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Molecular Basis Key:  Act—Activated  Amp—Amplified  Del—Deleted  Expr—Expression  GOF—Gain-of-function  Inh—Inhibitor Studies  LOF—Loss-of-function  LOH—Loss-of-heterozygosity  Meth—Methylation  Model—model organism studies  Mut—Mutation  OE—Overexpression  SNP—Single Nucleotide Polymorphism  Splice—Splicing change  Trans—Translocation

NameGroupDisease TypeMolecular BasisNotes
Abl1 TK Cancer Trans The Philadephia chromosome translocation t(9;22)(q34;q11) creates a Bcr-Abl fusion protein responsible for 90% of chronic myelogenous leukemia (CML) [OMIM:608232] and ~25% of acute lymphoblastic leukemia (ALL) [OMIM:159555]. Inhibitor: imatinib. OMIM:189980.
ACK TK Cancer Amp Amplification in primary tumors correlates with metastatic potential (Medline:16247015). OMIM:606994.
ACTR2B TKL Development Mut Two human mutations and a mouse model implicate ACTR2B in left-right axis malformations. OMIM:602730.
Akt1 AGC Cancer Amp, OE, Act Mediates survival signals downstream of PI3-kinase and several growth factor receptors by phosphorylating apoptotic proteins. First found in a mouse transforming retrovirus. Tumorigenic in a mouse lymphoma model and overexpressed in a number of cancers including breast, prostate, lung, pancreatic, liver, ovarian and colorectal. Inhibitors: RX-0201 (Rexahn; Phase 1 cancer). OMIM:164730.
Akt2 AGC Cancer, Diabetes Amp, OE, Mut Amplified and overexpressed in human ovarian carcinoma cell lines and amplified in some primary ovarian and pancreatic tumors. Antisense blocks invasiveness in xenografts. Expressed in several insulin-responsive tissues with one case of Type II diabetes associated with a likely LOF point mutation. Mouse mutants have defects in insulin response. OMIM:164731.
ALK TK Cancer Trans About one third of large-cell lymphomas are caused by a t(2;5)(p23;q35) translocation that fuses ALK to nucleophosmin (NPM1A). Other cases caused by fusions of ALK to moesin, non-muscle myosin heavy chain 9, clathrin heavy chain and other genes. Several fusions also seen in inflammatory myofibroblastic tumors and expression has been briefly noted in a range of tumors (Medline:15095281). Proposed as tumor antigen (Medline:11877285). OMIM:105590.
ALK1 (ACVRL1) TKL Cardiovascular Mut Fourteen distinct mutations linked to hereditary hemorrhagic telangiectasia type 2 (Osler-Rendu-Weber syndrome 2) [OMIM:600376], associated with intestinal bleeding, arterial hypertension and arteriovenous malformations. OMIM:601284.
ALK2 (ACVR1) TKL Development Mut Single heterozygous mutation seen in many independent cases of fibrodysplasia ossificans progressiva [OMIM:135100], causing skeletal malformations and extra-skeletal bone formation. OMIM:102576.
ALK4 (ACVR1B) TKL Cancer Mut, Splice Two somatic truncation mutations seen in pancreatic carcinoma. Unique splice forms with predicted dominant negative activity expressed in pituitary tumors. OMIM:601300.
ANKK1 (SgK288) TKL Behavior SNP One coding SNP in ankyrin repeat may change substrate binding specificity; linked to neuropsychiatric disorders including addiction. OMIM:608774.
ANPα (NPR1) RGC Hypertension SNP, Expr Animal models indicate a role in blood pressure regulation. Hypertensive SHR Rat has polymorphism at the locus. Human non-coding polymorphisms can alter expression up to two-fold (Medline:12483301) and have been associated with hypertension [OMIM:145500] (Medline:12872042). A coding SNP is associated with hypertension and myocardial infarction (Medline:14646971). OMIM:108960.
ANPβ (NPR2) RGC Development Mut Twenty-one mutations linked to acromesomelic dysplasia [OMIM:602875] (Medline:15146390). OMIM:108961.
ARG (Abl2) TK Cancer Trans, Expr Two cases of translocations fusing ARG to ETV6 (TEL) seen in acute myeloid leukemia. Differentially expressed (increased and decreased) in several cancer types. OMIM:164690.
ATM Atypical Cancer, CNS LOF Mut LOF mutations associated with ataxia talangiectasia [OMIM:208900], causing progressive loss of motor control (ataxia), dilation of superficial blood vessels (telangiectasia), cancer and immune deficiency. Approximately 30% of cases develop tumors, mostly lymphomas and leukemias, due to defects in DNA damage repair. Somatic mutations seen in leukemias and lymphomas. OMIM:607585.
ATR Atypical Cancer, Development, Virology Mut, Splice Functions in DNA damage responses. A splice-altering mutation seen in cases of Seckel syndrome [OMIM:210600], featuring dwarfism and mental retardation. Heterozygous knockout mice are cancer-prone. Mutations seen in cancers of the stomach (Medline:11691784) and endometrium (Medline:12124347), tumors with high mutation rates due to microsatellite instability. May also be required for retroviral DNA integration (Medline:12679521). OMIM:601215.
AurA Other Cancer Amp, OE, SNP Required for centrosome duplication and chromosome segregation. Overexpression in culture drives transformation and aneuploidy, and negatively regulates p53. Amplified or overexpressed in many tumors or cell lines. Found as a skin tumor susceptibility gene in mouse and a human SNP in a degradation domain is weakly cancer-associated and undergoes allele-specific amplification (Medline:15466974, 15271853, 12881723). Inhibitors: VX-680 (Vertex), ZM447439 (Astra-Zeneca), Hesperadin (Boehringer Ingelheim), SNS-595 (Sunesis). OMIM:602687.
AurB Other Cancer OE Required for chromosome segregation and cytokinesis. Overexpressed in colorectal and other cancer cell lines (Medline:9809983) and thought to cause aneuploidy via histone phosphorylation (Medline:12884918). OMIM:604970.
Axl TK Cancer OE Overexpression in tissue culture causes oncogenic transformation. Overexpressed in several cancers including thyroid (Medline:10411118), ovarian (Medline:15452374), gastric (Medline:12168903), ER+ breast cancer (Medline:11484958) and acute myeloid leukemia, where it is associated with poor prognosis (Medline:10482985). OMIM:109135.
BARK1 (GRK2, ADRBK1) AGC Cardiac Expr, Model Expression consistently elevated in chronic human heart failure. Inhibition increases survival and cardiac function in mouse models of severe heart failure. OMIM:109635.
Bcr Atypical Cancer Trans Chronic myelogenous leukemia. See under Abl. OMIM:151410.
BMPR1A (ALK3) TKL Cancer LOF Mut Truncations and point mutations are one cause of juvenile polyposis syndrome [OMIM:174900], which is associated with increased susceptibility to gastrointestinal cancers. OMIM:601299.
BMPR1B (ALK6) TKL Development Mut Two mutations associated with type A2 brachydactyly (hand malformations). A homozygous truncation associated with one case of acromesomelic chondrodysplasia (bone malformations) and external genital abnormalities. OMIM:603248.
BMPR2 TKL Cardiopulmonary LOF Mut Mutations cause primary pulmonary hypertension (PPH1) [OMIM:178600], a weakly penetrant dominant disorder associated with lesions in pulmonary arterioles, elevated pulmonary arterial pressure and right ventricular failure. OMIM:600799.
BRAF TKL Cancer, Cardiac, Development GOF Mut, LOF Mut An activating mutation, mimicking phosphorylation of the activation loop, is seen in 60% of malignant melanoma samples (Medline:15035987). Raf mutations are generally exclusive to Ras activating mutations. Activating mutations are also seen in ~10% of colorectal cancers, in lung cancers and gliomas and at a lower rate in several other tumors. Inactivating mutations are also seen and may result in activation of c-Raf and Erk (Medline:15035987). Mutations in Braf, Mek1 and Mek2 also associated with cardiofaciocutaneous syndrome [OMIM:115150], displaying morphological, cardiac and mental defects. Approved Inhibitor: Nexavar/Sorafenib (Bayer/Onyx). OMIM:164757.
BRD4 Atypical Cancer, Virology Trans Chromosome-associated atypical kinase with cell cycle function. Translocation creates fusion protein with testis-specific NUT gene product in juvenile midline carcinomas. Binds to papillomavirus E2 protein and is required for its transforming ability. Expression correlated with breast tumor progress (Medline:18427120). OMIM:608749.
BRK TK Cancer OE Selectively expressed in breast tumors and cell lines, and perhaps in colon and prostate cancers. Enhances anchorage-independent growth and responsiveness to EGF. RNAi reduces proliferation in breast cancer cells. Kinase-inactive mutant indicates tumor function may be independent of catalytic function. OMIM:602004.
BTK TK Cancer, Immunity LOF Mut LOF mutations cause X-linked agammaglobulinemia [OMIM:300300], arresting development of B cells and causing recurrent bacterial infections. Truncated splice forms found in childhood leukemias may underlie radiation resistance of tumors through inhibition of apoptosis (Medline: 12854903). Inhibitors developed to target B cell maturation and function. Inhibitor: Dasatinib. OMIM:300300.
BUB1 Other Cancer LOF Mut LOF mutations seen in two colon cancer cell lines exhibiting chromosomal instability, in several leukemias and lymphomas (Medline:12096343), and in a pancreatic cancer cell line (Medline:12655561). BUB1 functions in mitotic spindle assembly and may cause chromosomal instability. In mouse BRCA2 knockouts, mutations in BUB1 and BUBR1 are frequently seen in the resulting tumors (Medline:14646599). BUB1 and BUBR1 are overexpressed, but not mutated, in many gastric cancers (Medline:12692836). OMIM:602452.
BUBR1 (BUB1B) Other Cancer Mut, OE Two mutations found in colon cancer cell lines. In mouse BRCA2 knockout, mutations in BUB1 and BUBR1 are frequently seen in the resulting tumors (Medline:14646599). BUB1 and BUBR1 are overexpressed, but not mutated, in many gastric cancers (Medline:12692836). BUBR1-deficient mice show early aging phenotypes. OMIM:602860.
CAMK2δ CAMK Cardiovascular Expr, Models, Inh Activity elevated in cardiac arrhythmias and other diseased heart states. Overexpression drives hypertrophy, dilation and dysfunction and inhibition suppresses arrhythmias in animal models (Medline:15781121). OMIM:607708.
CDC2 (CDK1) CMGC Cancer Act, Splice Cell cycle checkpoint. Activated in many cancers including colon, liver and breast (Medline:10091728, 12100577, 11091571). The delta T isoform, which lacks a regulatory region, is expressed in breast cancer. Inhibition in cancer cells may drive cells into apoptosis (Medline:12150824). May also drive cell migration (Medline:12771130). Inhibitors: BMS-265246, BMS-265246-01 (Bristol-Myers Squibb). OMIM:116940.
CDK2 CMGC Cancer Cell cycle checkpoint and part of the Rb pathway disregulated in most tumors (Medline:12888290). Target of several candidate cancer drugs. However, inhibition does not always prevent cancer cell growth (Medline:12676582) due possibly to CDK redundancy. Inhibitors: BMS-265246, BMS-265246-01 (Bristol-Myers Squibb), R-roscovitine (CYC200, CYC202) (Cyclacel; Ph. 2), SU9516 (Sugen), R547 (Roche), L868276. OMIM:116953.
CDK4 CMGC Cancer Act, GOF Mut, Amp, Meth Point mutations found in somatic and familial melanoma. Amplified in sarcomas (Medline:9703873, 9935200), glioma (Medline:14756442) and lymphoma (Medline:12203778). Amplified, methylated or deleted in head and neck squamous cell carcinoma (Medline:14586645). Overexpression drives epithelial tumors in mice (Medline:14647432). Disruption makes mice resistant to cancer (Medline:12435633). Inhibitor: PD332991 (Onyx). OMIM:123829.
CDK5 CMGC Neurodegeneration SNP Implicated in the pathology of neurofibrillary tangles and formation of senile plaques, hallmarks of Alzheimer disease (AD). Induces tau phosphorylation and aggregation and neurofibrillary tangle deposition and neurodegeneration in in vitro and in vivo animal models. Brain samples from AD patients show elevated CDK5 activity, possibly induced by Aβ amyloid. SNPs show weak AD association (Medline:18350355) OMIM:123831.
CDK6 CMGC Cancer OE, Trans Overexpressed and/or disrupted by translocation in leukemias, lymphomas and other cancers; amplified in gliomas (Medline:9102208) and rodent cancers (Medline:12538879, 11719459). OMIM:603368.
CDK9 CMGC Cardiovascular, Viral infection Expr Transcriptional elongation factor and cofactor for HIV Tat protein; RNAi against CDK9 blocks HIV replication and inhibitors also block varicella zoster replication. Mediates signals leading to cardiac hypertrophy (Medline:12695656). Inhibitor: Flavopiridol. OMIM:603251.
CDKL5 CMGC CNS, Development Mut, Trans Missense, splice and truncating mutations linked to the neurodevelopmental Rett Syndrome [OMIM:312750]. A chromosomal translocation which silences the gene is associated with severe X-linked infantile spasm syndrome [OMIM:308350]. OMIM:300203.
CHK1 (CHEK1) CAMK Cancer Mut Cell cycle G2 checkpoint kinase implicated in resistance to apoptosis in response to chemotherapy. Inhibitors under development to chemosensitize tumors. Somatic mutations found in stomach tumors (Medline:11691784) and in colon and endometrial tumors, where CHK1 may be a target of microsatellite instability (Medline:14657665). Inhibitors: SB218078, UNC-01. OMIM:603078.
CHK2 CAMK Cancer Mut Tumor suppressor involved in DNA damage and cell cycle arrest. LOF mutants cause Li-Fraumeni syndrome [OMIM:151623], a highly penetrant familial cancer phenotype also caused by p53 mutations. Familial mutations also associated with prostate and breast cancer, and mutations also seen in a variety of sporadic cancers and cell lines. OMIM:604373.
CK1δ, CK1α CK1 Neurodegeneration Several CK1 isoforms including CK1δ and CK1α associate with and phosphorylate tau, which forms the neurofibrillary tangles of Alzheimer’s disease. Tau phosphorylation and microtubule association is inhibited by the CK1 inhibitor IC261 (Medline:14761950). CK1 phosphorylation is involved in trafficking of the Alzheimer’s plaque component, β-secretase (Medline:11278841). CK1 levels are increased in Alzheimer’s brains. CK1δ is also associated with tau tangles in several other neurodegenerative diseases (Medline:10924763). CK1δ mRNA and protein are upregulated in Alzheimer’s brain regions with most pathology (Medline:10814741). CK1 also phosphorylates the Parkinson’s-associated α synuclein protein (Medline:10617630). OMIM:600864, 60050.
CK1ε (CSNK1ε) CK1 Behavior, Cancer SNP, Mut, LOH Mutations in hamster and Drosophila orthologs have circadian rhythm phenotypes as the circadian gene period (per) is a substrate in both human and fly. A coding SNP variant in human increases CK1ε activity and is negatively associated with circadian disorder (Medline:15187983). LOF mutations and LOH seen in mammary ductal carcinoma (Medline:14871824). OMIM:600863.
CK2α1, CK2α2 (CSNK2α1/2) Other Cancer, Circadian Rhythm, Neurodegeneration OE, Act Two gene products (α1/α2 or α/α’) complex with each other and a regulatory β subunit. The isoforms are rarely distinguished from each other in publications. Transgene expression in mice leads to lymphoma and activation by bovine parasites leads to fatal lymphoproliferation (Medline: 7846532). Expression and activity are elevated in lung tumors (Medline:15355908, 12017291) and breast tumors (Medline:11423974). Mouse transgene causes mammary gland hyperplasia. Antisense drives apoptosis of tumor cell lines (Medline:11827168) and xenografts (Medline:14965269). Involved in DNA break repair by phosphorylation of scaffold protein XRCC1 (Medline:15066279), phosphorylation of BRCA1 (Medline:10403822) and phosphorylation of p53 in response to UV irradiation. The Drosophila CK2 ortholog (Timekeeper) is involved in circadian regulation. Phosphorylates and binds to a major component of the inclusion bodies seen in Parkinson patients (Medline:14645218). Inhibitors: DMAT, Antisense, P15 peptide, 4,5,6,7-tetrabromobenzotriazole (TBB). OMIM:115440, 115442.
COT/TPL2 STE Cancer, Inflammation OE, Amp, Mut Overexpressed and amplified in breast tumors. Viral insertions induce rat lymphomas and mouse mammary carcinomas. Isolated as a transforming factor in two cell lines. Mediates LPS activation of macrophages (Medline:15485931). OMIM:191195.
CTK/MATK TK Cancer OE Expressed in cancerous but not normal breast tissue. Interacts with activated ErbB2 receptor and is likely to inhibit proliferation. OMIM:600038.
CYGD (GUCY2D) RGC Vision Mut Implicated in several visual diseases including dominant cone-rod dystrophy (CORD) type 5 [OMIM:600977] and type 6 [OMIM:601777], in which photoreceptor cells degenerate leading to partial or total blindness and Leber congenital amaurosis type 1 (LCA1) [OMIM:204000], characterized by total blindness or loss of central vision. OMIM:600179.
CYGF (GUCY2F) RGC Cancer Mut Eighteen point mutations seen in a survey of 182 colon, lung, breast and pancreatic tumors (Medline:12738854, 16941478) despite previous expectation of expression restricted to sensory tissues. OMIM:300041.
DAPK1 CAMK Cancer, Epilepsy Meth, Expr Putative tumor suppressor activating p53-dependent apoptosis. Expression is reduced in some cancers and the promoter is frequently hypermethylated in invasive cancers. Methylation and rare mutations seen in familial chronic lymphocytic leukemia (Medline:17540169). Increased expression and mislocalization is seen in epilepsy, where it may regulate neuronal death. OMIM:600831.
DCAMKL1 CAMK Neurodegeneration Genetic and physical interactions with doublecortin (Medline:16387638; OMIM:300121), which causes lissencephaly. OMIM:604742.
DMPK1 AGC Neurodegeneration Mut An extended CTG triplet repeat in the noncoding sequence reduces protein expression and causes myotonic dystrophy [OMIM:160900], leading to myotonia, muscle wasting, cataracts, hypogonadism, defective endocrine functions, male baldness, and cardiac arrhythmias. Normally localized to the neuromuscular junction. The repeat can expand during aging by somatic mutation and can act in trans as a dominant negative, possibly affecting several other genes. OMIM:605377.
DNAPK Atypical Cancer Mut Required for repair of radiation-induced dsDNA breaks. Loss of function in mice or horses leads to the SCID (severe combined immune deficiency) phenotype due to failure of immunoglobulin rearrangement. Target of mutation in mismatch repair-deficient colorectal cancer (Medline:11888892). Inhibitor: KU-7059 (Kudos). OMIM:600899.
DYRK1A CMGC Cognition Candidate gene for some aspects of Down Syndrome (DS). Located in DS critical region and overexpression in mice gives rise to similar neurological abnormalities (Medline:15198122). OMIM:600855.
eEF2K (CaMKIII) Atypical Cancer OE, Act Overexpressed in breast cancer cell lines and tumors (Medline:10408694). Activated in rat glioblastoma (Medline:7647041) and growth was inhibited by the drug Rottlerin. Activity induced in ischemic heart muscle (Medline:12920134). Inhibitors have been derived (Medline:10913818). OMIM:606968.
EGFR TK Cancer Amp, OE, GOF Mut Overexpressed in breast, head and neck cancers (Medline:15254682) and correlated with poor survival. Activating somatic mutations seen in lung cancer, corresponding to minority of patients with strong response to EGFR inhibitor gefinitib. Mutations and amplification also seen in glioblastoma, and upregulation seen in colon cancer and neoplasms. In xenografts, inhibitors synergized with cytotoxic drugs in inhibition of many tumor types (Medline:10815932). Inhibitors: gefinitib/ZD1839 (Astra Zeneca), cetuximab (mAb, Imclone), Tarceva (OSI/Genentech) lapatinib (Tykerb, GSK). OMIM:131550.
Eph family TK Cancer, Sensory A 14-member family of receptor tyrosine kinases with similar functions in intercellular communication, migration, patterning and angiogenesis. Ephrins are implicated in development of tumor vasculature and intercellular contacts required for metastasis. Several members are overexpressed in cancers. Soluble forms (competitive receptors) have shown some anti-tumor activity and extracellular domains have been used as tumor-specific antigens.
EphA1 TK Cancer Expr Misexpressed in several cancers and upregulated in head and neck cancer (Medline:15023838). Downregulated in invasive breast cancer cell lines (Medline:15147954) and glioblastoma (Medline:14726470). OMIM:179610.
EphA2 TK Cancer OE Overexpressed in many cancers including aggressive ovarian (Medline:15297418), cervical (Medline:15297167), breast carcinomas (Medline: 15147954) and lung cancer (Medline:12576426). Expression correlates with degree of angiogenesis (Medline:14965363), metastasis (Medline: 14767510) and xenograft tumor growth (Medline:14973554). Soluble receptor inhibits tumor growth and angiogenesis in mice (Medline:12370823, 14670182). OMIM:176946.
EphA3 (HEK) TK Cancer Mut Two point mutations seen in a survey of colorectal tumors (Medline:12738854). Soluble receptors reduce tumor growth and angiogenesis in mouse models (Medline:12370823, 14670182). Nine point mutations found in 294 colon and lung tumors (Medline:16941478) OMIM:179611.
EphB2 TK Cancer OE, Mut Point mutations seen in prostate cancer (Medline:15300251). Overexpressed and required for migration of glioblastoma (Medline:15126357). Overexpressed and correlated with poor survival in breast cancer (Medline:15029258). Overexpression and loss of heterozygosity seen in colorectal cancers (Medline:11920461, 11166921). Target for immunoconjugate drug therapy (Medline:14871799). OMIM:600997.
EphB4 (HTK) TK Cancer OE Required for normal development and angiogenesis of the mammary gland. Angiogenic functions may be kinase-independent by means of retrograde signaling through its ephrin-B2 ligand (Medline:15067119). High expression correlates with malignancy in breast, ovarian and other cancers, but appears to be a survival factor (Medline:16816380, 17353927). Also upregulated in head and neck (Medline:14661437), endometrial (Medline:12562648) and colon carcinomas (Medline:11801186). OMIM:600011.
Erk5 (BMK1) CMGC Cancer, Cardiovascular Expr Mouse knockout shows a role in development and integrity of blood vessels. May block apoptosis in endothelial cells (Medline:14670836). Required for transduction of EGF growth signal (Medline:9790194), constitutively activated in ErbB2-overexpressing breast cancer (Medline:11739740) and downstream of activated Mek5 in metastatic prostate cancer (Medline:12618764). Inhibitor: PD98059. OMIM:602521.
FAK (PTK2) TK Cancer OE, Amp, Act Required for cell migration and contact-dependent survival signaling. Downstream of integrins and Src, upstream of Ras/MAPK. Required for full Ras transformation of fibroblasts. Increased expression in breast and other cancers, related to chromosome 8q amplification (Medline:10523844). Overexpression and activation associated with increased migration, invasion and progression of ovarian cancer (Medline:15466376), and with progression in hepatocellular carcinoma (Medline:15246215), thyroid cancer (Medline:8770310) and acute myelogenous leukemia (Medline:15126359). siRNA increases chemosensitivity of pancreatic adenocarcinoma xenografts (Medline:14623342). Inhibitors: PF-562,271 (Pfizer), ISI15421 (antisense, ISIS). OMIM:600758.
FER TK Cancer Expr Increased expression associated with prostate cancer proliferation and antisense blocks soft agar growth (Medline:10687853). OMIM:176942.
FES TK Cancer Mut, Trans? Four LOF point mutations seen in colorectal cancer (Medline:12738854, 16455651). Orthologous to v-fes from feline leukemia virus and v-fps from avian transforming virus. Mutant forms are angiogenic. Promotes survival during differentiation and may act both to promote and inhibit tumors. May be disrupted in the t(15q+;17q-) found in acute promyelocytic leukemia, but the breakpoint does not occur within the gene. OMIM:190030.
FGFR1 TK Cancer, Development Mut, Trans Point mutations cause Pfeiffer syndrome [OMIM:101600] (finger and toe malformations and other skeletal errors) and dominant Kallmann syndrome 2 [OMIM:147950]. Stem cell leukemia lymphoma syndrome (SCLL) may be caused by a t(8;13)(p12;q12) translocation that fuses a zinc finger gene (ZNF198) to FGFR1. Various myeloproliferative disorders have been linked to translocations that fuse FGFR1 to FOP, FIM, CEP1 or the atypical kinase, BCR. Inhibitor: SU5402. OMIM:136350.
FGFR2 TK Cancer, Development Mut, Amp Mutations cause syndromes with defects in facial and limb development, including Crouzon syndrome [OMIM:123500], Beare-Stevenson cutis gyrata syndrome [OMIM:123790], Pfeiffer syndrome [OMIM:101600], Apert syndrome [OMIM:101200], and Jackson-Weiss syndrome [OMIM:123150]. Somatic mutations seen in gastric cancer (Medline:11325814). Amplified in gastric (Medline:14595756), breast (Medline:11564899) and some B cell cancers (Medline:12203778), but deleted in glioblastoma (Medline:14756442). Promoter SNP associated with breast cancer occurrence (Medline: 17529967). OMIM:176943.
FGFR3 TK Cancer, Development GOF Mut, Trans Activating point mutations cause dwarfism, including achondroplasia [OMIM:100800], hypochrondroplasia [OMIM:146000] and thanatophoric dysplasia [OMIM:187600]; facial and other morphogenetic disorders, including Crouzon syndrome [OMIM:123500], craniosynostosis Adelaide type [OMIM:600593], San Diego skeletal displasia [OMIM:270230] and Muenke syndrome [OMIM:602849]. Translocations t(4;14) involving the IgH region are common in multiple myeloma and frequently involve FGFR3. Activated FGFR3 found in 30% of bladder cancers and several cervical cancers but not in other tumors. Two mutations found in colorectal cancer. OMIM:134934.
FGFR4 TK Cancer SNP A common SNP variant associated with increased motility and progression of breast cancer (Medline:11830541, but see also Medline:14710228), head and neck cancer (Medline:15197773) and soft tissue sarcomas (Medline:14601095). Increased expression seen in pituitary adenomas, pancreatic cancer and breast cancer cell lines. OMIM:134935.
FGR TK Cancer Amp Ortholog of v-fgr feline oncogene. Mildly amplified in hormone-resistant prostate cancer (Medline:14614009). Copy number either increased or decreased in other cancers. OMIM:164940.
FLT1 (VEGFR1) TK Cancer Meth, OE Angiogenesis modulator that may both co-operate with and antagonize KDR/VEGFR2 (Medline:14984769). Overexpressed in several tumor types (Medline:12681367, 9582527, 10738243, 10893635) and an antagonistic soluble form is inhibited in progressive tumors (Medline:15112269, 14605010, 15173272). Downregulated by hypermethylation in prostate cancer (Medline:12824880). The soluble receptor and mutant forms have anti-tumor activity in model systems (Medline:15221961, 15126877). Inhibitors: SU11248, PKC412, CEP-5214. OMIM:165070.
FLT3 TK Cancer GOF Mut Activating mutations found in one third of cases of acute myeloid leukemia (AML), as well as in acute lymphoblastic leukemia, acute promyelocytic leukemia and myelodysplastic syndrome. Inhibitors: SU11248 and PKC412. OMIM:136351.
FLT4 (VEGFR3) TK Lymphangiogenesis Act, LOF Mut Lymphatic-specific VEGF receptor. LOF mutations cause hereditary lymphedema [OMIM:153100], and one case of capillary infantile hemangioma [OMIM:602089]. Expression of FLT4 ligands is seen in a variety of tumors, including colorectal, prostate, gastric, breast and thyroid cancers where it is associated with lymph node metastasis (Medline:15086167, 14614015, 14534690, 10430087, 14716745, 15107801). In model systems, overexpression of ligand increases lymph node metastasis and blocking antibodies and soluble receptors have been used to reduce lymphangiogenesis (Medline:15072591, 11175849). Inhibitors: BAY 43-9006, CEP-7055. OMIM:136352.
FMS (CSF1R) TK Cancer Mut Two point mutations seen in 10-20% of patients with acute myeloid leukemia, chronic myelomonocytic leukemia or myelodysplasia. One mutation appears to be both somatic and germline and disrupts Cbl binding and receptor turnover (Medline:11847211). v-fms lacks the Cbl binding site and causes feline leukemia. Mutations may also develop after chemotherapy for lymphoma (Medline:9403002). A distinct point mutation was found in some cases of hepatocellular carcinoma and related to increased expression, and another mutation was found in 2 of 40 patients with idiopathic myelofibrosis (Medline:12580961). Expression of fms and its CSF-1 ligand are elevated in breast tumors and cell lines and expression in xenografts and transgenic mice has been correlated with xenograft growth and breast cancer development (Medline:15289345, 15205327, 11205275). Inhibitors: Ki-20227 (Kirin) and other Kit/PDGFR inhibitors. OMIM:164770.
Fyn TK Cancer, Epilepsy Induced expression aids in cellular transformation and xenograft metastasis (Medline:3287380, 8325712). In squamous cell carcinoma, Fyn transduces signals from EGFR and Src and is required for cell migration and invasiveness (Medline:11684709). Activity linked to migration in a murine melanoma model (Medline:13129922). Appears to block late stage development of neuroblastoma (Medline:12450793). Mouse knockout deficient in kindling response, a model for human epilepsy. OMIM:137025.
GRK4 (GPRK4) AGC Hypertension SNP Multiple SNPs implicated in hypertension and believed to increase kinase activity on dopamine D1 receptor. One SNP validated in rodent model. OMIM:137026.
GSK3 (α & β) CMGC Cardiovascular, CNS, Diabetes, Neurodegeneration SNP, Act GSK3α and GSK3β have similar functions and are covered together here. GSK3α phophorylates tau, the principal component of neurofibrillary tangles in Alzheimer disease [AD; OMIM:104300] and is required for maximal production of amyloid plaque peptides by γ-secretase. A GSK3β promoter SNP effects progression of bipolar disorder [OMIM:125480]. The GSK3 inhibitor, lithium, is used to treat bipolar disorder and is seen to block plaque formation. GSK3 generally opposes the action of insulin and GSK3 hyperactivity may contribute to insulin resistant (type II) diabetes (Medline:15102436, 15078145). GSK3β also negatively regulates cardiac hypertrophy (Medline:12039794). A tumor suppressor role is indicated by the oncogenic potential of stabilized β-catenin mutants that lack GSK3 phosphorylation sites, but no oncogenic mutants have been reported. Inhibitors: AR-A014418 (Astra Zeneca), NP031112 (Zeltia). OMIM:606784, 605004.
HER2 (ErbB2) TK Cancer Amp, OE EGF family receptor. Overexpression induces constitutive activity and the gene is amplified or overexpressed in up to 30% of breast cancers, correlating with poor survival. The antibody trastuzumab is approved for treatment of metastatic breast cancer with HER2 amplification/overexpression. Somatic mutations seen in 4% of lung cancers and also in breast, gastric, ovarian cancer and glioblastoma. One SNP shows predisposition to breast and gastric cancer (Medline:10699071, 14520697). Inhibitors: trastuzumab (mAb, Genentech), lapatinib (Tykerb, GSK), PKI-166 (Novartis), EKB-569, CI-1033. OMIM:164870.
HER3 (ErbB3) TK Cancer OE EGF family receptor. Kinase domain lacks activity but heterodimerizes with other EGFRs to transduce growth signals. May be required for HER2 activity (Medline:12853564). Elevated expression in breast and other tumors is indicative of poor outcome (Medline:12866037, 12896906, 14614020, 15150091, 7656248). A secreted form is expressed in metastatic prostate cancer (Medline:15141384). OMIM:190151.
HER4 (ErbB4) TK Cancer Expr Heterodimerizes and signals with other EGF receptors. May act as a tumor suppressor and is overexpressed in head and neck cancer (Medline: 15476268) but downregulated in renal cancer (Medline:15360049), papillary carcinoma (Medline:15279891), high-grade gliomas (Medline:15148612) and invasive breast cancer (Medline:15084248). OMIM:600543.
HGK (ZC1) STE Cancer OE Upregulated in primary tumors and tumor cell lines (Medline:12612079). Required for anchorage-independent growth and ras-dependent focus formation in multiple cell lines (Medline:12612079). OMIM:604666.
HIPK1 CMGC Cancer OE Expression elevated in many breast cancer cell lines. Null mice are resistant to carcinogens. Binds the p53 tumor suppressor (Medline:12702766). OMIM:608003.
HIPK2 CMGC Cancer LOH, Expr Possible tumor suppressor. Activates p53 in response to UV light, causing growth arrest and apoptosis. Required for cisplatin-induced apoptosis (Medline:14729469). Downregulated in breast and thyroid carcinomas. OMIM:606868.
IGF1R TK Cancer, Growth, Longevity Mut, SNP, OE Mutated in rare cases of pre- and post-natal growth retardation. One SNP associated with increased human longevity. Increased expression of IGF1R and other pathway members associated with progression and malignancy in a range of cancers (Medline:15050909, 15050914, 14710347, 12884909). Several blocking antibody inhibitors in early trials, particularly in multiple myeloma, including CP-751871 (Pfizer, Ph II: NSCLC). Small molecule inhibitors include NDGA (Ph. I, Prostate) NVP-AEW541 (Novartis; Phase 1 multiple myeloma), OSI-906 (Ph. 1), AG1024 (preclinical). OMIM:147370.
IKKα, IKKβ Other Cancer, Diabetes, Inflammation Two closely related kinases that comprise the IKK complex along with the non-kinase nemo/IKKγ. Part of NF-κB pathway with inhibitors under development to treat arthritis, inflammation, and apoptotic aspects of cancer (Medline:14579522, 15013524). Aspirin (sodium salicylate) selectively binds IKKβ and reduces inflammation. Misexpression and inhibitors show involvement in insulin sensitization in obese rodents. Mutations in nemo [OMIM:300248] are found in several immune deficiencies: hyper IgM syndrome (Medline:15358621; recurrent infections and immune recombination defects), incontinentia pigmenti [OMIM:308300; embryonic lethal in males, defects in skin, hair, teeth in females] and hypohidrotic ectodermal dysplasia [OMIM:300291; recurrent infections and defects in teeth, hair, and sweat glands]. Inhibitors: CHS 828, NBD peptide, BMS-345541. OMIM:600664, 603258.
IKKε Other Cancer, inflammation Amp, Expr, Inh Amplified and overexpressed in many breast cancer tumors and cell lines where IKKε inhibition leads to cell death (Medline:17574021). SNPs weakly associated with rheumatoid arthritis in one study (Medline:18434448). OMIM:605048.
ILK TKL Cancer OE Increased expression is correlated with progression of several tumor types, including breast, prostate and colon carcinomas. Overexpression drives anchorage-independent growth and faster cell cycle. OMIM:602366.
INSR TK Diabetes, Development Mut, SNP Key regulator of energy metabolism closely linked to diabetes and obesity. Familial mutations associated with insulin resistant diabetes, acanthosis nigricans [OMIM:100600; skin thickening and hyperpigmentation], pineal hyperplasia (Rabson-Mendenhall syndrome [OMIM:262190]) and polycystic ovary syndrome. SNP variants may be associated with polycystic ovary syndrome, atypical migraine and diabetic hyperlipidemia (Medline:12477518, 11735220, 11846745). Mutations also cause leprechaunism [OMIM:246200], a severe insulin resistance syndrome causing growth retardation and death in early infancy. OMIM:147670.
IRAK2 TKL Cancer, Inflammation Mut One liver tumor linked to a hepatitis B virus insert into this locus (Medline:12813464). A dominant negative construct inhibits bacterial-induced macrophage apoptosis (Medline:11971008). OMIM:603304.
IRAK4 TKL Infection Mut Two truncation mutations associated with pyrogenic bacterial infections [OMIM:607676]. OMIM:606883.
ITK TK Cancer, Virology Inh, Trans Inhibition (drug, siRNA, dead kinase) inhibits HIV spread in culture (Medline:18443296). A Syk-ITK fusion seen in some T cell lymphomas (Medline:16341044). Inhibitors under development from BMS (BMS509744), Boehringer Ingelheim and Vertex to target T cell and mast cell inflammatory/immune diseases. OMIM:186973.
Jak1 TK Cancer Mut, Act A selective Jak1 inhibitor induces apoptosis in NRP-154 prostate cancer cell line. A single mutation seen in tyrosine kinome screen of colon cancers (Medline:12738854, see supplementary materials) and in prostate (Medline:16102578) and uterine leiomyosarcoma (Medlne:16474838) cell lines. Activated in B cell lines from patients with post-transplant lymphoproliferative disorder (Medline:12177620) and in a mouse Lck-driven T cell lymphoma (Medline:9548458). Inhibitor: Piceatannol. OMIM:147795.
Jak2 TK Cancer Trans Fusion to TEL1 (ETV6) by t(9;12)(p24;p13) causes myeloproliferative disease (MPD) in humans and mouse models. Somatic point mutations associated with MPD, polycythermia vera [OMIM:263300] and leukemias. The Jak inhibitor AG490 inhibits constitutive Jak2 phosphorylation and causes apoptosis in cells from breast cancer and relapsing acute lymphoblastic leukemia (Medline:8628398, 11420660). Inhibitor: AG490, WHI-P154. OMIM:147796.
Jak3 TK Cancer, Immunity LOF Mut Several LOF mutations associated with a form of SCID (Severe Combined Immune Deficiency) [OMIM:600802]. Activating mutations found in acute megakaryoblastic leukemia (Medline:16843266). Inhibitor: CP690,550 (Pfizer). OMIM:600173.
JNK1 CMGC Cancer, Diabetes, Inflammation Activity increased in obesity. Inhibition or mouse knockout increases insulin sensitivity (Medline:12447443). Part of NF-κB pathway involved in inflammation and cancer and signals downstream of Ras though possibly as an apoptotic negative regulator of growth (Medline:12734425). OMIM:601158.
JNK3 CMGC Cancer, CNS Expr Brain-selective Jnk isoform. Pro-apoptotic gene and potential tumor suppressor. Expression lost in brain tumors (Medline:11322657). May function in neuronal cell death from injury and neurodegeneration, for which inhibitors are being developed (Medline:15501728, 14657393, 14704277). OMIM:602897.
KDR (FLK1, VEGFR2) TK Cancer Mut Required for tumor angiogenesis in solid cancers and the target of several anti-angiogenic therapies. Point mutation found in one case of capillary infantile hemangioma [OMIM:602089] and several seen in recent survey of colon cancers (Medline:12738854). Inhibitors: Sutent (Sugen), bevacizumab (mAb, Genentech), Nexavar (Bayer/Onyx), PTK787 (Novartis). OMIM:191306.
Kit TK Cancer, Depigmentation GOF Mut, LOF Mut, Act? Activating mutations cause >90% of gastrointestinal stromal tumors (GIST) [OMIM:606764]; successfully treated with inhibitors imatinib and Sutent (Sutinib, SU11248). Activating mutations also induce mastocytosis [OMIM:154800] (Medline:15507672). Autocrine/paracrine stimulation may drive some lung and other tumors (Medline:15036937). Loss of expression associated with melanoma progression (Medline:9687504). Familial loss of function mutations cause piebaldism [OMIM:172800] with defects in hair and skin pigmentation due to lack of melanocytes. OMIM:164920.
LATS1 AGC Cancer Meth, Expr, Mut Likely tumor suppressor and ortholog of Drosophila warts tumor suppressor. Binds and inactivates CDC2 causing G2 arrest. Knockout mice are susceptible to soft-tissue sarcomas and sensitive to chemical carcinogenesis. Human soft tissue sarcomas have downregulated, mutated, and/or hypermethylated LATS1 (Medline:12379777). Transgenic expression blocks anchorage independent growth in culture and tumor growth in xenografts (Medline:11850843). OMIM:603473.
LATS2 AGC Cancer Expr Tumor suppressor blocks CDK2 activity leading to G1 arrest. Ectopic expression induces apoptosis in lung cancer cell lines (Medline:15265683). Negatively regulates the androgen receptor and is downregulated in prostate cancer (Medline:15131260). OMIM:604861.
LCK TK Cancer, Immunity Trans, Mut, Expr, Splice Overexpression in mice leads to thymic tumors (Medline:1708890). Aberrant expression is seen in T cell leukemias (Medline:10706447) and colon cancer (Medline:9416836). The leukemic translocation t(1;7)(p34;q34) has breakpoints at the T cell receptor β gene and close to the Lck promoters and can cause increased Lck expression and, in one case, point mutations (Medline:8139546). A mutated Lck has also been seen in a cell line. One patient with aberrant Lck splicing suffered from SCID-like T cell deficiency. Inhibitor: BMS-279700. OMIM:153390.
LIMK1 TKL Cancer, Development OE, Amp, LOH Mediates Rho signaling to cytoskeleton. Overexpressed in prostate tumors and prostate and breast cancer cell lines. Manipulation of activity correlates with invasiveness in breast and prostate cancer models. Located within the 7q11.2 amplicon associated with metastatic prostate cancer (Medline:12821664, 12777619). Loss of one copy of LIMK1 is the likely cause of visuospatial cognition defects seen in small chromosomal deletions associated with dominant Williams-Beuren syndrome [OMIM:194050]. OMIM:601329.
LKB1 (STK11) CAMK Cancer LOF Mut Several distinct loss of function point mutants cause Peutz-Jeghers syndrome [OMIM:175200], causing gastrointestinal polyps and cancer susceptibility. Sporadic mutations also seen in melanoma, pancreatic cancer and testicular cancer. OMIM:602216.
LRRK2 TKL Cognition Mut A G2019S activating mutation within the activation loop is the most common cause of autosomal dominant Parkinson disease (5% of all diagnoses). Seven other mutations also linked to Parkinson. OMIM:609007.
LTK TK Immunity SNP Polymorphism associated with the autoimmune disease systemic lupus erythematosus [OMIM:152700] in both mice and humans; likely impact via PI3K signaling. OMIM:151520.
LYN TK Cancer Act Mouse knockout develops monocyte/macrophage tumors, while an activated transgene does not induce tumors. Hyperactivated in acute myeloid leukemia; treatment by antisense or drug inhibitors reduces proliferation (Medline:10360372). Lyn-specific inhibitors block proliferation in three prostate cancer cell lines (Medline:14871838). OMIM:165120.
MASTL AGC Hematopoiesis Mut One mutation found in autosomal dominant thrombocytopenia (incomplete megakaryocyte differentiation). OMIM:608221.
MEK1,2 (MAP2K1,2) STE Cancer, Cardiac, Development,Virology Mut, OE Two closely related kinases targeted by the small molecule CI-1040 (PD184352), which inhibits colon cell line growth and motility in culture and xenografts. Overexpressed/overactivated in multiple tumor types. The Mek1/2 inhibitor U0126 blocks export of influenza viral particles and has been suggested as an antiviral treatment. Inhibitors: U0126, CI-1040/PD184352, PD-0325901 (Pfizer, Phase I cancer), ARRY-142886 (Phase 1, cancer). Single mutations at the same point of each gene also associated with cardiofaciocutaneous syndrome (also linked with Braf and Kras mutations), displaying morphological, cardiac and mental defects. OMIM:176872, 601263.
MELK CAMK Cancer Expr, Inh Expression increased in breast, brain and other tumors; knockdown blocks proliferation in cell lines (Medline:17960622, 17722061, 17280616, 16266996). OMIM:607025.
Mer TK Vision LOF Mut LOF mutations cause photoreceptor degeneration in retinitis pigmentosa [OMIM:268000], thought to be due to lack of clearance of apoptotic cells. OMIM:604705.
Met TK Cancer GOF Mut, OE, Trans Activating point mutations cause hereditary papillary renal carcinoma [OMIM:605074]. Mutations also seen in sporadic renal cell carcinoma and childhood hepatocellular carcinoma. Upregulation in carcinomas and sarcomas correlates with metastasis and poor outcome (Medline:14617781). Some gastric carcinomas harbor a translocation that creates an activated TPR-Met fusion protein (Medline:2052572). A small molecule inhibitor (PHA-665752) shows an effect in gastric carcinoma xenografts (Medline:14612533). Inhibitors: SU11274, PHA-665752, MGCD265 mAbs. OMIM:164860.
MISR2 (AMHR2) TKL Reproduction Mut Mutations cause Müllerian duct syndrome type II [OMIM:261550], a developmental failure of Müllerian duct (female genital primordia) to regress in males. OMIM:600956.
MKK3 (MAP2K3) STE Cancer Mut, Del A deletion and two point mutants found in colon cancer cell lines (Medline:11414763). OMIM:602315.
MKK4 (MAP2K4) STE Cancer LOF Mut, Del Inactivating mutations or deletions seen in approximately 5% of tumors from diverse backgrounds (Medline:11754110). OMIM:601335.
MLK4 TKL Cancer Mut Nine distinct point mutations found in a sample of 182 colon cancer tumors and cell lines (Medline:12738854).
skMLCK (MYLK2) CAMK Cardiovascular Mut A single case of familial hypertrophic cardiomyopathy [OMIM:192600] has been linked to a mutation in skMLCK. Expression increased during some metastasis (15970650) and invasion susceptible to skMLCK inhibition (11741180, 12970723). Inhibitors: ML-7, KT5926. OMIM:606566.
smMLCK (MYLK) CAMK Hypertension Model Increased expression leads to phenotype in spontaneously hypertensive rat (SHR) model. nsSNP associated with severe asthma and promoter SNP with sepsis in African populations (Medline:17266121, 17472811). Inhibitor: ML-9. OMIM:600922.
Mst4 STE Cancer OE Expression correlates with tumorigenicity in prostate tumors and cell lines. Expression of wild type and inactivating mutant transgenes indicates a role in anchorage-independent growth and tumorigenic proliferation downstream of the EGFR family (Medline:12810671). OMIM:300547
mTOR (FRAP) Atypical Cancer Controls cell growth through protein synthesis regulation. Downstream of PI3K/Akt pathway and required for cell survival. Inhibitors: rapamycin, temsirolimus (CCI-779; Wyeth), everolimus (RAD-001; Novartis). OMIM:601231.
MusK TK Neuro Mut, Auto-antibodies Agrin receptor expressed on neuromuscular junction. Auto-antibodies seen in some cases of the neuromuscular disease myasthenia gravis (Medline: 16155434) and cause disease in animal model (Medline:16557298). Two LOF mutations seen in one human case (Medline:16550915). OMIM:601296.
MYO3A STE Sensory Mut Three mutations associated with progressive deafness. OMIM:606808.
NEK1 Other Development, Renal Mouse mutants lead to facial malformation, male sterility and polycystic kidney disease [OMIM:601313]. OMIM:604588.
NEK2 Other Cancer OE Overexpressed in Ewing’s tumors (Medline:11836553) and diffuse large B cell lymphoma (Medline:12594241). OMIM:604043.
NEK8 Other Cancer, Renal OE Mutations cause polycystic kidney disease in mouse and (by gene knockdown) in zebrafish (Medline:12421721). Overexpressed in breast tumors (Medline:15019993). OMIM:609799.
p38 (α,β,γ,δ) CMGC Cancer, Inflammation Four closely related isoforms (α,β,γ,δ) involved in apoptosis and stress reponses. Mediate actions of pro-inflammatory cytokines; inhibitors under development to treat inflammation, autoimmunity, diabetes and cancer (Medline:12725866, 12783612, 12790339). Inhibitors: doramapimod/BIRB-796 (Boehringer Ingelheim; Phase 2-3 for psoriasis, Crohn disease and arthritis), SCIO-469, SCIO-323 (Scios; Phase 1 arthritis), AMG-548 (Amgen), ARQ-101 (ArQule), CDP-11 (Celltech), VX-702 (Vertex; Phase 2 acute coronary syndrome). OMIM:600289, 602898, 602899, 602399.
p70S6K (RPS6KB1) AGC Cancer, Diabetes OE, Amp Mouse knockout shows symptoms of insulin resistance and increased insulin senstivity, resulting in protection against diet-induced obesity (Medline:15306821). Protein expression and activation upregulated in colon adenocarcinoma cell lines (Medline:14578160). Increased expression in breast cancer correlated with poor survival (Medline:15083183). Selectively amplified and overexpressed within the 17q23 breast cancer amplicon (Medline:12755490, 11331760). Mediator of signaling from the oncogenic kinase mTOR. OMIM:608938.
PAK3 STE Cognition LOF Mut Missense and truncation mutations linked to nonsyndromic mental retardation type 30 (MRX30) (Medline:12884430, 10946356, 9731525). OMIM:300412.
PAK4 STE Cancer OE Overexpressed in several cancers. Required for ras-dependent anchorage-independent growth of tumor cell lines (Medline:11668177). OMIM:605451.
PDGFRα TK Cancer, Development Trans, Del, Mut Chromosomal rearrangments activate PDGFRα by fusion to Bcr causing atypical chronic myelogenous leukemia (CML), and to FIP1L1 causing idiopathic hypereosinophilic syndrome [OMIM:607685]. Activating point mutations cause a minority of gastrointestinal stromal tumors (GIST). Promoter polymorphisms linked to neural tube defects including spina bifida (Medline:11175793) as verified by mouse mutant model (Medline:9826722). Inhibitors: imatinib, SU11248. OMIM:173490.
PDGFRβ TK Cancer Trans, OE A variety of myeloproliferative disorders and cancers result from translocations that activate PDGFRβ by fusion with proteins such as TEL/ETV6, H2, CEV14/TRP11, rabaptin 5 and huntington interacting protein 1. Imatinib treatment of TEL fusions has been successful. PDGFRβ is also overexpressed in metastatic medulloblastoma. Inhibitors: imatinib, SU11248. OMIM:173410.
PEK (PERK) Other Diabetes LOF Mut Functions in the ER unfolded protein response and is linked to insulin processing. LOF mutations cause Wolcott-Rallison syndrome (WRS) [OMIM:226980], characterized by insulin-dependent diabetes in early infancy and multiple system abnormalities. Neuronal death in Alzheimer and Parkinson diseases is thought to be due to ER stress and has been weakly linked to PEK. OMIM:604032.
PHKγ2 CAMK Metabolism LOF Mut LOF mutations cause liver glycogenosis and one form of liver cirrhosis. OMIM:172471.
Pim-1 CAMK Cancer Trans, OE, Mut Expression increased in prostate cancer where it may lead to genomic instability (Medline:14678956) and reduce androgen receptor-dependent transcription (Medline:13679438). Expression level has prognostic value. Overexpression also seen in hematopoietic malignancies and is a target of aberrant somatic hypermutation in diffuse large-cell lymphomas. T cell lymphomas are induced in Pim-1 transgenic mice and by frequent viral insertions at the Pim-1 locus. OMIM:164960.
Pim-2 CAMK Cancer Similar to Pim-1. Mouse T cell lymphomas are induced by a Pim-2 transgene and by viral insertions. OMIM:300295.
Pim-3 CAMK Cancer May substitute for Pim-1 and Pim-2 in mouse virally driven cancer models (Medline:12185366). OMIM:610580.
PINK1 Other Cancer, Neurodegeneration Mut, Expr Two mutations cause hereditary early onset Parkinson disease (Medline:15087508). Association with PTEN tumor suppressor and decreased expression in ovarian tumors may indicate a role in cancer. OMIM:608309.
PKACα AGC Cancer Multiple mutations of regulatory subunit (PRKAR1A; OMIM:188830) cause Carney complex tumors and sporadic adrenal and thyroid tumors. Altered PRKAR1A transcript editing associated with lupus. PKACα knockout mouse has phenotypes similar to Carney complex (Medline:18413734). OMIM:601639.
PKC (multi-isoform) AGC CNS Inh Multiple agonists and antagonists of the PKC family have consistent effects on inhibiting or activating manic behavior in humans and rats. Tamoxifen has secondary effect as PKC inhibitor and shown anti-manic activity in rat model and a clinical trial (Medline:18316672, 17641532).
PKCα AGC Cancer, Cardiovascular Mut, Del, OE, Act A point mutation seen in several pituitary and thyroid tumors (Medline:9167945). Deleted in a melanoma cell line. Complex expression pattern in breast cancer (Medline 15459489, 15454252). Therapeutic target in lung, gastric and prostate cancer (Medline:15447994, 15313921, 15174974). May mediate multidrug resistance (Medline:12390766). Mouse models indicate a role in heart contractility (Medline:14966518). Inhibitors: LY-900003 (antisense. aka Affinitak/ISIS 3521/aprinocarsen), Safingol, Go6976. OMIM:176960.
PKCβ AGC Autism, Cancer, Diabetes SNP Two promoter SNPs associated with diabetic nephropathy (Medline:12874455), correlating with induction of renal expression by high glucose, reduction in renal function by a specific PKCβ inhibitor and successful inhibitor treatment of rodent models of diabetic nephropathy (Medline:12955673). PKCβ inhibition has also been proposed to treat diabetic retinopathy (Medline:12507628) and diabetic vascular complications (Medline:11903393). Ectopic expression in mouse heart leads to cardiac hypertrophy. Elevated expression is seen in and promotes early stages of colon cancer in mouse models (Medline:11245437). May mediate multidrug resistance (Medline:12697075). Activation protects astrocytes from ischemic injury (Medline:15165841). SNPs associated with autism (Medline:16027742). Inhibitors: LY333531 (ruboxistaurin; Phase 3 for diabetic neuropathy and retinopathy), LY317615 (Eli Lilly: isoform selective). OMIM:176970.
PKCγ AGC Neurodegeneration, Pain Mut Point mutations linked to dominant spinocerebellar ataxia type 14 [OMIM:605361]. Knockout and inhibitor studies show role in pain perception (Medline:14762097, 9323205). OMIM:176980.
PKCδ AGC Cancer, Cardiovascular, CNS Expr Pro-apoptotic. Reduced expression correlated with progression of colon and other cancers (Medline:15054085, 12657722, 12591726). Inhibition may drive chemo-resistant cancers to apoptosis. Activated and promotes apoptosis in cardiac and neuronal cells after ischemic-reperfusion injury (Medline:14654063, 15295022). Activator: bistrane A. Inhibitors: rottlerin, KAI-9803 (KAI; Phase 2 trials for reperfusion injury), dV1-1. OMIM:176977.
PKCε AGC Cancer, Cardiovascular, CNS Amp, Mut Amplified and rearranged in thyroid cancers (Medline:9683604, 10438519, 11994357). Promotes growth of an androgen-independent prostate cancer cell line (Medline:11956106) and transforms fibroblasts in culture (Medline:11968018). Activation protects cardiac myocytes and neurons from ischemic injury (Medline:15165841) and antagonizes PKCδ. Amyloid β peptide inhibits PKCε activity and may contribute to the pathogenesis of Alzheimer disease (Medline:15207847). Inhibitor studies indicate role in pain perception (Medline:1043272). Multi-isoform inhibitors include: Bryostatin-1 (BRYO) from Aphios and Perifosine/D-21266 from Baxter while KAI-1678 is a selective inhibitor. OMIM:176975.
PKCη AGC Cancer Expression progressively increased in renal cell carcinoma (Medline:14666709). Antisense knockdown enhances apoptotic effect of TRAIL on cancer cells (Medline:15252138) and of chemotherapeutics (Medline:15159020). May act as a tumor supressor in mouse skin knockout model (Medline:12750259, 12473186). OMIM:605437.
PKCτ AGC Cancer, Immunity Required for activation and proliferation of mature T cells. Proposed as a target for T cell leukemias (Medline:12188914). Knockout is resistant to fat-induced insulin resistance. OMIM:600448.
PKR (PRKR) Other Cancer, Virology, Neurodegeneration Mut, Expr, Act Mediates translational arrest and apoptosis in response to viral infection and inflammation. Activation by dsRNA against tumor transcripts under investigation as an anti-tumor agent (Medline:15174900). Posttranslationally inactivated in leukemia (Medline:14961569) and rearranged in a mouse leukemia line (Medline:9806790). Expression and activity are elevated in breast cancer lines (Medline:10871861) and hepatocellular carcinoma (Medline:14638359) and is prognostic of neoplastic progression in melanoma and colon carcinoma (Medline:12483527). Binds to transcripts containing trinucleotide repeats, including Huntingtin and DMPK, which underlies myotonic dystrophy (Medline:11468270,10668800, 12437593). OMIM:176871.
PLK1 Other Cancer Expr Elevated expression in many cancers including prostate and colon. Transforms cells to grow in soft agar. Involved in cell cycle. siRNA induces apoptosis in cancer cells and xenografts. OMIM:602098.
PRKX AGC Reproduction Trans A chromosomal translocation with breakpoints at the PRKX and PRKY loci [t(X;Y)(p22;p11)] accounts for approximately 30% of sex reversal cases (XX males and XY females). OMIM:300083.
PRKY AGC Reproduction Trans A chromosomal translocation with breakpoints at the PRKX and PRKY loci [t(X;Y)(p22;p11)] accounts for approximately 30% of sex reversal cases (XX males and XY females). OMIM:400008.
PYK2 TK Osteoporosis Model, Inh, Expr Inhibition by mouse KO or drug increases osteoblast bone-forming function in rat model (Medline:17537919, 17846174). Increased expression in osteoarthritic cartilage. Inhibitors: PF-431396, AG-17 (tyrphostin A9). OMIM:601212.
Raf1 (c-Raf) TKL Cancer Amp Mediator of ras signaling and of an anti-apoptotic signal downstream from VEGF and FGF receptors (Medline:12843393). Amplified in several tumors including bladder, hormone resistant prostate, nasopharyngeal carcinoma and anaplastic large cell leukemia (Medline:11389083, 12696066, 1461400, 11836556). Antisense regresses xenograft tumors (Medline:12022686). Inhibitors: sorafenib/BAY-43-9006 (Bayer), ISIS5132 (Isis, antisense). OMIM:164760.
Ret TK Cancer, Development LOF and GOF Mut, Trans Familial GOF mutations cause endocrine cancers including familial medullary thyroid carcinoma (FMTC) [OMIM:155240], multiple neoplasia type IIA (MEN2A) [OMIM:171400] and MEN2B [OMIM:162300], both of which are characterized by predisposition to FMTC and phaeochromocytoma. Translocation-mediated fusion of Ret to various genes (H4, ELE1, PKA-R1, TIF1A, TIF1G) results in papillary thyroid carcinoma [OMIM:188550]. Familial LOF mutations cause Hirschsprung disease [OMIM:142623] in which enteric (intestinal) neurons fail to develop. OMIM:164761.
RHOK AGC Vision LOF Mut Phosphorylates and inactivates photon-activated rhodopsin. LOF mutations lead to type 2 Oguchi disease [OMIM:258100], a form of night blindness. A link between RHOK and retinitis pigmentosa is now thought to be unlikely (Medline:9268593). OMIM:180381.
RNAseL Other Cancer, Virology Mut Point mutations associated with hereditary form of prostate cancer, HPC1 [OMIM:601518]. Mouse model indicates a role in interferon-mediated antiviral response. OMIM:180435.
ROCK1, ROCK2 AGC Cardiovascular, Hypertension, Neurodegeneration Two related Rho-activated kinases, ROCK1 and ROCK2, regulate contractility of smooth muscle. A ROCK-specific inhibitor causes smooth muscle relaxation and is effective in rat models of hypertension (Medline:9353125) and in reduction of intraocular pressure (Medline:11584347). ROCK1 controls formation of Aβ42 amyloid protein in Alzheimer plaques; inhibitors reduce Aβ42 levels in a mouse model. ROCK2 null mice indicate a role in blood coagulation (Medline:12832488). ROCK’s cytoskeletal links are associated with metastasis and invasion in bladder cancer (Medline:12855641) and in cellular and animal models (Medline:12524136, 12823259, 9930872). The inhibitor fasudil is approved for treatment of cerebral vasospasm and under investigation for treatment of angina and hypertension. Inhibitors: fasudil, Ki29035 (Kirin), Y-27632, Wf-536, HA-1077, H-1152P. OMIM:601702, 604002.
RON TK Cancer OE, Splice Functions in cell migration and epithelial-mesenchymal transition. Highly expressed in tumors including head and neck cancer (Medline:15023838), colon (Medline:12527888), breast (Medline:9671413) ovarian carcinoma (Medline:12915129) and renal oncocytoma (Medline:15252311). Unusual splice variants seen in cancer, including a constitutively active form lacking the extracellular domain (Medline:12527888, 15289319). Overexpression in mouse lung leads to pulmonary adenomas (Medline:12214279). OMIM:600168.
ROR2 TK Development Mut Carboxy-terminal deletions cause skeletal malformations including dominant brachydactyly type B [OMIM:113000] and recessive Robinow syndrome (RRS) [OMIM:268310]. OMIM:602337.
ROS TK Cancer Trans Fused to FIG1 gene and constitutively activated by a chromosomal deletion leading to glioblastoma (1 case). Reportedly misexpressed in CNS tumors. OMIM:165020.
RSK2 (RPS6KA3) AGC CNS, Development, Virology LOF Mut LOF mutations cause dominant Coffin-Lowry syndrome [OMIM:303600] characterized by severe mental retardation with facial, digital and progressive skeletal deformations. Required for activation of HIV tat protein (Medline:17225856). OMIM:300075.
SGK1 AGC Cancer, Cognition, Diabetes Expr Elevated expression in diabetic nephropathy stimulates sodium transport. Mediates anti-apoptotic effect of glucocorticoids in breast cancer cell lines. Elevated expression in brains of fast-learner rats in a water maze test and transient transfection of normal and mutant gene indicates a positive role in learning. OMIM:602958.
SRC TK Cancer Mut, OE, Act Homolog of Rous sarcoma virus v-src. A truncated, activated form seen in approximately 12% of colon cancers in one study and in one endometrial sarcoma but not seen in several other populations (Medline:9988270, 10804287, 10704743, 10485460, 11161376). Expression and kinase activity are frequently increased in a wide array of cancers, including tumors from breast, colon, pancreas, lung, ovary and CNS (Medline:9988270). Inhibitors: SU6656 (Sugen), PD173955, PD166285 (Pfizer), CGP76030 (Novartis), BMS-354825 (BMS; Phase 2 cancer). OMIM:190090.
Syk TK Allergy, Cancer Meth, Splice Tumor suppressor in breast; expression progressively reduced by hypermethylation in developing tumors (Medline:15455373). Silencing through methylation is also seen in gastric cancer. Aberrant splice forms encoding kinase-deficient isoforms found in childhood acute lymphoblastic leukemia (Medline:11494125). Required for mast cell activation and release of allergic mediators; potential target in allergy, asthma and inflammation (Medline:15212616). A Syk-ITK fusion seen in some T cell lymphomas (Medline:16341044). Inhibitors: R-406, R-788 (Rigel), BAY 61-3606, Piceatannol, and programs at Aventis, Yamanouchi, Boehringer Ingelheim, Novartis. OMIM:600085.
TGFβR1 (ALK5) TKL Cancer, Development SNP, Mut A common variant allele (TGFβR1*6A) carried by approximately 10% of the population is associated with higher incidence of breast, colon, ovarian and hematological cancers (Medline:14966109). A distinct intronic SNP is associated with both bladder and kidney carcinoma (Medline:15382067). Protein and RNA expression elevated in lung cancer (Medline:14596814) and the overall TGFβ signaling pathway has been observed as disrupted in a range of cancers. Mutated in Loeys-Dietz Syndrome [OMIM:609192] characterized by cardiovascular, craniofacial, neurocognitive, and skeletal abnormalities. Inhibitor: SB-505124. OMIM:190181.
TGFβR2 TKL Cancer, Development, Fibrosis LOF Mut Anti-growth receptor. Both TGFβR2 and IGFR2 have microsatellite repeat sequences with one of the two mutated in most colon and gastric tumors with microsatellite instability. Linked to esophageal cancer [OMIM:133239]. Mutations common in hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) [OMIM:114500], in which DNA repair genes are mutated leading to microsatellite instability. Germline mutations are associated with Marfan’s syndrome type II [OMIM:154705] and related connective tissue diseases. Mutated in Loeys-Dietz Syndrome [OMIM:609192], characterized by cardiovascular, craniofacial, neurocognitive and skeletal abnormalities. TGFβ signaling is also implicated in fibrosis and wound healing (Medline:15117886). Inhibitor: Fibrogen. OMIM:190182.
Tie2 (TEK) TK Angiogenesis, Cancer Mut, OE Point mutations cause dominantly inherited venous malformations [OMIM:600195]. Expression is increased in non-small cell lung cancer (Medline:9681823), myeloid leukemia (Medline:11755466) and hepatocellular carcinoma (Medline:11915032). Expression is prognostic of metastasis in breast cancer (Medline:12527939, 15026804) and expression and activation correlate with malignancy in astrocytomas (Medline:14742253). Soluble receptor used to inhibit tumor growth in mice (Medline:14985859). OMIM:600221.
TITIN CAMK Cardiovascular Mut Mutations found in hypertrophic and dilated cardiomyopathies and tibial muscular dystrophy. OMIM:188840.
TrkA (NTRK1) TK Cancer, Sensory Mut, Trans Point mutations and translocations creating TrkA fusion proteins found in papillary thyroid carcinoma. Fusion partners include TPM3 (tropomyosin), TRP, TFG and Tag. Trk signaling has also been implicated in breast and ovarian cancer (Medline:15379632, 14997042, 12796393) and some melanomas (Medline:15362372). Neuroblastomas, gliomas and astrocytomas have dynamic TrkA expression with increased expression correlated with good prognosis (Medline:9049830). Mutations in TrkA have been seen in cases of congenital insensitivity to pain with anhidrosis [OMIM:256800], characterized by insensitivity to pain and noxious stimuli, anhidrosis (absence of sweating), self-mutilation and mental retardation. A mouse TrkA knockout has similar phenotypes. Inhibitor: K-252a. OMIM:191315.
TrkB (NTRK2) TK Cancer Mut Two separate point mutations found in a set of 182 colon tumors and cell lines (Medline:12738854). In rat, TrkB inhibits anoikis and enhances metastasis (Medline:15329723). One liver tumor linked to a hepatitis B virus insert into this locus (Medline:12813464). TrkB elevated expression is associated with poor prognosis in neuroblastoma (Medline:10994551) and may mediate chemoresistance (Medline:12438236). OMIM:600456.
TrkC (NTRK3) TK Cancer Trans, Mut Fusion gene EV6-TrkC found in pediatric mesenchymal cancers and rat secretory breast carcinoma. Ten point mutations found in breast, colon, lung, pancreas tumors and cell lines (Medline:12738854, 16941478). OMIM:191316.
Tyk2 TK Immunity SNP, Model Signals in immunity downstream of IFNα. Natural mouse strain with Tyk2 mutation is susceptible to parasite infection and resistant to autoimmune arthritis (Medline:14500783). Human SNPs associated with lupus (Medline:17384181, 15657875). Inhibitor: Piceatannol. OMIM:176941.
TYRO3 (SKY) TK Cancer OE Transforming oncogene in culture studies (Medline:7896835). Overexpression leads to ligand-independent activation (Medline:8545119). Overexpressed in mouse mammary tumors (Medline:7896835) and human multiple myeloma (Medline:11468178). Downregulated in astrocytomas (Medline:11156382) and a triple knockout of TYRO3/Mer/Axl in mouse has hyperproliferation defects (Medline:11452127), indicating positive and negative growth control functions. OMIM:600341.
Wnk1 Other Hypertension Intronic Mut Two separate intronic deletions in Wnk1 found in cases of familial hypertension (pseudohypoaldosteronism type II) [OMIM:145260]. OMIM:605232.
Wnk4 Other Hypertension Mut Expressed exclusively in distal convoluted tubule of kidney and localized to tight junctions. Distinct point mutations found in 4 cases of familial hypertension (pseudohypoaldosteronism type II) [OMIM:145260]. OMIM:601844.
Yes TK Cancer Amp, Act Ortholog of Yamaguchi sarcoma virus v-yes oncogene, which can transform fibroblasts in vitro (Medline:3303862). Amplified in one case of gastric cancer and in canine mammary tumors (Medline:3935622, 10081762). Kinase activity is increased in colon carcinoma cell lines and tumors (Medline:7690925, 7806032) and in melanoma cell lines and brain metastases (Medline:7690926, 9681823). Mouse knockouts have no strong phenotype due to compensation by Src and Fyn (Medline:7958873). OMIM:164880.
Zap-70 TK Immunity Mut Mutations cause selective T cell defect [OMIM:176947], a recessive form of severe combined immunodeficiency (SCID) exhibiting selective absence of CD8+ T cells. Reduced expression predicts positive outcome in B cell chronic lymphocytic leukemia. The SKG mouse is mutated at Zap-70, producing increased numbers of self-reactive T cells and resulting in chronic arthritis. OMIM:176947.

Molecular Basis Key:  Act—Activated  Amp—Amplified  Del—Deleted  Expr—Expression  GOF—Gain-of-function  Inh—Inhibitor Studies  LOF—Loss-of-function  LOH—Loss-of-heterozygosity  Meth—Methylation  Model—model organism studies  Mut—Mutation  OE—Overexpression  SNP—Single Nucleotide Polymorphism  Splice—Splicing change  Trans—Translocation



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