Kinase Targets and Their Disease Relevance
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Abl Abl is a non-receptor tyrosine kinase distinguished by its localization in the nucleus as well as the cytoplasm. Cytoplasmic Abl associates with F-actin and is capable of stimulating cell growth. Nuclear Abl is thought to participate with DNA-PK and ATM to initiate signaling in response to DNA damage. Chromosomal translocations involving Abl and the breakpoint cluster region on chromosme 22 produce the bcr-Abl fusion protein, resulting in an constitutively active Abl thought to be critical in the pathogenesis of chronic myelogenous leukemia (CML). |
Abl (Q252H & H396P mutations) The product of abl proto-oncogene (Abl) is a tyrosine kinase that transduces signals from cell surface receptors as well as DNA damaging agents to regulate actin dynamics, cell cycle, differentiation, and apoptosis. Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder brought about by a chromosomal translocation that fuses bcr sequence with the abl gene. This fusion encodes a constitutively active Bcr-Abl tyrosine kinase responsible for transformation and leukemogenic effects. The Abl tyrosine kinase inhibitor STI-571 (Gleevec™) is an effective therapy for stable phase CML patients. However, many patients responding to Gleevec later relapse, due to the reactivation of Bcr-Abl activity. A number of point mutations within the Abl kinase domain, such as E225K, Q252H, T315I, M351T and H396P have been shown to be associated with this acquired clinical resistance to the drug. |
ACK1 Activated Cdc42-associated Kinase-1 (ACK1) is a non-receptor tyrosine kinase that has been implicated in a variety of signaling pathways such as growth factor, cell adhesion and muscarinic receptor signaling. Recent data demonstrate an important role for ACK1 in cancer cell survival, as well as in tumor formation and metastasis. Over-expression of ACK1 in cancer cell lines has also been shown to result in a more invasive phenotype both in vitro and in vivo. |
Akt/PKB Akt/Protein kinase B (PKB) is a serine/threonine kinase known to be a major effector of the PI 3 kinase pathway in response to growth factors or insulin. It is thought to contribute to multiple cellular processes including nutrient metabolism, cell growth and apoptosis. Mis-regulation of Akt/PKB's activity has been shown to contribute to various human diseases including atherosclerosis and diabetes mellitus. |
Arg Abl-related gene (Arg) is a non-receptor tyrosine kinase homologous to Abl which also binds to the EphB2 and AphA4 receptors. These receptor tyrosine kinases regulate actin cytoskeletal organization in the developing nervous system and participate in axon growth, suggesting a role in tissue morphogenesis. |
Ask Ask-1 (apotosis signal-regulating kinase) is a MAP kinase kinase kinase involved in the stress-induced apoptosis-signaling cascade that activates the SEK-JNK and MKK3/MKK6-p38 MAP kinase cascades. Its role in ER stress-induced cell death, suggests its importance in neuropathological disorders in polyQ diseases. |
Aurora Important regulators of cell division, the Aurora family of serine/threonine kinases includes Aurora A, B and C. Aurora A and B kinases have been identified to have direct but distinct roles in mitosis. Over-expression of these three isoforms have been linked to a diverse range of human tumor types, including leukemia, colorectal, breast, prostate, pancreatic, melanoma and cervical cancers. |
Axl Axl is a receptor tyrosine kinase that includes, Axl, Rse, and Mer. Axl plays a role in mediating cell growth and survival through apoptosis-mediated pathways and is thought to be up-regulated in melanomas. |
Blk B-lymphoid tyrosine kinase (Blk) is a B-cell specific Src-family (non-receptor) tyrosine kinase, implicated in cacner, whose expression is regulated by the AML-1 protein. |
Bmx Bmx is a non-receptor tyrosine kinase involved in VEGF-induced cell migration. Bmx belongs to the Tec kinase family that also includes Btk, Itk, Rlk and Tec. Bmx is thought to interact with Cas at membrane ruffles, the site of active remodeling. Its role in cellular adhesion and migration makes Bmx an interesting kinase for the study of angiogenesis. |
Brk Breast tumor kinase (Brk) is a nonreceptor tyrosine kinase that is overexpressed in many breast and colon cancers. Brk contains SH3, SH2, and tyrosine kinase catalytic domains in a similar arrangement as Src family kinases. Like c-Src, overexpression of Brk leads to sensitization to EGF. |
BTK Bruton's tyrosine kinase (BTK) is a cytoplasmic non-receptor tyrosine kinase of the Tec family, that is expressed in most hematopoietic tissues. BTK is critical for B cell development and function, and is the defective gene in human x-linked agammaglobulinemia and mouse X-linked immunodeficiency. |
BTK (E41K mutation) Bruton's tyrosine kinase (BTK) is a TEC family non-receptor protein tyrosine kinase involved in signal transduction pathways regulating growth and differentiation of B cells. The E41K substitution is a PH domain gain-of-function mutation that has been shown to be associated with increased membrane localization and tyrosine phosphorylation of BTK. Using animal models, this mutation has been shown to arrest the development of immature B cells and to act as a tumour suppressor in B-cell linker protein (BLNK/SLP-65)-deficient hosts. |
BTK (R28H mutation) Bruton's tyrosine kinase (BTK) is a TEC family non-receptor protein tyrosine kinase involved in signal transduction pathways regulating growth and differentiation of B cells. Mutations in the human BTK gene, such as F25S, R28H, T33P, V64F and V113D, are the cause of X-linked agammaglobulinemia (XLA), an immune deficiency disorder characterized by a lack of mature, immunoglobulin-producing, peripheral B cells. In mice, mutations in the BTK gene have been identified as the cause of murine X-linked immune deficiency. |
CaMKIδ Ca/calmodulin-dependent protein kinase-Iδ is a Ser/Thr kinase almost exclusively expressed in human polymorphonuclear leukocytes. Recent evidence indicates that this enzyme is involved in a calcium-triggered signaling cascade that regulates calcium-mediated granulocyte function. The enzyme may also play a role in apoptosis of erythroleukemia cells. |
CaMKIIβ, CaMKIIγ, CaMKIIδ Calcium/calmodulin-dependent protein kinase-II (CaMKII) is a serine/threonine protein kinase composed of four different isoforms: α, β, γ, and δ which assemble in vivo into homo- or heteromultimeric holoenzymes composed of 8 to 12 subunits. CaMKII has been implicated in regulating numerous cellular processes; in particular, there is evidence that CaMKII is involved in cardiac hypertrophy and heart failure. |
Casein Kinase Casein kinases (CK) are ubiquitous serine/threonine kinases that are constitutively active. CKI and CKII are thought to regulate critical processes such as Wnt signaling, circadian rhythm, nuclear import, and Alzheimer's disease progression. |
Cdk Cyclin-dependent kinases (cdk) are proline-directed serine/threonine kinases which are activated at specific times in the cell cycle, phosphorylate regulatory substrates and cause cell cycle progression. Cdks play a role in diverse processes including cell cycle control, neuronal development, and transcriptional regulation. Cdks, when mutated or over-expressed, may cause uncontrolled proliferation and tumorigenesis. Interest in their role in neurodegerative diseases such as Alzheimer's disease and Amyotrophic Lateral Sclerosis, in particular cdk5, is growing due to their role in the development of the central nervous system during embryogenesis. |
CDK9/cyclin T1 Cyclin-dependent protein kinase-9/cyclin T1 is one of three CDKs which regulate transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II. Phosphorylation converts the initiating form of the polymerase to the elongating form. |
CK1γ1, CK1γ2, CK1γ3 Casein kinases (CKs) are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Casein kinase-1 is the most abundant serine/threonine kinase in eukaryotic cell extracts. The 1γ1 & 1γ3 isoforms are involved in growth and morphogenesis of eukaryotic cells. CK1γ2 appears to be involved in PDGFRβ inactivation and recent findings suggest that CK1γ2 also plays a role in regulating the functions of metastatic tumor antigen 1 in human mammary epithelial and cancer cells. |
CK2α2 Casein kinase-2α2 (CK2α2) is a pleiotropic and ubiquitous protein kinase known to phosphorylate many proteins. It plays roles in signal transduction, transcriptional control, apoptosis and cell cycle regulation. |
CHK Chk is involved in cell cycle arrest when DNA damage has occurred or when unligated DNA is present. It binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25C creates a binding site for 14-3-3 protein, which inhibits CDC25C. This prevents activation of the CDC2-Cyclin-B complex and prevents mitotic entry. |
CHK2 mutants: R145W & I157T Checkpoint kinase-2 (CHK 2) is a DNA damage-activated protein kinase that has been shown to play a critical role in the DNA damage response pathway essential for prevention of neoplastic transformation. R145W and I157T are mutations found in the forkhead homology-associated (FHA) domain of CHK 2 that have been identified in patients with Li-Fraumeni syndrome (a highly penetrant familial cancer phenotype). |
c-Kit (D816H) The product of the c-kit proto-oncogene (c-Kit) is a tyrosine kinase receptor for stem cell factor. Ligand binding and activation of the receptor is critical for early stem cell differentiation in haematopoiesis and gametogenesis and melanogenesis. The D816H mutation has been shown to constitutively activate the protein and has been found in patients with gastrointestinal stromal tumors and mast cell leukemia. This mutation has also been shown to confer resistance to the kinase inhibitor Gleevec®. |
c-Kit (V560G) The product of the c-kit proto-oncogene (c-Kit) is a tyrosine kinase receptor for stem cell factor. Ligand binding and activation of the receptor is critical for early stem cell differentiation in haematopoiesis, gametogenesis and melanogenesis. The V560G substitution is a somatic mutation associated with some gastrointestinal stromal tumors (GISTs). This mutation lies within the juxtamembrane region of the protein; mutations in this region of c-Kit have been found to be present in >50% of GISTs. |
c-Kit (V654A) The product of the c-kit proto-oncogene (c-Kit) is a tyrosine kinase receptor for stem cell factor. Ligand binding and activation of the receptor is critical for early stem cell differentiation in haematopoiesis, gametogenesis and melanogenesis. The V654A substitution is a somatic mutation associated with some gastrointestinal stromal tumors (GISTs). This mutation has been shown to confer constitutive activity as well as resistance to the kinase inhibitor Gleevec®. |
CLK2 cdc-like kinase-2 (CLK2) has been shown to be involved in the control of RNA splicing through phosphorylation of serine/arginine rich (SR) proteins. Recent evidence suggests that CLK2 is involved in linking important cellular processes such as cell cycle control, apoptosis, and telomere length regulation. |
CLK3 cdc-like kinase-3 (CLK3) is a dual-specificity protein kinase found predominantly in the nucleus. CLK family kinases phosphorylate serine- and arginine-rich (SR) proteins of the spliceosomal complex suggesting that they are constituents of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. |
Cot1 Cot1 was identified by its oncogenic transforming activity in cells. This kinase can activate both the MAP kinase and JNK kinase pathways. Cot1 also activates IκB kinases, and thus induces the nuclear production of NF-κB in addition to promoting the production of TNFα and IL-2 during T lymphocyte activation. |
Csk C-terminal c-Src kinase (Csk) is a non-receptor tyrosine kinase that negatively regulates members of the Src- family of protein kinases by phosphorylation of a carboxy 1-terminal tyrosine residue. Csk is thought to be important for vascular development and mediates integrin-mediated cell adhesion signaling, suggesting a role in cancer metastasis. |
DAPK1 Death-associated protein kinase-1 (DAPK1) is a calcium/calmodulin-dependent serine/threonine kinase of the CAMK subfamily. Recent studies have shown that DAPK1 protein expression is reduced or silenced in some carcinoma cells by CpG methylation of the DAPK1 gene promoter region. |
DCAMKL2 The doublecortin and CAM kinase-like-2 (DCAMKL2) protein kinase contains an N-terminal doublecortin domain highly homologous to DCX, a microtubule-associated protein that plays an essential role in the development of the mammalian cerebral cortex. As with other members of the DCAMKL family, DCAMKL2 has microtubule binding activity and, together with DCX, may form a signaling pathway that regulates microtubules in migrating neurons. |
DDR Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are tyrosine kinase receptors activated by collagens. Aberrant expression and signaling of these receptors have been implicated in tumor invasion, atherosclerosis and liver fibrosis through its ability to influence extracellular maxtrix remodeling. |
EGFR Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a key role in the regulation of essential normal cellular processes and in the pathophysiology of hyperproliferative diseases such as cancer. Receptor autophosphoyrlation activates the intrinsic kinase activity toward heterologous substrates, as well as creating docking sites for adapter proteins to bind and nucleate signaling complexes that activate the Ras, PI 3-kinase, and PLC-γ pathway. |
EGFR (T790M) Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase known to be essential for mediation of both proliferative and survival signals to cells. Activation of the EGFR signaling pathway has been linked with increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. It has been shown experimentally that the T790M mutation leads to high-level functional resistance to Iressa®. In patients with tumors bearing Iressa®-sensitive mutations (eg. L858R, L861Q), resistant subclones containing the T790M mutation emerge in the presence of the drug. |
EGFR (T790M, L858R) Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase known to be essential for mediation of both proliferative and survival signals to cells. Activation of the EGFR signaling pathway has been linked with increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. The amino acid substitution L858R is one of several heterozygous mutations that have been identified in Non-Small-Cell Lung Cancer (NSCLC) patients who have clinical responses to the EGFR inhibitor Iressa®. There is some evidence that these mutations result in elevated activity and enhanced sensitivity to Iressa®. In patients with tumors bearing Iressa®-sensitive mutations, resistant subclones containing an additional EGFR mutation, T790M, emerge in the presence of the drug. It has been shown experimentally that the T790M mutation leads to high-level functional resistance to Iressa®. |
Ephs Eph receptors are a family of 15 receptor tyrosine kinases, constituting the largest family of receptor protein tyrosine kinases. Eph receptors consist of two subfamilies, EphA and EphB, that bind to their respective ephrin ligands. Eph-ephrin complexes initiate bi-directional signaling to mediate multiple cellular processes such as neural development, cellular migration, angiogenesis, and cystoskeletal reorganization. |
HER/ErbB HER/ErbB is the viral counterpart to the receptor tyrosine kinase EGFR. All family members heterodimerize with each other to activate downstream signaling pathways and are aberrantly expressed in many cancers, namely breast cancer. |
FAK Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a key role in integrin-mediated signaling pathways regulating cell migration. Numerous studies have linked the protein to tumor cell survival and recent evidence indicates that elevation of FAK activity in human carcinoma cells is associated with increased invasive potential. A central role in tumor formation and progression suggest that FAK is an attractive target for therapeutic intervention. |
Fer Fer is a non-receptor tyrosine kinase shown to influence cytoskeletal rearrangements and inside out signalling, cell adhesion, and cell-cell interactions. Fer has been implicated in inflammation and prostate cancer. |
Fes/Fps Fes is a non-receptor tyrosine kinase with close homology to Fer. Fes is expressed in myeloid hematopoietic cells and plays a role in their differentiation. Aberrant expression of Fes is shown in breast and prostate cancer. |
FGFR Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase. Mutations in this receptor can result in constitutive activation through receptor dimerization, kinase activation, and increased affinity for FGF. FGFR has been implicated in achondroplasia, angiogenesis, and congenital diseases. |
FGFR1 (V561M) Fibroblast growth factor receptor-1 (FGFR1) is a transmembrane receptor tyrosine kinase that can bind fibroblast growth factors and elicit a cascade of downstream signals to modulate mitogenesis and differentiation. FGFR1 has been identified as a potential target for cancer therapy. Inhibition of FGFR1 may result in antiangiogenic and antiproliferative effects in some disease states. The V561M mutation is targeted at the “gatekeeper” residue in the ATP-binding pocket of the catalytic domain. This mutation has been demonstrated to affect sensitivity to selective inhibitors. |
Fgr Fgr is a member of the Src family of non-receptor tyrosine kinases. It is expressed in neturophils, monocytes, macrophages and natural killer cells. Expression of Fgr is developmentally regulated and required for normal myelomonocytic differentiation. |
Flt Fns-like tyrosine kinase (Flt) is a receptor tyrosine kinase whose gene family encodes receptors for VEGF. VEGF is an important angiogenic factor of many solid tumors and is involved in the differentiation of endothelial cells. |
Flt4 Fms-like tyrosine kinase-4 (Flt4) is also known as VEGFR-3, and is predominantly expressed in adult lymphatic endothelium. It mediates both angiogenesis and lymphangiogenesis in tumors, and appears to play a role in tumor metastasis via the lymphatics. |
Fms/CSF-1 R Fms is a receptor tyrosine kinase and the receptor for CSF-1. Fms is expressed primarily in monocytes and macrophages, but has been detected introphoblasts of developing embryo and human breast carcinoma derived cell lines and tumor tissue. |
Fyn Fyn is a Src-family non-receptor tyrosine kinase involved in T and B cell activation as well as keratinocyte differentiation. Fyn regulates various signal transduction pathways in the central nervous system and plays an essential role in the neuronal cell differentiation and survival. |
GRK5, GRK6 G protein-coupled receptor kinases (GRKs) mediate desensitization of agonist-occupied G protein-coupled receptors (GPCRs). In addition to their function as terminators of GPCR-signaling, recent evidence suggests that phosphorylation of AT1AR by GRK5 and GRK6 results in β-arrestin 2-mediated ERK1/2 activation, a signaling pathway antagonized by GRK2/3. |
GRK7 G protein-coupled receptor kinase-7 (GRK7) belongs to the Ser/Thr protein kinase family, GRK subfamily. GRK7 catalyzes rhodopsin phosphorylation in a light-dependent manner, thereby initiating deactivation of cone opsins. |
GSK Glycogen synthase kinase (GSK) is a serine/threonine kinase that differs than most kinases in that it is active in the absence of stimulus. Two isoforms exist, GSK-3α and GSK-3β. Their function is to phosphorylate glycogen synthase and thereby inactivate it. GSK has been the target of many diabetes and Alzheimer's disease drug discovery programs. |
Hck Hematopoietic cell kinase (Hck) is a Src-family non-receptor tyrosine kinase expressed mainly in B-lymphoid and myeloid cells and is involved in signaling from antigen and cytokine receptors. Hck plays an important part in the activation of macrophages and tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and nitric oxide (NO) production. These processes result in the destruction of beta cells, important for diabetes development and progression. |
HIPK1 Homeodomain-interacting protein kinase-1 (HIPK1) belongs to the same family of nuclear protein kinases as HIPK3 (see below). It appears to modulate the transcriptional activity of p53 and Daxx. |
HIPK2 Homeodomain-interacting protein kinase-2 (HIPK2) is a serine/threonine kinase that binds and phosphorylates p53 to promote apoptosis, suggesting its role in the suppression of tumorigenesis. |
HIPK3 Homeodomain-interacting protein kinase-3 (HIPK3) belongs to a novel family of nuclear protein kinases that potentiate the transcriptional activities of homeoproteins. As such, it is likely that these proteins play roles in developmental processes such as organogenesis and the determination of cell fate in various organisms. Recent studies also indicate that increased endogenous JNK activity during prostate cancer progression causes an increase in the expression of HIPK3 and appears to be a key event in increasing the resistance of prostate cancer cells to Fas receptor-mediated apoptosis. |
IGF-IR Insulin-like growth factors (IGF) I is a tyrosine kinase receptor that is activated by both IGF I and II. The IGF system is involved in skeletal growth, and is essential for the prevention of apoptosis in most cells. Strong evidence emphasizes the role of the IGF-IR signaling in tumorigenesis. |
IKK The multi-subunit protein kinase, IKB kinase (IKK) is serine/threonine kinase that is considered the master regulator of NFKB-mediated inflammatory responses. Inhibition of IKK activity may prevent the upregulation of various proinflammatory genes, thereby reducing inflammation. In addition to inflammatory diseases such as rheumatoid arthritis, IKK has also been implicated in cancer and diabetes. |
Insulin R The insulin receptor is a tyrosine kinase receptor that when bound to insulin, initiates multiple signal transduction pathways, including JNK, PI 3-kinase, Akt, and PKC. Pharmacological intervention of these Insulin R-dependent pathways is of great interest for the treatment of insulin resistance, obesity, and diabetes. |
IRAK IL-1 receptor associated kinase (IRAK) is a serine/threonine kinase which associates with the IL-1 receptor after ligand binding, to initiate a signaling cascade that ultimate results in nuclear localization of NF-kB thought to important for inflammation. |
IRAK1 Interleukin-1 receptor-associated kinase-1 (IRAK1) is a member of the TKL subfamily of protein kinases. Recent studies suggest that IRAK1 is involved in the complex Toll-like receptor (TLR) signaling network and that regulation of IRAK1 may be linked with the pathogenesis and/or resolution of atherosclerosis. |
JAK JAKs (JAK1, JAK2, JAK3, Tyk2) are non-receptor tyrosine kinases which couple to cytokine receptors, and are activated by cytokines. The principal effectors of JAKs are the STATs, which are direct activators of transcription, but JAKs are also know to signal the Ras-dependent MAP kinase pathway and the PI 3-kinase pathway through Tec. JAK2 and JAK3 have been found be involved in T cell-derived pathologic disorders and inflammation as well as promoting cell survival and proliferation. |
JNK/SAPK The stress-activated protein kinase 1 (SAPK) family is also referred to as the jun N-terminal kinase family in light of the substrate preference of these serine/threonine kinases. In addition to regulating many biological processes including proliferation and apoptosis, the JNK/SAPK family has been implicated in many neurodegenerative diseases including Alzheimer disease, Parkinson's disease, and Amyotrophic lateral sclerosis. |
KDR Kinase insert domain-containing receptor (KDR) is a tyrosine kinase receptor that VEGF primarily signals through. The other receptor is Flt-1. KDR is expressed on endothelial cells and stimulates angiogenesis, but is also expressed on bone marrow cells, and is thought to play a role in driving the proliferation of most or all leukemic cells. |
c-Kit C-kit is a transmembrane receptor tyrosine kinase that is expressed on various of cell types, including mast cells, hematopoietic progenitor cells, melanocytes, germ cells, and gastrointestinal pacemaker cells. Activating or gain-of-function mutations in the c-kit gene have been identified many gastrointestinal stromal tumors (GISTs). |
Lck Lck is a lymphocyte-specific member of the Src-family of non-receptor tyrosine kinases. Lck is activated by the phosphatase CD45, signaling the recruitment and activation of ZAP-70, which is essential for T-cell activation. T-cells have been implicated in the pathogenesis of many diseases, including multiple sclerosis, inflammatory bowel diseases, and type I diabetes. |
LIMK LIM kinase (LIMK) is a serine/threonine kinases known to play a role in the cognitive function. LIMK regulates actin cytoskeletal reorganization, through the phosphorylation of the actin-depolymerizing factor, cofilin. Misregulation of LIMK activity has resulted in cytoskeletal defects associated with Williams Syndrome, a neurodevelopmental disorder. |
LOK Lymphocyte-oriented kinase (LOK) is a member of the STE20 kinase family and is expressed predominantly in lymphoid organs. It appears to be involved in the regulation of LFA-1-mediated lymphocyte adhesion. |
Lyn Lyn is a Src-family member expressed in B-cells and certain other lymphoid cells. Together with Syk, it is essential for signaling through the B-cell receptor/FcR, and also appears to be involved in interferon-α signaling. Reduced Lyn activity or expression leads to autoimmune diseases. |
MAPK/Erk MAPKs comprise a family of serine/threonine kinases that transduce signals in response to numerous stimuli, modulating essential cellular processes including cell division, death, proliferation, and motility. There are three categories of MAPKs: c-Jun NH2-terminal kinases (JNKs), p38 MAPK, and extracellular signal-related kinases (Erks). Because of their role in mediating cellular processes, MAPK/Erks are key targets for anti-cancer therapies. |
MAPKAP Kinase MAPK-activated protein kinases (MAPKAP K or MK) are serine/threonine kinases activated by phosphorylation by ERK1/2 and p38 MAPKs. MAPKAP kinases mediate biological processes, including cell proliferation and survival. |
MEK MAP kinase/Erk Kinase (MEK), alternatively known as MKK, is a true dual-specificity kinase, in that it phosphorylates the MAP kinases on both the threonine and tyrosine of the activation motif TEY. Inhibition of MEK as a potential anti-cancer treatment is attractive given its role in mediating the MAPK/Erk pathway. |
MELK Maternal embryonic leucine zipper kinase (MELK) is a cell cycle-regulated member of the AMPK subfamily of serine/threonine kinases. Unlike other AMPK family members, it is not activated by the LKB1 tumor suppressor kinase. There is evidence that MELK has a role in the cell cycle-regulated control of pre-mRNA splicing. |
Met Met is a tyrosine kinase receptor for Hepatocyte Growth Factor (HGF), thought to stimulate multiple cellular processes including cell proliferation, differentiation, cell migration and tumorigenesis. Chronic stimulation of Met on cancer cells is thought to play a role in metastasis. |
Mer The product of the mer proto-oncogene (Mer) is a transmembrane protein belonging to the Mer/Axl/Tyro3 receptor tyrosine kinase family. Mer is required for phagocytosis of apoptotic debris by macrophages and retinal pigment epithelial cells, and has been shown to be capable of producing an anti-apoptotic signal. Although not detected in normal lymphocytes, Mer is expressed in B- and T-cell leukemia cell lines, suggesting an association with lymphoid malignancies. |
MINK Misshapen/NIK-related kinase (MINK) is serine/threonine kinase belonging to the germinal center kinase (GCK) family kinase. MINK activates the JNK and p38 pathways and thought to play a role in brain development. |
MKK Mitogen activated protein kinase kinase is a member of the STE family of protein serine/threonine kinases. MKK3, MKK4, and MKK6 activates the p38 mitogen-activated protein kinase pathway after stimulation by pro-inflammatory cytokines and cellular stress. MKK3 is activated in human inflammatory disease, appearing to play a critical role in the TNF-stimulated signaling pathway that causes increased expression of inflammatory cytokines. |
MLK1 Mixed lineage kinase-1 (MLK1) is a MAP kinase kinase kinase capable of activating the JNK pathway. MLK family members are thought to play a role in death signaling - overexpression induces apoptotic death of cultured neuronal PC12 cells, while expression of dominant-negative forms suppress death evoked by NGF-deprivation. |
MRCKα Myotonic dystrophy kinase-related Cdc42-binding kinaseα (MRCKα) is a member of the AGC family of serine/threonine kinases. MRCKα and its closely related isoform MRCKβ preferentially phosphorylate non-muscle myosin light chain at serine 19, thus activating actin-myosin contractility. |
MSK1 Mitogen-and-stress-activated protein kinase 1 (MSK1) is a serine/threonine protein kinase thought to mediate the growth factor and stress-induced activation of CREB, believed to be important in the regulation of neuron survival, differentiation, and maturation. |
MST Mammalian STE20-like kinase (MST) is a serine/threonine protein kinase where its isoforms, MST1 and MST2 play a role in apoptosis. MST is thought to be activated via proteolytic cleavage by caspase, inducing cell death. Elevated levels of MST4 induce cellular proliferation and tumorigenesis in prostate carcinoma. |
MST3 Mammalian STE20-like protein kinase-3 (MST3) is a member of the germinal center kinase-III family. Caspase-mediated activation of MST3 appears to contribute to the onset of apoptosis. |
mTor The mammalian target of rapamycin (mTOR, a.k.a. FRAP, RAFT) is a member of the phosphoinositol kinase-related kinase (PIKK) family of serine/threonine protein kinases. mTOR plays a key role in cell growth and homeostasis and may be abnormally regulated in tumors. Recent studies have linked mTOR to several human diseases including cancer, diabetes, obesity, cardiovascular and age-related diseases and neurological disorders. |
mTor/FKBP12 The mammalian target of rapamycin (mTOR) is an important protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. Current research indicates that mTOR integrates the input from multiple upstream pathways, including insulin, growth factors and mitogens. mTOR also functions as a sensor of cellular nutrient/energy levels and redox status. The dysregulation of the mTOR pathway is implicated as a contributing factor to a number of human diseases including various types of cancer. FKBP12 is a 12kDa immunophilin that binds immunosuppressant drugs such as FK-506 (tacrolimus) and rapamycin (sirolimus). The FKBP12-rapamycin complex is able to interact with mTOR resulting in inhibition of its kinase activity. In the absence of FKBP12, mTOR is insensitive to rapamycin. |
NEK NEK are serine/threonine kinases belonging to a 11-member family sharing an amino-terminal catalytic domain related to NIMA, an Aspergillus kinase involved in the control of mitosis. |
NEK3 NIMA-related protein kinase-3 (NEK3) is one of the family of protein kinases that are structurally related to the NIMA protein of A. nidulans. It is predominantly cytoplasmic and is elevated in G0-arrested, quiescent fibroblasts. |
NEK9 NIMA-related protein kinase-3 (NEK3) is one of the family of protein kinases that are structurally related to the NIMA protein of A. nidulans. It is predominantly cytoplasmic and is elevated in G0-arrested, quiescent fibroblasts. |
p38/SAPK The p38 family refers to the SAPK2/3 kinases, a subfamily of JNK/SAPK family. P38/SAPK is a serine/threonine kinase activated by stress and inflammatory cytokines, playing an important role in many diseases including inflammation, rheumatoid arthritis, cardiovascular disease, and Alzheimer's disease. |
PAK P21-activated kinases (PAK) are serine/threonine kinases, which are activated by and are effectors of Rac, Rho and Cdc42 small GTPases in response to ras and AKT activation. Pak plays a central role in regulating cell motility and invasiveness, by modulating cytoskeletal reorganization. PAK has been implicated in colorectal cancer. |
PAK3 p21-activated protein kinase-3 (PAK3) is a member of the STE family of serine/threonine kinases. Mutations of the gene coding for PAK3 are associated with X-linked, nonsyndromic forms of mental retardation (MRX). |
PAR PAR-1 kinase is a serine/threonine kinase, initiating signal transduction events involving GSK-3 and Cdk5. PAR-1 has been implicated in neurodegenerative diseases including Alzheimer's disease. |
PDGFR Platelet-derived Growth Factor Receptors (PDGFR) are tyrosine receptors with two isoforms, α and β. PDGF signaling have been an important targets for cancer therapies due to their role in tumor angiogenesis. PDGFR antagonists, such as Gleevec, have spurred renewed interest in the PDGF in various tumor models. |
PDGFRα (D842V) Platelet-derived growth factor receptorα (PDGFRα) is a tyrosine kinase receptor involved in regulating essential cell processes such as cell proliferation, motility and survival. The D842V substitution is a somatic mutation found in some gastrointestinal stromal tumors (GISTs). Such mutations of PDGFR? may play an important role in the development of GISTs without c-Kit mutations. |
PDGFRα (V561D) Platelet-derived growth factor receptor a (PDGFRα) is a tyrosine kinase receptor involved in regulating essential cell processes such as cell proliferation, motility and survival. The V561D substitution is an activating mutation found in some patients with gastrointestinal stromal tumors. |
PDK PI (3,4,5) P3-dependent kinase 1 (PDK1) is a serine/threonine kinase stimulated by PI (3,4,5) P3. PDK activates Akt as well as p70 S6 Kinase and serves as an interesting target for cancer therapy due to its role in apoptosis and angiogenesis. |
PhKγ2 Phosphorylase kinase (PhK) is a heterotetrameric protein with the subunit structure (α β γ δ)4 that mediates the neural and hormonal regulation of glycogen breakdown by glycogen phosphorylase. Heritable deficiency of PhK is responsible for 25% of all cases of glycogen storage disease and occurs with a frequency of 1 in 100,000 births. |
PI 3-Kinase Phosphatidylinositol (PI) 3-kinase is a family of lipid kinases that mediate many intracellular signaling responses required for cell survival. PI 3-kinases have been linked with numerous disease states, including allergic response, cancer, hypertension, atherosclerosis and inflammatory diseases. |
PI3Kα/p85α, PI3Kβ/p85β Phosphatidylinositol 3-kinaseα /p85α (PI3Kα/p85α) and phosphatidylinositol 3-kinaseβ/p85β (PI3Kβ/p85β) are members of a family of class I phosphatidylinositol 3-kinase (PI3K) enzymes that phosphorylate phosphoinositides at the 3-hydroxyl of the inositol ring. These enzymes play key roles in a diverse range of cellular processes including proliferation, survival, metabolism, adhesion and cell motility. A number of point mutations, including E542K, E545K & H1047R, within the catalytic subunit of PI3Kα have been associated with tumours of the colon, stomach, breast and brain. Combined in vitro and in vivo studies have shown that these mutations confer higher lipid kinase activity than wild type, and are able to induce oncogenic transformation. A truncated variant of the p85α regulator, p65α, has also been associated with cancer. This subunit has been shown to bind but not inhibit p110, leading to constitutive PI3K activity. |
PI3Kα(E542K)/p85α (m), PI3Kβ/p85α (m), PI3Kδ/p85α (m) Phosphatidylinositol 3-kinaseα/p85α (PI3Kα/p85α), phosphatidylinositol 3-kinaseβ/p85α (PI3Kβ/p85α) and phosphatidylinositol 3-kinaseδ/p85α (PI3Kδ/p85α) are members of a family of class I phosphatidylinositol 3-kinase (PI3K) enzymes that phosphorylate phosphoinositides at the 3-hydroxyl of the inositol ring. These enzymes play key roles in a diverse range of cellular processes including proliferation, survival, metabolism, adhesion and cell motility. A number of point mutations, including E542K, E545K & H1047R, within the catalytic subunit of PI3Kα have been associated with tumours of the colon, stomach, breast and brain. Combined in vitro and in vivo studies have shown that these mutations confer higher lipid kinase activity than wild type, and are able to induce oncogenic transformation. |
PlK1 Polo-like kinase-1 (Plk1) is a member of the Plk family of serine/threonine kinases. It is an important regulator of several events during mitosis and recent studies have suggested that Plk1 is involved in both G2 and mitotic DNA damage checkpoints. Overexpression of Plk1 has been detected in a variety of cancers, and expression levels often correlate with poor prognosis.. |
PIM PIM kinases are serine/threonine protein kinases involved in cytokine-mediated cell proliferation and lymphomagenesis. PIM is thought to be an oncogene involved in regulating apoptosis, cell cycle progression and transcription by modulating various targets, including HSP90, STAT3 and STAT5. Elevated levels of Pim-1 expression have been observed in prostate cancer. |
Pim-3 The Pim kinases are a family of three vertebrate protein serine/threonine kinases (Pim-1, -2, and -3) belonging to the CAMK (calmodulin-dependent protein kinase-related) group. Pim kinases are emerging as important mediators of cytokine signaling pathways in hematopoietic cells, and have been shown to contribute to the progression of certain leukemias and solid tumors. |
PKC Protein kinase C enzymes belong to a family of serine/threonine kinases that fall into three general categories: conventional (PKC α, βI, βII, γ) isoforms that require calcium and diacylclycerol (DAG) for activity; novel (δ, ε, h, m, q) isoforms that are calcium-independent; and atypical (l, x) isoforms that are calcium and DAG-independent. PKC isozymes play an important role in cell proliferation and apoptosis in many cancers, including prostate cancer. |
PKD2 PKD2 is the major isoform of the PKD family expressed in chronic myeloid leukemia cells and is tyrosine phosphorylated by Bcr-Abl in its pleckstrin homology domain. |
PKG1α cGMP-dependent protein kinase-1α (PKG1α) is a member of the AGC family of serine/threonine kinases. The cGMP/PKG pathway has been shown to play a role in multiple physiological processes including neural cell survival and platelet activation. |
PKR The double-stranded RNA-activated protein kinase (PKR) is a serine/threonine kinase that modulates protein synthesis through the phosphorylation of translation initiation factor eIF-2a. PKR has been linked to numerous signal transduction pathways including caspase-8, JNK, p38 MAPK, and NF-κB. PKR hyperactivity has been linked to neurodegenerative diseases, such as Huntington disease, Alzheimer disease, and Amyotrophic Lateral Sclerosis. |
PLK Polo-like kinase 1 (PLK1) is member of the PLK family of serine/threonine kinases. It is an important regulator of several events during mitosis and recent studies have suggested that PLK1 is involved in both G2 and mitotic DNA damage checkpoints. |
PRAK P38-regulated/activated protein kinase (PRAK) is a serine/threonine kinase activated in response to inflammatory stimuli and environmental stress. Activated PRAK phosphorylates HSP27 at is physiologically relevant sites in vitro, suggesting a potential role for PRAK in mediating stress-induced HSP27 phosphorylation. |
PTK5 Protein tyrosine kinase-5 (PTK5) is a Src-family tyrosine kinase that may function during the G1 and S phases of the cell cycle to suppress growth. |
Pyk Proline rich kinase (Pyk)2 is a relative of the FAK non-receptor tyrosine kinase. It has been identified as an effector of both G-protein-coupled receptors and stress signals leading to the activation of MAPK and SAPK pathways. Pyk2 is thought to play a role in cytoskeletal remodeling, cellular proliferation and migration. |
Raf The Raf proteins (Raf-1, A-Raf, B-Raf) are serine/threonine kinases that bind to activated Ras, resulting in their translocation to the plasma membrane, and subsequent activation. Inhibitors of Raf are of pharmacological importance, designed to block the Raf/MEK/ERK signaling pathway hyperactivated in many cancer tumor cell lines. |
Ret Ret is a tyrosine kinase receptor involved in the activation of several signaling pathways including the PLC gamma, Ras, JNK and inositol phosphate pathways. Ret mutations have been shown to be causative in several diseases, including Hirschsprung's disease (HD), papillary thyroid carcinoma, and multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial medullary thyroid carcinoma. |
Ret (V804M) and Ret (V804L) The product of ret proto-oncogene (Ret) is a receptor tyrosine kinase that plays a critical role in the development of the enteric nervous system and the kidney. Loss-of-function mutations in Ret are implicated in Hirschsprung disease, whereas activating mutations are found in human cancers, including familial medullar thyroid carcinoma (FMTC) and multiple endocrine neoplasias 2A and 2B. The V804M substitution is one of a number of single point mutations in the kinase domain of Ret that have been identified in patients with FMTC. |
RIPK2 Receptor-interacting serine/threonine kinase 2 (RIPK2) is adapter molecule in the signal pathway involved in Toll-like receptors. |
ROK/ROCK The Rho-associated coiled-coil-containing protein serine/threonine kinases ROKa/ROCK-I and ROKb/ROCK-II are downstream effectors of the Rho/Rac family. Because they modulate cytoskeletal reorganization, these kinases are thought to play a role in cancer and cardiovascular disease. |
Ron Ron is a receptor tyrosine kinase of the MET family thought to regulate macrophage function and inflammation by binding to its ligand, macrophage-stimulating protein (MSP). Ron is involved in cell proliferation, survival and motility and is implicated in cancer and inflammatory diseases. |
Ros Ros is a transmembrane tyrosine kinase implicated in a variety of tumors due to its role as a growth factor receptor. |
Rse Rse, also known as Brt, BYK, Dtk, Etk3, Sky, Tif, or sea-related receptor tyrosine kinase, is a receptor tyrosine kinase whose primary role is to protect neurons from apoptosis. |
Rsk4 Ribosomal protein S6 kinase-4 (Rsk4) is a member of the AGC family of protein serine/threonine kinases. Unlike Rsks1-3, which are known to be important mediators of cell growth/development, Rsk4 appears to be a growth inhibitor and has been shown to participate in non-growth factor signaling such as p53-induced growth arrest. |
Rsk/MAPKAP Kinase Rsk/MAPKAP kinases are serine/threonine kinases playing a role in the Ras/MAPK signaling pathway. The Rsk 1, 2, and 3 are expressed in various human tissues and are thought to play a role in embryogenesis and brain development. |
S6 Kinase P70 S6 kinase is a serine/threonine kinase which phosphorylates the 40S ribosomal protein S6, and several translation-regulatory factors. It is thought to mediate cell-cycle progression and survival. Overexpression of S6 kinase has been observed in breast cancer and Alzheimer's disease. |
SAPK2a (T106M) Threonine 106 is one of three active site ATP-binding domain residues in SAPK2a, and its presence is responsible for the specificity demonstrated by many SAPK2a inhibitors. When this residue is mutated to methionine the potency of arylimidazole and arylpyrrole class inhibitors is greatly reduced. |
SGK Serum- and glucocorticoid-induced kinase (SGK) is a serine/threonine kinase activated by PI-3 kinase, an important modulator of growth factor and insulin dependent signaling pathways. SGK may play a role in diabetic nephropathy as increased SGK mRNA was observed in human diabetic kidney tissues. |
c-Src pp60c-Src is a non-receptor tyrosine kinase overexpressed in several epithelial and non-epithelial cancers. Its role in cell division, motility, angiogenesis and survival has made c-Src an ideal target for cancer therapy. |
Src (1-530): Disease Relevant Deletion Mutant The cellular product of src oncogene (Src) is a non-receptor tyrosine kinase that plays a central role in a variety of cell signaling pathways that regulate cell growth, differentiation, apoptosis, and other important cellular processes. The mutant form of Src (Src, 1-530) has been identified in cases of advanced colon cancer. This truncating mutation generates an open active form of Src that has been found to be transforming, tumorigenic and metastasis promoting. |
Src (T341M) The cellular product of src oncogene (Src) is a non-receptor tyrosine kinase that plays a central role in a variety of cell signaling pathways that regulate cell growth, differentiation, apoptosis, and other important cellular processes. The T341M mutation is targeted at the “gatekeeper” residue in the ATP-binding pocket of the catalytic domain. This mutation has been demonstrated to affect sensitivity to selective inhibitors. |
Syk Syk is a non-receptor tyrosine kinase related to ZAP-70 involved in signaling from the B-cell receptor and the IgE receptor. Syk binds to ITAM motifs within these receptors, and initiates signaling through the Ras, PI 3-kinase, and PLCg signaling pathways. Syk plays a critical role in intracellular signaling and thus is an important target for inflammatory diseases and respiratory disorders. |
TAK1 TGF-β activated kinase (TAK1) is a member of the serine/threonine MAPKKK family and its kinase activity is stimulated in response to TGF-β, bone morphogenic protein (BMP) and ceramide. TAK1 may play a role in the pathophysiology of renal tubular disease and lung cancer. |
TAO1 thousand and one amino acid protein kinase-1 (TAO1) is a mitogen-activated protein kinase kinase kinase (MAP3K) that phosphorylates and activates the MAP kinase kinases (MAP2Ks) MKK3 and MKK6. Recent findings suggest that TAOs are the intermediates that link certain heterotrimeric G protein-coupled receptors (GPCRs) to the p38 MAPK pathway. |
TAO2 Thousand and one amino acid protein kinase-2 (TAO2) is a mitogen-activated protein kinase kinase kinase (MAP3K) that phosphorylates and activates the MAP kinase kinases (MAP2Ks) MEK3 and MEK6. Recent findings suggest that TAOs are the intermediates that link certain heterotrimeric G protein-coupled receptors (GPCRs) to the p38 MAPK pathway. |
Tec Tyrosine kinase expressed in hepatocellular carcinoma (Tec) is the prototypical member of the Tec tyrosine kinase family. These enzymes (Tec, Btk, Itk, Bmx, and Txk) are involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein coupled receptors, and integrin molecules. They are also key players in the regulation of the immune functions. Tec is an integral component of T cell signaling and has a distinct role in T cell activation leading to IL-2 production. |
Tie2/TEK Tie2/TEK is a receptor tyrosine kinase expressed in endothelial cells and primitive hematopoietic stem cells. This kinase plays an important role in angiogenesis and vascular maintenance and has been shown to be upregulated in tumors. |
Tie2 (Y897S, Y1108F & R849W mutations) Tyrosine kinase with Ig- and EGF-homology domains-2 (Tie2) is highly expressed in endothelial cells and is crucial for angiogenesis and vascular maintenance. Binding of angiopoietin-1 to the extracellular domain of Tie2 in endothelial cells results in receptor auto-phosphorylation and the activation of several intracellular signaling pathways leading to endothelial cell migration, tube formation, sprouting and survival. Gain-of-function mutations of Tie2, such as Y897S and R849W, are associated with hereditary venous malformations (VM), typified by vascular masses containing highly dilated vessels with very few supporting smooth muscle cells. |
TLK2 The Tousled-like kinases (TLKs) comprise an evolutionarily conserved family of proteins that have been implicated in chromatin remodeling, DNA replication and DNA repair. In mammals, their activity peaks during S phase, when they phosphorylate the antisilencing function protein 1 (ASF1), a histone chaperone involved in replication-dependent chromatin assembly. |
Trk The Trk family of receptor tyrosine kinases include Trk A, Trk B, and Trk C. Trk A is the high-affinity receptor for NGF, while Trk B is the high-affinity BDNF receptor, and Trk C serves as a receptor for neurotrophin-3 (NT-3). The signaling activity of these receptors includes the Ras, MAP kinase pathway, and the PI 3-kinase pathway. Trk receptors are thought to be great targets for cancer therapy. |
TSSK2 Testis specific serine kinases (TSSK) are novel serine/threonine protein kinases expressed exclusively in spermatids undergoing spermiogenesis. The three isoforms, TSSK1, 2, and 3, are expressed in the testis of sexually mature males. |
Txk Txk is a member of the Tec sub-family of non-receptor tyrosine kinases, consisting of Tec, Btk, Itk, Bmx, and Txk, all of which appear to play key roles in lymphocyte signalling pathways. Txk has been shown to specifically regulate interferon- gene expression in Th1/Th0 cells by binding to the interferon- promoter and enhancing transcriptional activity. |
ULK2 Unc-51-like kinase-2 (ULK2) is an atypical Ser/Thr kinase belonging to the ULK1 subfamily. ULK enzymes appear to be involved in neuronal differentiation and axonal elongation. |
ULK3 Unc-51-like kinase-3 (ULK3) is an atypical Ser/Thr kinase belonging to the ULK1 subfamily. ULK enzymes appear to be involved in neuronal differentiation and axonal elongation. |
VRK2 Vaccinia-related kinase-2 is a member of the VRK family of protein kinases; a group of enzymes characterized by their notable sequence homology to the vaccinia virus-encoded B1 kinase (vvB1). VRK2 is a Ser/Thr kinase that has a wide tissue distribution and may play a role during embryonic development of hematopoiesis. |
Wee Wee kinases are tyrosine kinases that block mitosis entry by inhibiting the activity of mitotic cyclin-dependent kinase, Cdk1 by phosphorylation. |
Yes Yes is a member of the Src family of non-receptor tyrosine kinases. Like Src, Yes amplifies signals generated by various receptors, in many cases duplicating the functionality of Src. Expression of Yes is elevated in melanocytes and in melanoma cells, and Yes kinase activity is stimulated by neurotrophins, which are mitogenic and metastatic factors for melanoma cells. In additon to melanoma, yes is also over-expressed in colon cancer. |
ZAP-70 ZAP-70 is a non-receptor tyrosine kinase of the Syk family. ZAP-70 is involved in T cell receptor signaling through its recruitment to T-cell receptor complexes once T-cells are activated by antigen presenting cells. ZAP-70, once activated, phosphorylates and activates several downstream targets, including SLP-76, PLCgamma1 and LAT. ZAP-70 has been identified as the newest biomarker for Chronic Lymphocytic Leukemia (CLL) prognosis. |
ZIPK Zipper interacting protein kinase (ZIPK) is a serine/threonine kinase involved in apoptosis. ZIPK is found in nuclear bodies or Kreb's bodies, nuclear structures involved in the regulation of transcription, tumor suppression, and apoptosis. |
