	84.09		Most isoforms are expressed in many tissues including heart, skeletal muscle, liver and brain, except for isoform 2 which is only found in the heart and skeletal muscle, and isoform 14 which is only found in the brain, with high levels in the striatum, cerebellar cortex and pons.	protein kinase		Dystrophia myotonica 1 (DM1) [MIM:160900]: A muscular disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness and cardiac arrhythmias. 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.	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.
dfzDYR1A	Dual specificity tyrosine-phosphorylation-regulated kinase 1A	1	1624	86.1		Ubiquitous. Highest levels in skeletal muscle, testis, fetal lung and fetal kidney.	protein kinase		Mental retardation, autosomal dominant 7 (MRD7) [MIM:614104]: A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. 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.
dfzDYRK2	Dual specificity tyrosine-phosphorylation-regulated kinase 2	1	169	89.44		Testis, after the onset of spermatogenesis.	protein kinase			Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser- 641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457', promoting TERT ubiquitination by the EDVP complex. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).
dfzEGFR	Epidermal growth factor receptor	2	4165	94.59		Ubiquitously expressed. Isoform <a href="#P00533-2" onclick="ensureIsoformSequenceVisible('P00533-2'); return true;">2</a> is also expressed in ovarian cancers. <a class="attribution" href="P00533#ref48" onclick="ensureReferenceVisible('ref48')">Ref.48</a>	protein kinase	Decreased appetite	Breast cancer Cancer, unspecific Colorectal cancer Glioblastoma multiforme Head and neck tumors Lymphangiomatosis Nonsmall cell lung cancer Ovarian cancer Pancreatic cancer Solid tumor Squamous cell carcinoma Tumors HCV infection	Receptor for egf, but also for other members of the egf family, as tgf-alpha, amphiregulin, betacellulin, heparin-binding egf-like growth factor, gp30 and vaccinia virus growth factor. Is involved in the control of cell growth and differentiation.	Epidermal growth factor receptor erbB1 inhibitor: Cetuximab, Erlotinib, Gefitinib, Lapatinib, Panitumumab
dfzEPHA3	Ephrin type-A receptor 3	2	106	91.61		Widely expressed. Highest level in placenta.	protein kinase		Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The gene represented in this entry may be involved in disease pathogenesis.	Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.
dfzEPHA4	Ephrin type-A receptor 4	1	133	82.99		Ubiquitous.	protein kinase			Receptor tyrosine kinase which binds 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, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. Beside its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, plays also a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium.
dfzEPHA7	Ephrin type-A receptor 7	1	83	87.85		Widely expressed.	protein kinase			Receptor tyrosine kinase which binds promiscuously GPI- anchored ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Among GPI-anchored ephrin-A ligands, EFNA5 is a cognate/functional ligand for EPHA7 and their interaction regulates brain development modulating cell-cell adhesion and repulsion. Has a repellent activity on axons and is for instance involved in the guidance of corticothalamic axons and in the proper topographic mapping of retinal axons to the colliculus. May also regulate brain development through a caspase(CASP3)-dependent proapoptotic activity. Forward signaling may result in activation of components of the ERK signaling pathway including MAP2K1, MAP2K2, MAPK1 AND MAPK3 which are phosphorylated upon activation of EPHA7.
dfzEPHB2	Ephrin type-B receptor 2	1	105	81.79		Brain, heart, lung, kidney, placenta, pancreas, liver and skeletal muscle. Preferentially expressed in fetal brain.	protein kinase		Colorectal cancer	Receptor for members of the ephrin-b family.
dfzEPHB4	Ephrin type-B receptor 4	2	426	92.18		Abundantly expressed in placenta but also detected in kidney, liver, lung, pancreas, skeletal muscle and heart. Expressed in primitive and myeloid, but not lymphoid, hematopoietic cells. Also observed in cell lines derived from liver, breast, colon, lung, melanocyte and cervix. <a class="attribution" href="P54760#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a>	protein kinase		Lung Cancer Solid tumors
dfzERBB2	Receptor tyrosine-protein kinase erbB-2	1	2000	90.31		Expressed in a variety of tumor tissues including primary breast tumors and tumors from small bowel, esophagus, kidney and mouth. <a class="attribution" href="P04626#ref14" onclick="ensureReferenceVisible('ref14')">Ref.14</a>	protein kinase		Not Available		Receptor protein-tyrosine kinase erbB-2 inhibitor: Lapatinib, Pertuzumab, Trastuzumab, Trastuzumab Emtansine
dfzERBB3	Receptor tyrosine-protein kinase erbB-3	1	74	82.3		Epithelial tissues and brain.	protein kinase		Advanced nonsmall cell lung cancer Lung adenocarcinomas	Binds and is activated by neuregulins and ntak.
dfzERBB4	Receptor tyrosine-protein kinase erbB-4	1	768	82.1		Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart. <a class="attribution" href="Q15303#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a> <a class="attribution" href="Q15303#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a> <a class="attribution" href="Q15303#ref15" onclick="ensureReferenceVisible('ref15')">Ref.15</a> <a class="attribution" href="Q15303#ref48" onclick="ensureReferenceVisible('ref48')">Ref.48</a>	protein kinase		Dermatologic Complications Ependymoma Metastatic (Stage IV) Breast Cancer	Specifically binds and is activated by neuregulins, nrg- 2, nrg-3, heparin-binding egf-like growth factor, betacellulin and ntak. Interaction with these factors induces cell differenciation. Not activated by egf, tgf-a, and amphiregulin.
dfzFAK1	Focal adhesion kinase 1	4	1079	92.04		Detected in B and T-lymphocytes. Isoform 1 and isoform 6 are detected in lung fibroblasts (at protein level). Ubiquitous.	protein kinase		Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.	Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.
dfzFAK2	Protein-tyrosine kinase 2-beta	1	668	83.51		Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes.	protein kinase		Note=Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.	Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T- cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2.
dfzFGFR1	Fibroblast growth factor receptor 1	1	1718	91.56		Detected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform <a href="#P11362-16" onclick="ensureIsoformSequenceVisible('P11362-16'); return true;">17</a>, isoform <a href="#P11362-18" onclick="ensureIsoformSequenceVisible('P11362-18'); return true;">18</a> and isoform <a href="#P11362-19" onclick="ensureIsoformSequenceVisible('P11362-19'); return true;">19</a> are not detected in these cells. <a class="attribution" href="P11362#ref19" onclick="ensureReferenceVisible('ref19')">Ref.19</a>	protein kinase		Peripheral Vascular Disease Severe Coronary Heart Disease Solid tumors Ulcers		Fibroblast growth factor receptor 1 inhibitor: Pazopanib, Regorafenib
dfzFGFR2	Fibroblast growth factor receptor 2	2	264	86.72			protein kinase		Angiogenesis in metastatic and atherosclerotic processes	Receptor for acidic and basic fibroblast growth factors.	Fibroblast growth factor receptor 2 agonist: Palifermin Fibroblast growth factor receptor 2 inhibitor: Regorafenib
dfzGAK	Cyclin-G-associated kinase	1	86	87.78		Ubiquitous. Highest in testis.	protein kinase			Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin- coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.
dfzGSK3B	Glycogen synthase kinase-3 beta	1	2990	90.81		Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Colocalizes with EIF2AK2/PKR and TAU in the Alzheimer's disease (AD) brain. <a class="attribution" href="P49841#ref38" onclick="ensureReferenceVisible('ref38')">Ref.38</a>	protein kinase		Alzheimer's disease Bipolar affective disorder Brain injury Immunodeficiency Ischemia Noninsulin-dependent diabetes mellitus	Participates in the wnt signaling pathway. Implicated in the hormonal control of several regulatory proteins including glycogen synthase, myb, and the transcription factor c-jun. Phosphorylates c-jun at sites proximal to its dna-binding domain.	Glycogen synthase kinase-3 inhibitor: Lithium Carbonate, Lithium Citrate
dfzHCK	Tyrosine-protein kinase HCK	1	368	96.29		Detected in monocytes and neutrophils (at protein level). Expressed predominantly in cells of the myeloid and B-lymphoid lineages. Highly expressed in granulocytes. Detected in tonsil.	protein kinase		Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity. Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation.	Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS.
dfzIGF1R	Insulin-like growth factor 1 receptor	1	1829	91.4		Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney. <a class="attribution" href="P08069#ref9" onclick="ensureReferenceVisible('ref9')">Ref.9</a> <a class="attribution" href="P08069#ref14" onclick="ensureReferenceVisible('ref14')">Ref.14</a> <a class="attribution" href="P08069#ref16" onclick="ensureReferenceVisible('ref16')">Ref.16</a> <a class="attribution" href="P08069#ref24" onclick="ensureReferenceVisible('ref24')">Ref.24</a>	protein kinase		Cancer, unspecific Colorectal cancer Ewing's sarcoma Medulloblastoma Peripheral neuroectodermal tumor Tumors	This receptor binds insulin-like growth factor I (IGF I) with a high affinity and igf ii with a lower affinity. It has a tyrosine-protein kinase activity.	Insulin-like growth factor I receptor agonist: Mecasermin, Mecasermin Rinfabate
dfzINSR	Insulin receptor	3	1369	89.58		Isoform <a href="#P06213" onclick="ensureIsoformSequenceVisible('P06213'); return true;">Long</a> and isoform <a href="#P06213-2" onclick="ensureIsoformSequenceVisible('P06213-2'); return true;">Short</a> 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 <a href="#P06213-2" onclick="ensureIsoformSequenceVisible('P06213-2'); return true;">Short</a> 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. <a class="attribution" href="P06213#ref15" onclick="ensureReferenceVisible('ref15')">Ref.15</a> <a class="attribution" href="P06213#ref28" onclick="ensureReferenceVisible('ref28')">Ref.28</a> <a class="attribution" href="P06213#ref32" onclick="ensureReferenceVisible('ref32')">Ref.32</a> <a class="attribution" href="P06213#ref33" onclick="ensureReferenceVisible('ref33')">Ref.33</a>	protein kinase		Diabetes mellitus	This receptor binds insulin and has a tyrosine-protein kinase activity.	Insulin receptor agonist: Insulin Aspart, Insulin Aspart Protamine Recombinant, Insulin Detemir, Insulin Glargine, Insulin Glulisine, Insulin Human, Insulin Lispro, Insulin Lispro Protamine Recombinant, Insulin Pork, Insulin Purified Beef, Insulin Purified Pork, Insulin Susp Isophane Beef, Insulin Susp Isophane Beef/Pork, Insulin Susp Isophane Purified Beef, Insulin Susp Isophane Purified Pork, Insulin Susp Isophane Recombinant Human, Insulin Susp Isophane Semisynthetic Purified Human, Insulin Susp Protamine Zinc Beef/Pork, Insulin Susp Protamine Zinc Purified Beef, Insulin Susp Protamine Zinc Purified Pork, Insulin Zinc Susp Beef, Insulin Zinc Susp Extended Beef, Insulin Zinc Susp Extended Purified Beef, Insulin Zinc Susp Extended Recombinant Human, Insulin Zinc Susp Prompt Beef, Insulin Zinc Susp Prompt Purified Pork, Insulin Zinc Susp Purified Beef, Insulin Zinc Susp Purified Beef/Pork, Insulin Zinc Susp Purified Pork, Insulin Zinc Susp Recombinant Human, Insulin Zinc Susp Semisynthetic Purified Human
dfzITK	Tyrosine-protein kinase ITK/TSK	1	1166	92.91		T-cell lines and natural killer cell lines.	protein kinase		Asthma	Plays a role in t cell proliferation and differentiation.	Tyrosine-protein kinase ITK/TSK inhibitor: Pazopanib
dfzJAK1	Tyrosine-protein kinase JAK1	2	562	82.24		Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue.	protein kinase			Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
dfzJAK2	Tyrosine-protein kinase JAK2	1	1986	89.91		Ubiquitously expressed throughout most tissues. <a class="attribution" href="O60674#ref12" onclick="ensureReferenceVisible('ref12')">Ref.12</a>	protein kinase		Hodgkin's disease, unspecified Leukemia, unspecified Vascular disease	Tyrosine kinase of the non-receptor type, involved in interleukin 3 signal transduction.	Tyrosine-protein kinase JAK2 inhibitor: Ruxolitinib
dfzJAK3	Tyrosine-protein kinase JAK3	1	1537	83.14		In NK cells and an NK-like cell line but not in resting T-cells or in other tissues. The S-form is more commonly seen in hematopoietic lines, whereas the B-form is detected in cells both of hematopoietic and epithelial origins. <a class="attribution" href="P52333#ref9" onclick="ensureReferenceVisible('ref9')">Ref.9</a>	protein kinase		Acute graft-versus-host disease Chronic graft-versus-host disease Immunosuppression Rheumatoid-arthritis	Tyrosine kinase of the non-receptor type, involved in the interleukin-2 and interleukin-4 signaling pathway. Phosphorylates stat6, irs1, irs2 and pi3k.
dfzKAPCA	cAMP-dependent protein kinase catalytic subunit alpha	2	1370	82.08		Isoform <a href="#P17612" onclick="ensureIsoformSequenceVisible('P17612'); return true;">1</a> is ubiquitous. Isoform <a href="#P17612-2" onclick="ensureIsoformSequenceVisible('P17612-2'); return true;">2</a> is sperm-specific and is enriched in pachytene spermatocytes but is not detected in round spermatids. <a class="attribution" href="P17612#ref6" onclick="ensureReferenceVisible('ref6')">Ref.6</a> <a class="attribution" href="P17612#ref28" onclick="ensureReferenceVisible('ref28')">Ref.28</a>	protein kinase		Not Available
dfzKC1D	Casein kinase I isoform delta	3	881	86.72		Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. However, kinase activity is not uniform, with highest kinase activity in splenocytes. In blood, highly expressed in hemopoietic cells and mature granulocytes. Also found in monocytes and lymphocytes.	protein kinase		Advanced sleep phase syndrome, familial, 2 (FASPS2) [MIM:615224]: A disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. 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.
dfzKC1G3	Casein kinase I isoform gamma-3	1	593	90.17			protein kinase			Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Regulates fast synaptic transmission mediated by glutamate (By similarity).
dfzKCC1D	Calcium/calmodulin-dependent protein kinase type 1D	1	328	85.16		Widely expressed. Highly and mostly expressed in polymorphonuclear leukocytes (neutrophilic and eosinophilic granulocytes) while little or no expression is observed in monocytes and lymphocytes.	protein kinase			Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine- induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta.
dfzKCC1G	Calcium/calmodulin-dependent protein kinase type 1G	1	80	87.8		Mainly expressed in brain with small amounts in skeletal muscles, kidney, spleen and liver. Strongly expressed in forebrain neocortex, striatum and limbic system.	protein kinase			Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade. In vitro phosphorylates transcription factor CREB1 (By similarity).
dfzKCC2A	Calcium/calmodulin-dependent protein kinase type II subunit alpha	1	413	84.25			protein kinase			CaM-kinase II (CAMK2) is a prominent kinase in the central nervous system that may function in long-term potentiation and neurotransmitter release. Member of the NMDAR signaling complex in excitatory synapses it may regulate NMDAR-dependent potentiation of the AMPAR and synaptic plasticity (By similarity).
dfzKCC2D	Calcium/calmodulin-dependent protein kinase type II subunit delta	2	830	82.02		Expressed in cardiac muscle and skeletal muscle. Isoform Delta 3, isoform Delta 2, isoform Delta 8 and isoform Delta 9 are expressed in cardiac muscle. Isoform Delta 11 is expressed in skeletal muscle.	protein kinase			Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser- 2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program. Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis. May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor- coupling factor.
dfzKCC4	Calcium/calmodulin-dependent protein kinase type IV	1	104	89.59		Expressed in brain, thymus, CD4 T-cells, testis and epithelial ovarian cancer tissue.	protein kinase			Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal roles in immune response, inflammation, and memory consolidation. In the thymus, regulates the CD4(+)/CD8(+) double positive thymocytes selection threshold during T-cell ontogeny. In CD4 memory T-cells, is required to link T-cell antigen receptor (TCR) signaling to the production of IL2, IFNG and IL4 (through the regulation of CREB and MEF2). Regulates the differentiation and survival phases of osteoclasts and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and the regulation of temporal expression of BCL2. Phosphorylates the transcription activator CREB1 on 'Ser-133' in hippocampal neuron nuclei and contribute to memory consolidation and long term potentiation (LTP) in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1 and MAPK14/p38 and stimulate transcription through the phosphorylation of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A and STMN1/OP18.
dfzKIT	Mast/stem cell growth factor receptor Kit	1	1364	93.44		Isoform <a href="#P10721" onclick="ensureIsoformSequenceVisible('P10721'); return true;">1</a> and isoform <a href="#P10721-2" onclick="ensureIsoformSequenceVisible('P10721-2'); return true;">2</a> are detected in spermatogonia and Leydig cells. Isoform <a href="#P10721-3" onclick="ensureIsoformSequenceVisible('P10721-3'); return true;">3</a> 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. <a class="attribution" href="P10721#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a> <a class="attribution" href="P10721#ref28" onclick="ensureReferenceVisible('ref28')">Ref.28</a>	protein kinase		Cancer, unspecific Gastrointestinal stromal tumors Inflammation Malignant phyllodes tumours Ovarian cancer Phyllodes tumours Renal cell carcinoma Small cell lung cancer	This is the receptor for stem cell factor (mast cell growth factor). It has a tyrosine-protein kinase activity. binding of the ligands leads to the autophosphorylation of kit and its association with substrates such as phosphatidylinositol 3-kinase (pi3k).	Stem cell growth factor receptor inhibitor: Dasatinib, Imatinib, Pazopanib, Regorafenib, Sorafenib, Sunitinib
dfzKKCC2	Calcium/calmodulin-dependent protein kinase kinase 2	1	104	82.24		Ubiquitously expressed with higher levels in the brain. Intermediate levels are detected in spleen, prostate, thyroid and leukocytes. The lowest level is in lung.	protein kinase			Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Isoform 1, isoform 2 and isoform 3 phosphorylate CAMK1 and CAMK4. Isoform 3 phosphorylates CAMK1D. Isoform 4, isoform 5 and isoform 6 lacking part of the calmodulin- binding domain are inactive. Efficiently phosphorylates 5'-AMP- activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals (By similarity). Seems to be involved in hippocampal activation of CREB1 (By similarity). May play a role in neurite growth. Isoform 3 may promote neurite elongation, while isoform 1 may promoter neurite branching.
dfzKPCA	Protein kinase C alpha type	1	1126	81.4			protein kinase		Leukemia, unspecified Prostate cancer	This is a calcium-activated, phospholipid-dependent, serine- and threonine-specific enzyme.pkc is activated by diacylglycerol which in turn phosphorylates a range of cellular proteins. Pkc also serves as the receptor for phorbol esters.
dfzKPCB	Protein kinase C beta type	1	613	91.76			protein kinase		B-lineage malignancies Diabetes mellitus Diabetic retinopathy Macular edema	This is a calcium-activated, phospholipid-dependent, serine- and threonine-specific enzyme. Pkc is activated by diacylglycerol which in turn phosphorylates a range of cellular proteins. Pkc also serves as the receptor for phorbol esters.
dfzKPCI	Protein kinase C iota type	1	667	80.66		Predominantly expressed in lung and brain, but also expressed at lower levels in many tissues including pancreatic islets. Highly expressed in non-small cell lung cancers.	protein kinase			Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non- small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis.
dfzKPCL	Protein kinase C eta type	1	536	85.15		Most abundant in lung, less in heart and skin. <a class="attribution" href="P24723#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a>	protein kinase		Not Available
dfzKPCT	Protein kinase C theta type	2	1074	85.15		Expressed in skeletal muscle, T-cells, megakaryoblastic cells and platelets. <a class="attribution" href="Q04759#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a>	protein kinase		Not Available
dfzKS6A1	Ribosomal protein S6 kinase alpha-1	1	140	80.5			protein kinase			Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1, which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin- derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the 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.
dfzKS6A3	Ribosomal protein S6 kinase alpha-3	1	1162	84.51		Expressed in many tissues, highest levels in skeletal muscle.	protein kinase		Coffin-Lowry syndrome (CLS) [MIM:303600]: A X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders. 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. 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.
dfzKSYK	Tyrosine-protein kinase SYK	2	951	90.86		Widely expressed in hematopoietic cells (at protein level). Within the B-cells compartment it is for instance expressed for pro-B-cells to plasma cells. <a class="attribution" href="P43405#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a>	protein kinase		Allergic Reaction Asthma Inflammatory diseases Lymphoma, Non-Hodgkin's Obstructive airway disease Rheumatoid arthritis Thrombocytopenia	Positive effector of bcr-stimulated responses. Couples the b cell antigen receptor (bcr) to the mobilization of calcium ion either through a phosphoinositide 3-kinase-dependent pathway, when not phosphorylated on tyrosines of the linker region.
dfzLCK	Tyrosine-protein kinase Lck	1	2445	93.33		Expressed specifically in lymphoid cells.	protein kinase		Philadelphia-positive leukemia		Tyrosine-protein kinase LCK inhibitor: Dasatinib, Pazopanib
dfzLIMK2	LIM domain kinase 2	1	144	81.97		Highest expression in the placenta; moderate level in liver, lung, kidney, and pancreas. LIMK2a is found to be more abundant then LIMK2b in liver, colon, stomach, and spleen, while in brain, kidney, and placenta LIMK2b is the dominant form. In adult lung, both LIMK2a and LIMK2b is nearly equally observed.	protein kinase			Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro.
dfzLYN	Tyrosine-protein kinase Lyn	2	887	86.68		Detected in monocytes (at protein level). Detected in placenta, and in fetal brain, lung, liver and kidney. Widely expressed in a variety of organs, tissues, and cell types such as epidermoid, hematopoietic, and neuronal cells. Expressed in primary neuroblastoma tumors.	protein kinase		Note=Constitutively phosphorylated and activated in cells from a number of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) patients. Mediates phosphorylation of the BCR-ABL fusion protein. Abnormally elevated expression levels or activation of LYN signaling may play a role in survival and proliferation of some types of cancer cells.	Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down- regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down- regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, PTK2B/PYK2, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3- kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr- 72'.
dfzM3K5	Mitogen-activated protein kinase kinase kinase 5	2	136	90.84		Abundantly expressed in heart and pancreas.	protein kinase		Cardiac diseases Malignant fibrous histiocytomas	Phosphorylates and activates two different subgroups of map kinase kinases, mkk4/sek1 and mkk3/mapkk6 (or mkk6), which in turn activates stress-activated protein kinase (sapk, also known as jnk; c-jun amino-terminal kinase) and p38 subgroups of map kinase.
dfzM3K7	Mitogen-activated protein kinase kinase kinase 7	1	156	96.43		Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.	protein kinase			Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2- induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity.
dfzM3K9	Mitogen-activated protein kinase kinase kinase 9	1	139	85.56		Expressed in epithelial tumor cell lines of colonic, breast and esophageal origin. <a class="attribution" href="P80192#ref4" onclick="ensureReferenceVisible('ref4')">Ref.4</a>	protein kinase		Cancer, unspecific
dfzM4K4	Mitogen-activated protein kinase kinase kinase kinase 4	1	1007	93.23		Appears to be ubiquitous. Expressed in all tissue types examined. Isoform 5 appears to be more abundant in the brain. Isoform 4 is predominant in the liver, skeletal muscle and placenta.	protein kinase			Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322.
dfzMAPK2	MAP kinase-activated protein kinase 2	2	1516	89.99		Expressed in all tissues examined.	protein kinase			Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, ELAVL1, HNRNPA0, HSF1, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat- shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilize GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.
dfzMAPK3	MAP kinase-activated protein kinase 3	1	742	83.77		Widely expressed, with a higher expression level observed in heart and skeletal muscle. No expression in brain.	protein kinase			Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38- alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.
dfzMELK	Maternal embryonic leucine zipper kinase	1	627	88.11		Expressed in placenta, kidney, thymus, testis, ovary and intestine.	protein kinase		Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation.	Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.
dfzMERTK	Tyrosine-protein kinase Mer	2	137	85.83		Not expressed in normal B- and T-lymphocytes but is expressed in numerous neoplastic B- and T-cell lines. Highly expressed in testis, ovary, prostate, lung, and kidney, with lower expression in spleen, small intestine, colon, and liver.	protein kinase		Retinitis pigmentosa 38 (RP38) [MIM:613862]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Note=The disease is caused by mutations affecting the gene represented in this entry.	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll- like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.
dfzMK01	Mitogen-activated protein kinase 1	1	1083	86.61			protein kinase		Neurodegenerative diseases Proliferative diseases	Phosphorylates microtubule-associated protein-2 (map2). Myelin basic protein (mbp), and elk-1; may promote entry in the cell cycle.	Mitogen-activated protein kinase; ERK1/ERK2 inhibitor: Lithium Carbonate, Lithium Citrate
dfzMK07	Mitogen-activated protein kinase 7	1	104	81.98		Expressed in many adult tissues. Abundant in heart, placenta, lung, kidney and skeletal muscle. Not detectable in liver.	protein kinase			Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras- independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction.
dfzMK08	Mitogen-activated protein kinase 8	1	1834	89.77			protein kinase		Cancer, unspecific Crohn's disease, unspecified Hearing Loss Inflammatory Disorders, Unspecified Insulin resistance Obesity	Responds to activation by environmental stress and pro- inflammatory cytokines by phosphorylating a number of transcription factors, primarily components of ap-1 such as c-jun and atf2 and thus regulates ap-1 transcriptional activity.
dfzMK09	Mitogen-activated protein kinase 9	1	1497	84.68			protein kinase		Not Available
dfzMK10	Mitogen-activated protein kinase 10	2	961	90.66		Specific to a subset of neurons in the nervous system. Present in the hippocampus and areas, cerebellum, striatum, brain stem, and weakly in the spinal cord. Very weak expression in testis and kidney.	protein kinase		Ischemic stroke Neurological diseases	Responds to activation by environmental stress and pro- inflammatory cytokines by phosphorylating a number of transcription factors, primarily components of ap-1 such as c-jun and atf2 and thus regulates ap-1 transcriptional activity.
dfzMK11	Mitogen-activated protein kinase 11	2	731	86.89		Highest levels in the brain and heart. Also expressed in the placenta, lung, liver, skeletal muscle, kidney and pancreas.	protein kinase		Inflammation Psoriasis Rheumatoid arthritis, unspecified	Kinase involved in a signal transduction pathway that is activated by changes in the osmolarity of the extracellular environment, by cytokines, or by environmental stress. Phosphorylates preferentially transcription factor atf2.	MAP kinase p38 beta inhibitor: Regorafenib
dfzMK13	Mitogen-activated protein kinase 13	1	1312	85.54		Expressed in testes, pancreas, small intestine, lung and kidney. Abundant in macrophages, also present in neutrophils, CD4+ T-cells, and endothelial cells.	protein kinase			Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells.
dfzMK14	Mitogen-activated protein kinase 14	1	4178	93.63		Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney.	protein kinase	Abdominal pain upper	Adult respiratory distress syndrome Alzheimer's disease Crescentic glomerulonephritis Crohn's disease, unspecified Cytokine-mediated diseases Endotoxemia Inflammation Insulin resistance Multiple myeloma Psoriasis Rheumatoid arthritis, unspecified Skin diseases Thrombosis	Responds to activation by environmental stress, pro- inflammatory cytokines and lipopolysaccharide (lps) by phosphorylating a number of transcription factors, such as elk-1 and atf2 and several downstream kinases, such as mapkapk2 and mapkapk5.
dfzMP2K1	Dual specificity mitogen-activated protein kinase kinase 1	2	901	87.53		Widely expressed, with extremely low levels in brain. <a class="attribution" href="Q02750#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a>	protein kinase		Breast cancer Prostate cancer	Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a thr-glu-tyr sequence located in map kinases. Activates erk1 and erk2 map kinases.	Dual specificity mitogen-activated protein kinase kinase 1 inhibitor: Trametinib
dfzMRCKA	Serine/threonine-protein kinase MRCK alpha	1	827	80.35		Highly expressed in the brain and lung and present in lower levels in all other tissues tested.	protein kinase			Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates: PPP1R12A, LIMK1 and LIMK2. May play a role in TFRC-mediated iron uptake.
dfzMRCKB	Serine/threonine-protein kinase MRCK beta	2	79	86.1		Expressed in all tissues examined, with high levels in heart, brain, placenta and lung.	protein kinase			Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates PPP1R12A.
dfzMST4	Serine/threonine-protein kinase MST4	1	97	83.79			protein kinase			Mediator of cell growth. Modulates apoptosis.
dfzMYLK4	Myosin light chain kinase family member 4	1	81	90.34			protein kinase
dfzNEK1	Serine/threonine-protein kinase Nek1	1	85	88.41		High fetal expression in the brain and kidney.	protein kinase		Short-rib thoracic dysplasia 6 with or without polydactyly (SRTD6) [MIM:263520]: A form of short-rib thoracic dysplasia, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. Note=The disease is caused by mutations affecting the gene represented in this entry. In some cases NEK1 mutations result in disease phenotype in the presence of mutations in DYNC2H1 indicating digenic inheritance (digenic short rib- polydactyly syndrome 3/6 with polydactyly) (PubMed:21211617).	Phosphorylates serines and threonines, but also appears to possess tyrosine kinase activity. Implicated in the control of meiosis (By similarity). Involved in cilium assembly. In response to injury that includes DNA damage, NEK1 phosphorylates VDAC1 to limit mitochondrial cell death.
dfzNEK2	Serine/threonine-protein kinase Nek2	1	1008	86.42		Isoform 1 and isoform 2 are expressed in peripheral blood T-cells and a wide variety of transformed cell types. Isoform 1 and isoform 4 are expressed in the testis. Up- regulated in various cancer cell lines, as well as primary breast tumors.	protein kinase		Retinitis pigmentosa 67 (RP67) [MIM:615565]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Note=The disease is caused by mutations affecting the gene represented in this entry.	Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGOL1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Isoform 1 phosphorylates and activates NEK11 in G1/S- arrested cells. Isoform 2, which is not present in the nucleolus, does not.
dfzNTRK1	High affinity nerve growth factor receptor	2	1172	84.19		Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors. <a class="attribution" href="P04629#ref14" onclick="ensureReferenceVisible('ref14')">Ref.14</a> <a class="attribution" href="P04629#ref18" onclick="ensureReferenceVisible('ref18')">Ref.18</a>	protein kinase		Acute myeloid leukemia (AML) Analgesics Cancer, unspecific Neurodegenerative diseases Pain, unspecified Pancreatic Cancer Prostate cancer	Required for high-affinity binding to nerve growth factor (ngf), neurotrophin-3 and neurotrophin-4/5 but not brain- derived neurotrophic factor (bdnf). Known substrates for the trk receptors are shc, pi-3 kinase, and plc-gamma-1.
dfzNTRK2	BDNF/NT-3 growth factors receptor	1	973	85.2		Isoform TrkB is expressed in the central and peripheral nervous system. In the central nervous system (CNS), expression is observed in the cerebral cortex, hippocampus, thalamus, choroid plexus, granular layer of the cerebellum, brain stem, and spinal cord. In the peripheral nervous system, it is expressed in many cranial ganglia, the ophthalmic nerve, the vestibular system, multiple facial structures, the submaxillary glands, and dorsal root ganglia. Isoform TrkB-T1 is mainly expressed in the brain but also detected in other tissues including pancreas, kidney and heart. Isoform TrkB-T-Shc is predominantly expressed in the brain.	protein kinase		Obesity hyperphagia and developmental delay (OHPDD) [MIM:613886]: A disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language. Note=The disease is caused by mutations affecting the gene represented in this entry.	Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin- 4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin- dependent calcium signaling in glial cells and mediate communication between neurons and glia.
dfzNTRK3	NT-3 growth factor receptor	1	717	84.24		Widely expressed but mainly in nervous tissue. Isoform 2 is expressed at higher levels in adult brain than in fetal brain.	protein kinase			Receptor for neurotrophin-3 (NT-3). This is a tyrosine- protein kinase receptor. Known substrates for the trk receptors are SHC1, PI-3 kinase, and PLCG1. The different isoforms do not have identical signaling properties.
dfzPAK1	Serine/threonine-protein kinase PAK 1	1	830	86.69			protein kinase			Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2- induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F- actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation.
dfzPAK6	Serine/threonine-protein kinase PAK 6	1	80	87.89		Selectively expressed in brain and testis, with lower levels in multiple tissues including prostate and breast.	protein kinase			Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Inhibits also ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. May protect cells from apoptosis through phosphorylation of BAD.
dfzPDPK1	3-phosphoinositide-dependent protein kinase 1	1	998	88.91		Appears to be expressed ubiquitously. The Tyr-9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast. <a class="attribution" href="O15530#ref34" onclick="ensureReferenceVisible('ref34')">Ref.34</a>	protein kinase		Cancer, unspecific Diabetes mellitus	Phosphorylates and activates not only pkb/akt, but also pka, pkc-zeta, p70s6k and p90s6k/rsk. May play a general role in signaling processes and in development (by similarity). Isoform 3 is catalytically inactive.
dfzPHKG2	Phosphorylase b kinase gamma catalytic chain, liver/testis isoform	1	645	80.86			protein kinase		Glycogen storage disease 9C (GSD9C) [MIM:613027]: A metabolic disorder manifesting in infancy with hepatomegaly, growth retardation, hypotonia, liver dysfunction, and elevated plasma aminotransferases and lipids. These symptoms improve with age in most cases; however, some patients may develop hepatic fibrosis or cirrhosis. Note=The disease is caused by mutations affecting the gene represented in this entry.	Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. May regulate glycogeneolysis in the testis. In vitro, phosphorylates PYGM (By similarity).
dfzPIM1	Serine/threonine-protein kinase pim-1	4	1839	90.53		Expressed primarily in cells of the hematopoietic and germline lineages. Isoform 1 and isoform 2 are both expressed in prostate cancer cell lines.	protein kinase			Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl- X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post- translational levels. Phosphorylation of CDKN1B,induces 14-3-3- proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.
dfzPIM2	Serine/threonine-protein kinase pim-2	1	1084	86.2		Highly expressed in hematopoietic tissues, in leukemic and lymphoma cell lines, testis, small intestine, colon and colorectal adenocarcinoma cells. Weakly expressed in normal liver, but highly expressed in hepatocellular carcinoma tissues.	protein kinase			Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti- apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Isoform 1 is less active in this respect. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate.
dfzPKN1	Serine/threonine-protein kinase N1	1	86	83.13		Found ubiquitously. Expressed in heart, brain, placenta, lung, skeletal muscle, kidney and pancreas. Expressed in numerous tumor cell lines, especially in breast tumor cells.	protein kinase			PKC-related serine/threonine-protein kinase involved in various processes such as regulation of the intermediate filaments of the actin cytoskeleton, cell migration, tumor cell invasion and transcription regulation. Regulates the cytoskeletal network by phosphorylating proteins such as VIM and neurofilament proteins NEFH, NEFL and NEFM, leading to inhibit their polymerization. Phosphorylates 'Ser-575', 'Ser-637' and 'Ser-669' of MAPT/Tau, lowering its ability to bind to microtubules, resulting in disruption of tubulin assembly. Acts as a key coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-11' of histone H3 (H3T11ph), a specific tag for epigenetic transcriptional activation that promotes demethylation of histone H3 'Lys-9' (H3K9me) by KDM4C/JMJD2C. Phosphorylates HDAC5, HDAC7 and HDAC9, leading to impair their import in the nucleus. Phosphorylates 'Thr-38' of PPP1R14A, 'Ser- 159', 'Ser-163' and 'Ser-170' of MARCKS, and GFAP. Able to phosphorylate RPS6 in vitro.
dfzPLK1	Serine/threonine-protein kinase PLK1	2	1333	86.37		Placenta and colon.	protein kinase		Acute myeloid leukemia Advanced or metastatic non-small cell lung cancer Advanced solid tumor Cancer, unspecific Metastatic hormone refractory Prostate cancer Non-Hodgkins Lymphoma Pancreatic cancer Pancreatic, prostate and a number of other cancers	May be required for cell division and may have a role during g1 or s phase.
dfzPLK2	Serine/threonine-protein kinase PLK2	2	198	81.3		Expressed at higher level in the fetal lung, kidney, spleen and heart.	protein kinase			Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress.
dfzPRP4B	Serine/threonine-protein kinase PRP4 homolog	1	72	86.25		Ubiquitous.	protein kinase			Has a role in pre-mRNA splicing. Phosphorylates SF2/ASF.
dfzRIPK1	Receptor-interacting serine/threonine-protein kinase 1	1	81	86.16			protein kinase			Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.
dfzRIPK2	Receptor-interacting serine/threonine-protein kinase 2	1	87	82.83		Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node.	protein kinase		Not Available
dfzROCK1	Rho-associated protein kinase 1	2	1479	86.07		Detected in blood platelets. <a class="attribution" href="Q13464#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a>	protein kinase		Asthma Atherosclerotic cardiovascular disease Cardiac allograft vasculopathy Glaucoma Hepatic fibrosis Hypertensive vascular disease Intimal hyperplasia Liver fibrogenesis Primary pulmonary hypertension Pulmonary hypertension Restenosis Vascular disease Ventricular hypertrophy
dfzSGK1	Serine/threonine-protein kinase Sgk1	1	91	88.69		Expressed in most tissues with highest levels in the pancreas, followed by placenta, kidney and lung. Isoform <a href="#O00141-2" onclick="ensureIsoformSequenceVisible('O00141-2'); return true;">2</a> is strongly expressed in brain and pancreas, weaker in heart, placenta, lung, liver and skeletal muscle. <a class="attribution" href="O00141#ref3" onclick="ensureReferenceVisible('ref3')">Ref.3</a> <a class="attribution" href="O00141#ref10" onclick="ensureReferenceVisible('ref10')">Ref.10</a>	protein kinase		Leukemia, Myeloid Myelodysplastic Syndrome Solid tumors
dfzSLK	STE20-like serine/threonine-protein kinase	1	677	86.7		Ubiquitously expressed. Highest expression is found in heart and in skeletal muscle.	protein kinase			Mediates apoptosis and actin stress fiber dissolution (By similarity).
dfzSRC	Proto-oncogene tyrosine-protein kinase Src	1	2979	94.81		Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues.	protein kinase	Diarrhoea	Breast cancer Cancer, unspecific Osteoporosis and other bone-related diseases Osteoporosis, unspecified		Tyrosine-protein kinase SRC inhibitor: Bosutinib, Vandetanib
dfzST17B	Serine/threonine-protein kinase 17B	2	81	88.02		Highly expressed in placenta, lung, pancreas. Lower levels in heart, brain, liver, skeletal muscle and kidney.	protein kinase			Phosphorylates myosin light chains (By similarity). Acts as a positive regulator of apoptosis.
dfzSTK10	Serine/threonine-protein kinase 10	1	82	94.02		Highly expressed in rapidly proliferating tissues (spleen, placenta, and peripheral blood leukocytes). Also expressed in brain, heart, skeletal muscle, colon, thymus, kidney, liver, small intestine and lung.	protein kinase		Testicular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. Note=The disease may be caused by mutations affecting the gene represented in this entry.	Serine/threonine-protein kinase involved in regulation of lymphocyte migration. Phosphorylates MSN, and possibly PLK1. Involved in regulation of lymphocyte migration by mediating phosphorylation of ERM proteins such as MSN. Acts as a negative regulator of MAP3K1/MEKK1. May also act as a cell cycle regulator by acting as a polo kinase kinase: mediates phosphorylation of PLK1 in vitro; however such data require additional evidences in vivo.
dfzSTK24	Serine/threonine-protein kinase 24	2	79	81.56		Isoform A is ubiquitous. Isoform B is expressed in brain with high expression in hippocampus and cerebral cortex.	protein kinase			Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress- induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase- independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.
dfzSTK25	Serine/threonine-protein kinase 25	1	79	85.92		Ubiquitously expressed. Highest levels are found in testis, large intestine, brain and stomach followed by heart and lung.	protein kinase			Oxidant stress-activated serine/threonine kinase that may play a role in the response to environmental stress. Targets to the Golgi apparatus where it appears to regulate protein transport events, cell adhesion, and polarity complexes important for cell migration.
dfzTBK1	Serine/threonine-protein kinase TBK1	2	447	84.74		Ubiquitous with higher expression in testis. Expressed in the ganglion cells, nerve fiber layer and microvasculature of the retina.	protein kinase		Glaucoma 1, open angle, P (GLC1P) [MIM:177700]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1P is characterized by early onset, thin central corneas and low intraocular pressure. Note=The disease may be caused by mutations affecting the gene represented in this entry. A copy number variation on chromosome 12q14 consisting of a 300 kb duplication that includes TBK1, XPOT, RASSF3 and GNS has been found in individuals affected by glaucoma. TBK1 is the most likely candidate for the disorder (PubMed:21447600).	Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser- 177', thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates and activates AKT1. Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates Borna disease virus (BDV) P protein.
dfzTGFR1	TGF-beta receptor type-1	1	690	97.47		Found in all tissues examined, most abundant in placenta and least abundant in brain and heart.	protein kinase		Cancer, unspecific Fibrosis	Type i/type ii tgf-beta receptors form an heteromeric complex after binding tgf-beta at the cell surface and act as signal transducers.
dfzTIE2	Angiopoietin-1 receptor	3	705	95.58		Detected in umbilical vein endothelial cells. Proteolytic processing gives rise to a soluble extracellular domain that is detected in blood plasma (at protein level). Predominantly expressed in endothelial cells and their progenitors, the angioblasts. Has been directly found in placenta and lung, with a lower level in umbilical vein endothelial cells, brain and kidney. <a class="attribution" href="Q02763#ref1" onclick="ensureReferenceVisible('ref1')">Ref.1</a> <a class="attribution" href="Q02763#ref8" onclick="ensureReferenceVisible('ref8')">Ref.8</a>	protein kinase	Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Mental disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia	Tumors	This protein is a protein tyrosine-kinase transmembrane receptor for angiopoietin 1. It may constitute the earliest mammalian endothelial cell lineage marker. Probably regulates endothelial cell proliferation, differentiation and guides the proper pattern.	Tyrosine-protein kinase TIE-2 inhibitor: Regorafenib, Vandetanib
dfzTNIK	TRAF2 and NCK-interacting protein kinase	1	97	90.79		Expressed ubiquitously. Highest levels observed in heart, brain and skeletal muscle. Expressed in normal colonic epithelia and colorectal cancer tissues.	protein kinase			Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway. Recruited to promoters of Wnt target genes and required to activate their expression. May act by phosphorylating TCF4/TCF7L2. Appears to act upstream of the JUN N-terminal pathway. May play a role in the response to environmental stress. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. More generally, it may play a role in cytoskeletal rearrangements and regulate cell spreading. Phosphorylates SMAD1 on Thr-322.
dfzTTK	Dual specificity protein kinase TTK	3	171	94.34		Present in rapidly proliferating cell lines.	protein kinase		Cancer, unspecific	Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation.
dfzTYK2	Non-receptor tyrosine-protein kinase TYK2	2	947	89.65		Observed in all cell lines analyzed. Expressed in a variety of lymphoid and non-lymphoid cell lines.	protein kinase		Protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:611521]: Consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE. Note=The disease is caused by mutations affecting the gene represented in this entry.	Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.
dfzVGFR1	Vascular endothelial growth factor receptor 1	1	1730	89.4		Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform <a href="#P17948-2" onclick="ensureIsoformSequenceVisible('P17948-2'); return true;">2</a> is strongly expressed in placenta. Isoform <a href="#P17948-3" onclick="ensureIsoformSequenceVisible('P17948-3'); return true;">3</a> is expressed in corneal epithelial cells (at protein level). Isoform <a href="#P17948-3" onclick="ensureIsoformSequenceVisible('P17948-3'); return true;">3</a> is expressed in vascular smooth muscle cells (VSMC). <a class="attribution" href="P17948#ref5" onclick="ensureReferenceVisible('ref5')">Ref.5</a> <a class="attribution" href="P17948#ref6" onclick="ensureReferenceVisible('ref6')">Ref.6</a>	protein kinase		Neovascular Age-Related Macular Degeneration Exudative age-related macular degeneration	Receptor for VEGF, VEGFB and PGF. Has a tyrosine-protein kinase activity. The VEGF-kinase ligand/receptor signaling system plays a key role in vascular development and regulation of vascular permeability. Isoform SFlt1 may have an inhibitory role in angiogenesis.	Vascular endothelial growth factor receptor inhibitor: Axitinib, Pazopanib, Regorafenib, Sorafenib, Sunitinib, Vandetanib
dfzVGFR2	Vascular endothelial growth factor receptor 2	1	5433	91.9		Detected in cornea (at protein level). Widely expressed. <a class="attribution" href="P35968#ref2" onclick="ensureReferenceVisible('ref2')">Ref.2</a>	protein kinase	Adrenal disorder Adrenal insufficiency Amenorrhoea Bone disorder Cushingoid Endocrine disorder Euphoric mood Hyperglycaemia Hypertension Hypertrichosis Hypokalaemia Intracranial pressure increased Menstrual disorder Muscular weakness Oedema Osteonecrosis Osteoporosis Pancreatitis acute Peptic ulcer Skin atrophy Skin striae Superinfection Telangiectasia	Angiogenesis Cancer, unspecific	Receptor for VEGF or VEGF-c, and has a tyrosine-protein kinase activity. the VEGF-kinase ligand/receptor signaling system plays a key role in vascular development and regulation of vascular permeability.	Vascular endothelial growth factor receptor 2 inhibitor: Cabozantinib
dfzWEE1	Wee1-like protein kinase	1	374	95.29			protein kinase		Cancer	May act as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDC2 before the onset of mitosis. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation. Specifically phosphorylates and inactivates cyclin B1-complexed CDC2 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDC2 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDC2 does not occur.
dfzFNTA	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	2	1654	92.64			protein prenyltransferase subunit alpha		Acute myeloid leukemia (AML) Amebiasis Bladder cancer Breast cancer Cancer, unspecific Colorectal Cancer Malaria Non-small cell lung cancer (NSCLC) Pancreatic Cancer Solid tumors	Catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the c-terminus of several proteins having the c-terminal sequence cys-aliphatic-aliphatic-x.
dfzFNTB	Protein farnesyltransferase subunit beta	3	1613	93.17			protein prenyltransferase subunit beta		Cancer, unspecific	Catalyzes the transfer of a farnesyl moiety from farnesyl pyrophosphate to a cysteine at the fourth position from the c-terminus of several proteins. The beta subunit is responsible for peptide-binding.
dfzPGTB1	Geranylgeranyl transferase type-1 subunit beta	1	429	93.02			protein prenyltransferase subunit beta			Catalyzes the transfer of a geranylgeranyl moiety from geranylgeranyl diphosphate to a cysteine at the fourth position from the C-terminus of proteins with the C-terminal sequence Cys- aliphatic-aliphatic-X. Known substrates include RAC1, RAC2, RAP1A and RAP1B.
dfzPTN1	Tyrosine-protein phosphatase non-receptor type 1	3	1256	89.45			protein-tyrosine phosphatase		Type 2 Diabetes	May play an important role in CKII- and p60c-src-induced signal transduction cascades (By similarity).
dfzPTN22	Tyrosine-protein phosphatase non-receptor type 22	1	150	88.63		Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells.	protein-tyrosine phosphatase		Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.	Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules. Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue. Dephosphorylates ZAP70 at its activating 'Tyr-493' residue. Dephosphorylates the immune system activator SKAP2.
dfzHPRT	Hypoxanthine-guanine phosphoribosyltransferase	1	71	92.21			purine/pyrimidine phosphoribosyltransferase		Lesch-Nyhan syndrome (LNS) [MIM:300322]: Characterized by complete lack of enzymatic activity that results in hyperuricemia, choreoathetosis, mental retardation, and compulsive self- mutilation. 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. 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.
dfzKPYM	Pyruvate kinase PKM	1	60	90.34		Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells.	pyruvate kinase			Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.
dfzPAI1	Plasminogen activator inhibitor 1	1	134	90.95		Found in plasma and platelets and in endothelial, hepatoma and fibrosarcoma cells.	serpin		Age-related macular degeneration Asthma Cancer, unspecific Coagulative disorders Diabetic retinopathy Inflammation Renal fibrosis Thrombotic disease	This inhibitor acts as "bait" for tissue plasminogen activator, urokinase, and protein c. Its rapid interaction with tpa may function as a major control point in the regulation of fibrinolysis.
dfzDHI1	Corticosteroid 11-beta-dehydrogenase isozyme 1	8	1918	87.82		Widely expressed. Highest expression in liver.	short-chain dehydrogenases/reductases		Cognitive deficits (age- and dementia-associated) Diabetes Mellitus Type 2 Metabolic disorder, unspecified Neurodegenerative diseases Noninsulin-dependent diabetes mellitus Obesity	Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.
dfzERG7	Lanosterol synthase	1	144	93.8			terpene cyclase/mutase		Hypercholesterolemia	Catalyzes the cyclization of (s)-2,3 oxidosqualene to lanosterol, a reaction that forms the sterol nucleus.
dfzTYPH	Thymidine phosphorylase	1	79	83.69			thymidine/pyrimidine-nucleoside phosphorylase		Angiogenesis Breast cancer Lung adenocarcinomas Renal cell carcinoma	May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro.catalyzes the reversible phosphorolysis of thymidine.
dfzTYSY	Thymidylate synthase	1	746	88.74			thymidylate synthase		Breast cancer Colorectal cancer Fungal diseases Gastric cancer Hepatocellular carcinoma Malaria Ovarian cancer Pancreatic cancer Proliferative diseases
dfzTKT	Transketolase	1	56	97.87			transketolase		Thiamine deficiency
dfzTOP1	DNA topoisomerase 1	2	266	98.64			type IB topoisomerase	Alopecia Anaemia Stomatitis	Brain tumors Breast cancer Cancer, unspecific Colorectal cancer Esophageal squamous cell cancer Fungal diseases Gastric cancer Lung cancer Lymphoblast tumor Ovarian cancer	The reaction catalyzed by topoisomerases leads to the conversion of one topological isomer of dna to another.
dfzTOP2B	DNA topoisomerase 2-beta	1	125	84.87			type II topoisomerase	Alopecia Anaemia Bone marrow failure Haemorrhagic diathesis Mucosal inflammation Stomatitis	Cancer, unspecific	Control of topological states of dna by transient breakage and subsequent rejoining of dna strands. Topoisomerase II makes double-strand breaks.
dfzACES	Acetylcholinesterase	3	2488	80.54		Isoform <a href="#P22303-2" onclick="ensureIsoformSequenceVisible('P22303-2'); return true;">H</a> is highly expressed in erythrocytes. <a class="attribution" href="P22303#ref11" onclick="ensureReferenceVisible('ref11')">Ref.11</a>	type-B carboxylesterase/lipase	Diarrhoea Nausea Salivary hypersecretion	Alzheimer's disease Cognitive deficits Hypoxic-ischemic encephalopathy Motor neurone disease Parkinson's disease	Rapidly hydrolyzes choline released into the synapse.	Acetylcholinesterase activator: Pralidoxime Acetylcholinesterase inhibitor: Ambenonium, Demecarium, Donepezil, Echothiophate, Edrophonium, Galantamine, Hexafluorenium, Isoflurophate, Neostigmine, Pyridostigmine
dfzCHLE	Cholinesterase	2	1819	80.67		Detected in blood plasma (at protein level). Present in most cells except erythrocytes. <a class="attribution" href="P06276#ref12" onclick="ensureReferenceVisible('ref12')">Ref.12</a> <a class="attribution" href="P06276#ref21" onclick="ensureReferenceVisible('ref21')">Ref.21</a>	type-B carboxylesterase/lipase	Bradycardia Salivary hypersecretion	Alzheimer's disease Schizophrenia		Cholinesterases; ACHE & BCHE inhibitor: Rivastigmine, Tacrine
dfzDHSO	Sorbitol dehydrogenase	1	76	99.99		Expressed in kidney and epithelial cells of both benign and malignant prostate tissue. Expressed in epididymis (at protein level). <a class="attribution" href="Q00796#ref9" onclick="ensureReferenceVisible('ref9')">Ref.9</a> <a class="attribution" href="Q00796#ref11" onclick="ensureReferenceVisible('ref11')">Ref.11</a> <a class="attribution" href="Q00796#ref12" onclick="ensureReferenceVisible('ref12')">Ref.12</a>	zinc-containing alcohol dehydrogenase		Diabetic complications Myocardial ischemia