Motif 1125 (n=88)

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uniprot genes site source protein function
A0A0A6YYL1 ST20-MTHFS Y59 ochoa 5-formyltetrahydrofolate cyclo-ligase (EC 6.3.3.2) None
A0A0B4J203 None Y609 ochoa receptor protein-tyrosine kinase (EC 2.7.10.1) None
O60674 JAK2 Y1008 psp Tyrosine-protein kinase JAK2 (EC 2.7.10.2) (Janus kinase 2) (JAK-2) Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin receptor (MPL/TPOR); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:15690087, PubMed:7615558, PubMed:9657743, PubMed:15899890). Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:15690087, PubMed:9618263). Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain (PubMed:9657743). Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430). Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214). Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980). Up-regulates the potassium voltage-gated channel activity of KCNA3 (PubMed:25644777). {ECO:0000269|PubMed:12023369, ECO:0000269|PubMed:15690087, ECO:0000269|PubMed:19783980, ECO:0000269|PubMed:20098430, ECO:0000269|PubMed:21368206, ECO:0000269|PubMed:21423214, ECO:0000269|PubMed:25644777, ECO:0000269|PubMed:7615558, ECO:0000269|PubMed:9618263, ECO:0000269|PubMed:9657743}.
P00519 ABL1 Y393 ochoa|psp Tyrosine-protein kinase ABL1 (EC 2.7.10.2) (Abelson murine leukemia viral oncogene homolog 1) (Abelson tyrosine-protein kinase 1) (Proto-oncogene c-Abl) (p150) Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9 (PubMed:22810897). Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. In response to oxidative stress, phosphorylates serine/threonine kinase PRKD2 at 'Tyr-717' (PubMed:28428613). ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-153' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. ABL1 also acts as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Regulates T-cell differentiation in a TBX21-dependent manner (By similarity). Positively regulates chemokine-mediated T-cell migration, polarization, and homing to lymph nodes and immune-challenged tissues, potentially via activation of NEDD9/HEF1 and RAP1 (By similarity). Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity (By similarity). {ECO:0000250|UniProtKB:P00520, ECO:0000269|PubMed:10391250, ECO:0000269|PubMed:11971963, ECO:0000269|PubMed:12379650, ECO:0000269|PubMed:12531427, ECO:0000269|PubMed:12672821, ECO:0000269|PubMed:15031292, ECO:0000269|PubMed:15556646, ECO:0000269|PubMed:15657060, ECO:0000269|PubMed:15886098, ECO:0000269|PubMed:16424036, ECO:0000269|PubMed:16678104, ECO:0000269|PubMed:16943190, ECO:0000269|PubMed:17306540, ECO:0000269|PubMed:17623672, ECO:0000269|PubMed:18328268, ECO:0000269|PubMed:18945674, ECO:0000269|PubMed:19891780, ECO:0000269|PubMed:20357770, ECO:0000269|PubMed:20417104, ECO:0000269|PubMed:22810897, ECO:0000269|PubMed:28428613, ECO:0000269|PubMed:9037071, ECO:0000269|PubMed:9144171, ECO:0000269|PubMed:9461559}.
P04049 RAF1 S499 ochoa|psp RAF proto-oncogene serine/threonine-protein kinase (EC 2.7.11.1) (Proto-oncogene c-RAF) (cRaf) (Raf-1) Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation. {ECO:0000269|PubMed:11427728, ECO:0000269|PubMed:11719507, ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:15618521, ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:16892053, ECO:0000269|PubMed:16924233, ECO:0000269|PubMed:9360956}.
P04626 ERBB2 T875 ochoa Receptor tyrosine-protein kinase erbB-2 (EC 2.7.10.1) (Metastatic lymph node gene 19 protein) (MLN 19) (Proto-oncogene Neu) (Proto-oncogene c-ErbB-2) (Tyrosine kinase-type cell surface receptor HER2) (p185erbB2) (CD antigen CD340) Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. {ECO:0000305}.; FUNCTION: In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth. {ECO:0000269|PubMed:10358079, ECO:0000269|PubMed:15380516, ECO:0000269|PubMed:21555369}.
P04629 NTRK1 Y680 ochoa|psp High affinity nerve growth factor receptor (EC 2.7.10.1) (Neurotrophic tyrosine kinase receptor type 1) (TRK1-transforming tyrosine kinase protein) (Tropomyosin-related kinase A) (Tyrosine kinase receptor) (Tyrosine kinase receptor A) (Trk-A) (gp140trk) (p140-TrkA) Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1281417, PubMed:15488758, PubMed:17196528, PubMed:1849459, PubMed:1850821, PubMed:22649032, PubMed:27445338, PubMed:8325889). Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. {ECO:0000250|UniProtKB:P35739, ECO:0000250|UniProtKB:Q3UFB7, ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:17196528, ECO:0000269|PubMed:1849459, ECO:0000269|PubMed:1850821, ECO:0000269|PubMed:22649032, ECO:0000269|PubMed:27445338, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:8155326, ECO:0000269|PubMed:8325889}.; FUNCTION: [Isoform TrkA-III]: Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed. {ECO:0000269|PubMed:15488758}.
P04629 NTRK1 Y681 psp High affinity nerve growth factor receptor (EC 2.7.10.1) (Neurotrophic tyrosine kinase receptor type 1) (TRK1-transforming tyrosine kinase protein) (Tropomyosin-related kinase A) (Tyrosine kinase receptor) (Tyrosine kinase receptor A) (Trk-A) (gp140trk) (p140-TrkA) Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1281417, PubMed:15488758, PubMed:17196528, PubMed:1849459, PubMed:1850821, PubMed:22649032, PubMed:27445338, PubMed:8325889). Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. {ECO:0000250|UniProtKB:P35739, ECO:0000250|UniProtKB:Q3UFB7, ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:17196528, ECO:0000269|PubMed:1849459, ECO:0000269|PubMed:1850821, ECO:0000269|PubMed:22649032, ECO:0000269|PubMed:27445338, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:8155326, ECO:0000269|PubMed:8325889}.; FUNCTION: [Isoform TrkA-III]: Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed. {ECO:0000269|PubMed:15488758}.
P06213 INSR Y1189 ochoa|psp Insulin receptor (IR) (EC 2.7.10.1) (CD antigen CD220) [Cleaved into: Insulin receptor subunit alpha; Insulin receptor subunit beta] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. In adipocytes, inhibits lipolysis (By similarity). {ECO:0000250|UniProtKB:P15208, ECO:0000269|PubMed:12138094, ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16831875, ECO:0000269|PubMed:8257688, ECO:0000269|PubMed:8276809, ECO:0000269|PubMed:8452530, ECO:0000269|PubMed:9428692}.
P06213 INSR Y1190 ochoa|psp Insulin receptor (IR) (EC 2.7.10.1) (CD antigen CD220) [Cleaved into: Insulin receptor subunit alpha; Insulin receptor subunit beta] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. In adipocytes, inhibits lipolysis (By similarity). {ECO:0000250|UniProtKB:P15208, ECO:0000269|PubMed:12138094, ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16831875, ECO:0000269|PubMed:8257688, ECO:0000269|PubMed:8276809, ECO:0000269|PubMed:8452530, ECO:0000269|PubMed:9428692}.
P06239 LCK Y394 ochoa|psp Tyrosine-protein kinase Lck (EC 2.7.10.2) (Leukocyte C-terminal Src kinase) (LSK) (Lymphocyte cell-specific protein-tyrosine kinase) (Protein YT16) (Proto-oncogene Lck) (T cell-specific protein-tyrosine kinase) (p56-LCK) Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. Interacts with FYB2 (PubMed:27335501). {ECO:0000269|PubMed:16339550, ECO:0000269|PubMed:16709819, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20851766, ECO:0000269|PubMed:21269457, ECO:0000269|PubMed:22080863, ECO:0000269|PubMed:27335501, ECO:0000269|PubMed:38614099}.
P06241 FYN Y420 ochoa|psp Tyrosine-protein kinase Fyn (EC 2.7.10.2) (Proto-oncogene Syn) (Proto-oncogene c-Fyn) (Src-like kinase) (SLK) (p59-Fyn) Non-receptor tyrosine-protein kinase that plays a role in many biological processes including regulation of cell growth and survival, cell adhesion, integrin-mediated signaling, cytoskeletal remodeling, cell motility, immune response and axon guidance (PubMed:11536198, PubMed:15489916, PubMed:15557120, PubMed:16387660, PubMed:20100835, PubMed:7568038, PubMed:7822789). Inactive FYN is phosphorylated on its C-terminal tail within the catalytic domain (PubMed:15489916). Following activation by PKA, the protein subsequently associates with PTK2/FAK1, allowing PTK2/FAK1 phosphorylation, activation and targeting to focal adhesions (PubMed:15489916). Involved in the regulation of cell adhesion and motility through phosphorylation of CTNNB1 (beta-catenin) and CTNND1 (delta-catenin) (PubMed:17194753). Regulates cytoskeletal remodeling by phosphorylating several proteins including the actin regulator WAS and the microtubule-associated proteins MAP2 and MAPT (PubMed:14707117, PubMed:15536091). Promotes cell survival by phosphorylating AGAP2/PIKE-A and preventing its apoptotic cleavage (PubMed:16841086). Participates in signal transduction pathways that regulate the integrity of the glomerular slit diaphragm (an essential part of the glomerular filter of the kidney) by phosphorylating several slit diaphragm components including NPHS1, KIRREL1 and TRPC6 (PubMed:14761972, PubMed:18258597, PubMed:19179337). Plays a role in neural processes by phosphorylating DPYSL2, a multifunctional adapter protein within the central nervous system, ARHGAP32, a regulator for Rho family GTPases implicated in various neural functions, and SNCA, a small pre-synaptic protein (PubMed:11162638, PubMed:12788081, PubMed:19652227). Involved in reelin signaling by mediating phosphorylation of DAB1 following reelin (RELN)-binding to its receptor (By similarity). Participates in the downstream signaling pathways that lead to T-cell differentiation and proliferation following T-cell receptor (TCR) stimulation (PubMed:22080863). Phosphorylates PTK2B/PYK2 in response to T-cell receptor activation (PubMed:20028775). Also participates in negative feedback regulation of TCR signaling through phosphorylation of PAG1, thereby promoting interaction between PAG1 and CSK and recruitment of CSK to lipid rafts (PubMed:18056706). CSK maintains LCK and FYN in an inactive form (By similarity). Promotes CD28-induced phosphorylation of VAV1 (PubMed:11005864). In mast cells, phosphorylates CLNK after activation of immunoglobulin epsilon receptor signaling (By similarity). Can also promote CD244-mediated NK cell activation (PubMed:15713798). {ECO:0000250|UniProtKB:P39688, ECO:0000269|PubMed:11005864, ECO:0000269|PubMed:11162638, ECO:0000269|PubMed:11536198, ECO:0000269|PubMed:12788081, ECO:0000269|PubMed:14707117, ECO:0000269|PubMed:14761972, ECO:0000269|PubMed:15536091, ECO:0000269|PubMed:15557120, ECO:0000269|PubMed:15713798, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:16841086, ECO:0000269|PubMed:17194753, ECO:0000269|PubMed:18056706, ECO:0000269|PubMed:18258597, ECO:0000269|PubMed:19179337, ECO:0000269|PubMed:19652227, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:22080863, ECO:0000269|PubMed:7568038, ECO:0000269|PubMed:7822789, ECO:0000303|PubMed:15489916}.
P07332 FES Y713 ochoa|psp Tyrosine-protein kinase Fes/Fps (EC 2.7.10.2) (Feline sarcoma/Fujinami avian sarcoma oncogene homolog) (Proto-oncogene c-Fes) (Proto-oncogene c-Fps) (p93c-fes) Tyrosine-protein kinase that acts downstream of cell surface receptors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, cell attachment and cell spreading. Plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Acts down-stream of the activated FCER1 receptor and the mast/stem cell growth factor receptor KIT. Plays a role in the regulation of mast cell degranulation. Plays a role in the regulation of cell differentiation and promotes neurite outgrowth in response to NGF signaling. Plays a role in cell scattering and cell migration in response to HGF-induced activation of EZR. Phosphorylates BCR and down-regulates BCR kinase activity. Phosphorylates HCLS1/HS1, PECAM1, STAT3 and TRIM28. {ECO:0000269|PubMed:11509660, ECO:0000269|PubMed:15302586, ECO:0000269|PubMed:15485904, ECO:0000269|PubMed:16455651, ECO:0000269|PubMed:17595334, ECO:0000269|PubMed:18046454, ECO:0000269|PubMed:19001085, ECO:0000269|PubMed:19051325, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:2656706, ECO:0000269|PubMed:8955135}.
P07333 CSF1R Y809 psp Macrophage colony-stimulating factor 1 receptor (CSF-1 receptor) (CSF-1-R) (CSF-1R) (M-CSF-R) (EC 2.7.10.1) (Proto-oncogene c-Fms) (CD antigen CD115) Tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of pro-inflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding, including the ERK1/2 and the JNK pathway (PubMed:20504948, PubMed:30982609). Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. In the central nervous system, may play a role in the development of microglia macrophages (PubMed:30982608). {ECO:0000269|PubMed:12882960, ECO:0000269|PubMed:15117969, ECO:0000269|PubMed:16170366, ECO:0000269|PubMed:16337366, ECO:0000269|PubMed:16648572, ECO:0000269|PubMed:17121910, ECO:0000269|PubMed:18467591, ECO:0000269|PubMed:18814279, ECO:0000269|PubMed:19193011, ECO:0000269|PubMed:19934330, ECO:0000269|PubMed:20489731, ECO:0000269|PubMed:20504948, ECO:0000269|PubMed:20829061, ECO:0000269|PubMed:30982608, ECO:0000269|PubMed:30982609, ECO:0000269|PubMed:7683918}.
P07947 YES1 Y426 ochoa|psp Tyrosine-protein kinase Yes (EC 2.7.10.2) (Proto-oncogene c-Yes) (p61-Yes) Non-receptor protein tyrosine kinase that is involved in the regulation of cell growth and survival, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. Stimulation by receptor tyrosine kinases (RTKs) including EGFR, PDGFR, CSF1R and FGFR leads to recruitment of YES1 to the phosphorylated receptor, and activation and phosphorylation of downstream substrates. Upon EGFR activation, promotes the phosphorylation of PARD3 to favor epithelial tight junction assembly. Participates in the phosphorylation of specific junctional components such as CTNND1 by stimulating the FYN and FER tyrosine kinases at cell-cell contacts. Upon T-cell stimulation by CXCL12, phosphorylates collapsin response mediator protein 2/DPYSL2 and induces T-cell migration. Participates in CD95L/FASLG signaling pathway and mediates AKT-mediated cell migration. Plays a role in cell cycle progression by phosphorylating the cyclin-dependent kinase 4/CDK4 thus regulating the G1 phase. Also involved in G2/M progression and cytokinesis. Catalyzes phosphorylation of organic cation transporter OCT2 which induces its transport activity (PubMed:26979622). {ECO:0000269|PubMed:11901164, ECO:0000269|PubMed:18479465, ECO:0000269|PubMed:19276087, ECO:0000269|PubMed:21566460, ECO:0000269|PubMed:21713032, ECO:0000269|PubMed:26979622}.
P07948 LYN Y397 ochoa|psp Tyrosine-protein kinase Lyn (EC 2.7.10.2) (Lck/Yes-related novel protein tyrosine kinase) (V-yes-1 Yamaguchi sarcoma viral related oncogene homolog) (p53Lyn) (p56Lyn) Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Involved in the regulation of endothelial activation, neutrophil adhesion and transendothelial migration (PubMed:36932076). Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-107'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (By similarity). Phosphorylates CLNK (By similarity). Phosphorylates BCAR1/CAS and NEDD9/HEF1 (PubMed:9020138). {ECO:0000250|UniProtKB:P25911, ECO:0000269|PubMed:10574931, ECO:0000269|PubMed:10748115, ECO:0000269|PubMed:10891478, ECO:0000269|PubMed:11435302, ECO:0000269|PubMed:11517336, ECO:0000269|PubMed:11825908, ECO:0000269|PubMed:14726379, ECO:0000269|PubMed:15795233, ECO:0000269|PubMed:16467205, ECO:0000269|PubMed:17640867, ECO:0000269|PubMed:17977829, ECO:0000269|PubMed:18056483, ECO:0000269|PubMed:18070987, ECO:0000269|PubMed:18235045, ECO:0000269|PubMed:18577747, ECO:0000269|PubMed:18802065, ECO:0000269|PubMed:19290919, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:36122175, ECO:0000269|PubMed:36932076, ECO:0000269|PubMed:7687428, ECO:0000269|PubMed:9020138}.
P07949 RET Y905 psp Proto-oncogene tyrosine-protein kinase receptor Ret (EC 2.7.10.1) (Cadherin family member 12) (Proto-oncogene c-Ret) [Cleaved into: Soluble RET kinase fragment; Extracellular cell-membrane anchored RET cadherin 120 kDa fragment] Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15) (PubMed:20064382, PubMed:20616503, PubMed:20702524, PubMed:21357690, PubMed:21454698, PubMed:24560924, PubMed:28846097, PubMed:28846099, PubMed:28953886, PubMed:31118272). In contrast to most receptor tyrosine kinases, RET requires not only its cognate ligands but also coreceptors, for activation (PubMed:21994944, PubMed:23333276, PubMed:28846097, PubMed:28846099, PubMed:28953886). GDNF ligands (GDNF, NRTN, ARTN, PSPN and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways (PubMed:21994944, PubMed:23333276, PubMed:24560924, PubMed:25242331, PubMed:28846097, PubMed:28846099, PubMed:28953886). Acts as a dependence receptor via the GDNF-GFRA1 signaling: in the presence of the ligand GDNF in somatotrophs within pituitary, promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF (PubMed:20616503, PubMed:21994944). Required for the molecular mechanisms orchestration during intestine organogenesis via the ARTN-GFRA3 signaling: involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue (By similarity). Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses (PubMed:28846097, PubMed:28846099, PubMed:28953886). Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner (PubMed:20702524, PubMed:21357690). Also active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage (PubMed:21357690). Triggers the differentiation of rapidly adapting (RA) mechanoreceptors (PubMed:20064382). Involved in the development of the neural crest (By similarity). Regulates nociceptor survival and size (By similarity). Phosphorylates PTK2/FAK1 (PubMed:21454698). {ECO:0000250|UniProtKB:P35546, ECO:0000269|PubMed:20064382, ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698, ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:24560924, ECO:0000269|PubMed:25242331, ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886, ECO:0000269|PubMed:31118272}.; FUNCTION: [Isoform 1]: Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL. {ECO:0000269|PubMed:28846099}.
P08069 IGF1R Y1165 ochoa|psp Insulin-like growth factor 1 receptor (EC 2.7.10.1) (Insulin-like growth factor I receptor) (IGF-I receptor) (CD antigen CD221) [Cleaved into: Insulin-like growth factor 1 receptor alpha chain; Insulin-like growth factor 1 receptor beta chain] Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.; FUNCTION: When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.
P08069 IGF1R Y1166 ochoa|psp Insulin-like growth factor 1 receptor (EC 2.7.10.1) (Insulin-like growth factor I receptor) (IGF-I receptor) (CD antigen CD221) [Cleaved into: Insulin-like growth factor 1 receptor alpha chain; Insulin-like growth factor 1 receptor beta chain] Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.; FUNCTION: When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.
P08581 MET Y1234 ochoa|psp Hepatocyte growth factor receptor (HGF receptor) (EC 2.7.10.1) (HGF/SF receptor) (Proto-oncogene c-Met) (Scatter factor receptor) (SF receptor) (Tyrosine-protein kinase Met) Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of neuronal precursors, angiogenesis and kidney formation. During skeletal muscle development, it is crucial for the migration of muscle progenitor cells and for the proliferation of secondary myoblasts (By similarity). In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Also promotes differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity). {ECO:0000250|UniProtKB:P16056}.; FUNCTION: (Microbial infection) Acts as a receptor for Listeria monocytogenes internalin InlB, mediating entry of the pathogen into cells. {ECO:0000269|PubMed:11081636, ECO:0000305|PubMed:17662939, ECO:0000305|PubMed:19900460}.
P08631 HCK Y411 ochoa|psp Tyrosine-protein kinase HCK (EC 2.7.10.2) (Hematopoietic cell kinase) (Hemopoietic cell kinase) (p59-HCK/p60-HCK) (p59Hck) (p61Hck) Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS. {ECO:0000269|PubMed:10092522, ECO:0000269|PubMed:10779760, ECO:0000269|PubMed:10973280, ECO:0000269|PubMed:11741929, ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:12411494, ECO:0000269|PubMed:15010462, ECO:0000269|PubMed:15952790, ECO:0000269|PubMed:15998323, ECO:0000269|PubMed:17310994, ECO:0000269|PubMed:17535448, ECO:0000269|PubMed:19114024, ECO:0000269|PubMed:19903482, ECO:0000269|PubMed:20452982, ECO:0000269|PubMed:21338576, ECO:0000269|PubMed:7535819, ECO:0000269|PubMed:8132624, ECO:0000269|PubMed:9406996, ECO:0000269|PubMed:9407116}.
P09619 PDGFRB Y857 psp Platelet-derived growth factor receptor beta (PDGF-R-beta) (PDGFR-beta) (EC 2.7.10.1) (Beta platelet-derived growth factor receptor) (Beta-type platelet-derived growth factor receptor) (CD140 antigen-like family member B) (Platelet-derived growth factor receptor 1) (PDGFR-1) (CD antigen CD140b) Tyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:11297552, ECO:0000269|PubMed:11331881, ECO:0000269|PubMed:1314164, ECO:0000269|PubMed:1396585, ECO:0000269|PubMed:1653029, ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:1846866, ECO:0000269|PubMed:20494825, ECO:0000269|PubMed:20529858, ECO:0000269|PubMed:21098708, ECO:0000269|PubMed:21679854, ECO:0000269|PubMed:21733313, ECO:0000269|PubMed:2554309, ECO:0000269|PubMed:26599395, ECO:0000269|PubMed:2835772, ECO:0000269|PubMed:2850496, ECO:0000269|PubMed:7685273, ECO:0000269|PubMed:7691811, ECO:0000269|PubMed:7692233, ECO:0000269|PubMed:8195171}.
P09769 FGR Y412 ochoa|psp Tyrosine-protein kinase Fgr (EC 2.7.10.2) (Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog) (Proto-oncogene c-Fgr) (p55-Fgr) (p58-Fgr) (p58c-Fgr) Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocyte, macrophage and mast cell functions, cytoskeleton remodeling in response to extracellular stimuli, phagocytosis, cell adhesion and migration. Promotes mast cell degranulation, release of inflammatory cytokines and IgE-mediated anaphylaxis. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as MS4A2/FCER1B, FCGR2A and/or FCGR2B. Acts downstream of ITGB1 and ITGB2, and regulates actin cytoskeleton reorganization, cell spreading and adhesion. Depending on the context, activates or inhibits cellular responses. Functions as a negative regulator of ITGB2 signaling, phagocytosis and SYK activity in monocytes. Required for normal ITGB1 and ITGB2 signaling, normal cell spreading and adhesion in neutrophils and macrophages. Functions as a positive regulator of cell migration and regulates cytoskeleton reorganization via RAC1 activation. Phosphorylates SYK (in vitro) and promotes SYK-dependent activation of AKT1 and MAP kinase signaling. Phosphorylates PLD2 in antigen-stimulated mast cells, leading to PLD2 activation and the production of the signaling molecules lysophosphatidic acid and diacylglycerol. Promotes activation of PIK3R1. Phosphorylates FASLG, and thereby regulates its ubiquitination and subsequent internalization. Phosphorylates ABL1. Promotes phosphorylation of CBL, CTTN, PIK3R1, PTK2/FAK1, PTK2B/PYK2 and VAV2. Phosphorylates HCLS1 that has already been phosphorylated by SYK, but not unphosphorylated HCLS1. Together with CLNK, it acts as a negative regulator of natural killer cell-activating receptors and inhibits interferon-gamma production (By similarity). {ECO:0000250|UniProtKB:P14234, ECO:0000269|PubMed:10739672, ECO:0000269|PubMed:17164290, ECO:0000269|PubMed:1737799, ECO:0000269|PubMed:7519620}.
P10721 KIT Y823 psp Mast/stem cell growth factor receptor Kit (SCFR) (EC 2.7.10.1) (Piebald trait protein) (PBT) (Proto-oncogene c-Kit) (Tyrosine-protein kinase Kit) (p145 c-kit) (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (CD antigen CD117) Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1. {ECO:0000269|PubMed:10397721, ECO:0000269|PubMed:12444928, ECO:0000269|PubMed:12511554, ECO:0000269|PubMed:12878163, ECO:0000269|PubMed:17904548, ECO:0000269|PubMed:19265199, ECO:0000269|PubMed:21135090, ECO:0000269|PubMed:21640708, ECO:0000269|PubMed:7520444, ECO:0000269|PubMed:9528781}.
P11362 FGFR1 Y653 ochoa|psp Fibroblast growth factor receptor 1 (FGFR-1) (EC 2.7.10.1) (Basic fibroblast growth factor receptor 1) (BFGFR) (bFGF-R-1) (Fms-like tyrosine kinase 2) (FLT-2) (N-sam) (Proto-oncogene c-Fgr) (CD antigen CD331) Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation. {ECO:0000250|UniProtKB:P16092, ECO:0000269|PubMed:10830168, ECO:0000269|PubMed:11353842, ECO:0000269|PubMed:12181353, ECO:0000269|PubMed:1379697, ECO:0000269|PubMed:1379698, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19261810, ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:20133753, ECO:0000269|PubMed:20139426, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:8622701, ECO:0000269|PubMed:8663044}.
P11362 FGFR1 Y654 ochoa|psp Fibroblast growth factor receptor 1 (FGFR-1) (EC 2.7.10.1) (Basic fibroblast growth factor receptor 1) (BFGFR) (bFGF-R-1) (Fms-like tyrosine kinase 2) (FLT-2) (N-sam) (Proto-oncogene c-Fgr) (CD antigen CD331) Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation. {ECO:0000250|UniProtKB:P16092, ECO:0000269|PubMed:10830168, ECO:0000269|PubMed:11353842, ECO:0000269|PubMed:12181353, ECO:0000269|PubMed:1379697, ECO:0000269|PubMed:1379698, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19261810, ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:20133753, ECO:0000269|PubMed:20139426, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:8622701, ECO:0000269|PubMed:8663044}.
P12931 SRC Y419 ochoa|psp Proto-oncogene tyrosine-protein kinase Src (EC 2.7.10.2) (Proto-oncogene c-Src) (pp60c-src) (p60-Src) Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors (PubMed:34234773). Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (PubMed:21411625). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Phosphorylates PKP3 at 'Tyr-195' in response to reactive oxygen species, which may cause the release of PKP3 from desmosome cell junctions into the cytoplasm (PubMed:25501895). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (By similarity). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1 (PubMed:11389730). Plays a role in EGF-mediated calcium-activated chloride channel activation (PubMed:18586953). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (PubMed:7853507). Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:14585963, PubMed:8755529). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation (PubMed:16186108). Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731' (PubMed:20100835, PubMed:21309750). Enhances RIGI-elicited antiviral signaling (PubMed:19419966). Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376' (PubMed:14585963). Phosphorylates BCAR1 at 'Tyr-128' (PubMed:22710723). Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity (PubMed:20525694). Phosphorylates synaptic vesicle protein synaptophysin (SYP) (By similarity). Involved in anchorage-independent cell growth (PubMed:19307596). Required for podosome formation (By similarity). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159). Phosphorylates OTUB1, promoting deubiquitination of RPTOR (PubMed:35927303). Phosphorylates caspase CASP8 at 'Tyr-380' which negatively regulates CASP8 processing and activation, down-regulating CASP8 proapoptotic function (PubMed:16619028). {ECO:0000250|UniProtKB:P05480, ECO:0000250|UniProtKB:Q9WUD9, ECO:0000269|PubMed:11389730, ECO:0000269|PubMed:12615910, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:16186108, ECO:0000269|PubMed:16619028, ECO:0000269|PubMed:18586953, ECO:0000269|PubMed:19307596, ECO:0000269|PubMed:19419966, ECO:0000269|PubMed:20100835, ECO:0000269|PubMed:20525694, ECO:0000269|PubMed:21309750, ECO:0000269|PubMed:21411625, ECO:0000269|PubMed:22710723, ECO:0000269|PubMed:25501895, ECO:0000269|PubMed:25731159, ECO:0000269|PubMed:34234773, ECO:0000269|PubMed:35927303, ECO:0000269|PubMed:7853507, ECO:0000269|PubMed:8755529, ECO:0000269|PubMed:8759729, ECO:0000305|PubMed:11964124, ECO:0000305|PubMed:8672527, ECO:0000305|PubMed:9442882}.; FUNCTION: [Isoform 1]: Non-receptor protein tyrosine kinase which phosphorylates synaptophysin with high affinity. {ECO:0000250|UniProtKB:Q9WUD9}.; FUNCTION: [Isoform 2]: Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation (By similarity). The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (By similarity). Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs (By similarity). Plays a role in L1CAM-mediated neurite elongation, possibly by acting downstream of L1CAM to drive cytoskeletal rearrangements involved in neurite outgrowth (By similarity). {ECO:0000250|UniProtKB:Q9WUD9}.; FUNCTION: [Isoform 3]: Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation (By similarity). The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (By similarity). Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs (By similarity). Plays a role in neurite elongation (By similarity). {ECO:0000250|UniProtKB:Q9WUD9}.
P15056 BRAF S607 ochoa Serine/threonine-protein kinase B-raf (EC 2.7.11.1) (Proto-oncogene B-Raf) (p94) (v-Raf murine sarcoma viral oncogene homolog B1) Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role in the postsynaptic responses of hippocampal neurons (PubMed:1508179). {ECO:0000269|PubMed:1508179, ECO:0000269|PubMed:21441910, ECO:0000269|PubMed:29433126, ECO:0000269|PubMed:36402789, ECO:0000305}.
P16234 PDGFRA Y849 ochoa|psp Platelet-derived growth factor receptor alpha (PDGF-R-alpha) (PDGFR-alpha) (EC 2.7.10.1) (Alpha platelet-derived growth factor receptor) (Alpha-type platelet-derived growth factor receptor) (CD140 antigen-like family member A) (CD140a antigen) (Platelet-derived growth factor alpha receptor) (Platelet-derived growth factor receptor 2) (PDGFR-2) (CD antigen CD140a) Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor. {ECO:0000269|PubMed:10734113, ECO:0000269|PubMed:10947961, ECO:0000269|PubMed:11297552, ECO:0000269|PubMed:12522257, ECO:0000269|PubMed:1646396, ECO:0000269|PubMed:17087943, ECO:0000269|PubMed:1709159, ECO:0000269|PubMed:17141222, ECO:0000269|PubMed:20972453, ECO:0000269|PubMed:21224473, ECO:0000269|PubMed:21596750, ECO:0000269|PubMed:2554309, ECO:0000269|PubMed:8188664, ECO:0000269|PubMed:8760137, ECO:0000269|PubMed:8943348}.
P16591 FER Y714 ochoa|psp Tyrosine-protein kinase Fer (EC 2.7.10.2) (Feline encephalitis virus-related kinase FER) (Fujinami poultry sarcoma/Feline sarcoma-related protein Fer) (Proto-oncogene c-Fer) (Tyrosine kinase 3) (p94-Fer) Tyrosine-protein kinase that acts downstream of cell surface receptors for growth factors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, lamellipodia formation, cell adhesion, cell migration and chemotaxis. Acts downstream of EGFR, KIT, PDGFRA and PDGFRB. Acts downstream of EGFR to promote activation of NF-kappa-B and cell proliferation. May play a role in the regulation of the mitotic cell cycle. Plays a role in the insulin receptor signaling pathway and in activation of phosphatidylinositol 3-kinase. Acts downstream of the activated FCER1 receptor and plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Plays a role in the regulation of mast cell degranulation. Plays a role in leukocyte recruitment and diapedesis in response to bacterial lipopolysaccharide (LPS). Plays a role in synapse organization, trafficking of synaptic vesicles, the generation of excitatory postsynaptic currents and neuron-neuron synaptic transmission. Plays a role in neuronal cell death after brain damage. Phosphorylates CTTN, CTNND1, PTK2/FAK1, GAB1, PECAM1 and PTPN11. May phosphorylate JUP and PTPN1. Can phosphorylate STAT3, but the biological relevance of this depends on cell type and stimulus. {ECO:0000269|PubMed:12972546, ECO:0000269|PubMed:14517306, ECO:0000269|PubMed:19147545, ECO:0000269|PubMed:19339212, ECO:0000269|PubMed:19738202, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21518868, ECO:0000269|PubMed:22223638, ECO:0000269|PubMed:7623846, ECO:0000269|PubMed:9722593}.
P21709 EPHA1 T780 ochoa Ephrin type-A receptor 1 (hEpha1) (EC 2.7.10.1) (EPH tyrosine kinase) (EPH tyrosine kinase 1) (Erythropoietin-producing hepatoma receptor) (Tyrosine-protein kinase receptor EPH) Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Binds with a low affinity EFNA3 and EFNA4 and with a high affinity to EFNA1 which most probably constitutes its cognate/functional ligand. Upon activation by EFNA1 induces cell attachment to the extracellular matrix inhibiting cell spreading and motility through regulation of ILK and downstream RHOA and RAC. Also plays a role in angiogenesis and regulates cell proliferation. May play a role in apoptosis. {ECO:0000269|PubMed:17634955, ECO:0000269|PubMed:19118217, ECO:0000269|PubMed:20043122}.
P21802 FGFR2 Y656 psp Fibroblast growth factor receptor 2 (FGFR-2) (EC 2.7.10.1) (K-sam) (KGFR) (Keratinocyte growth factor receptor) (CD antigen CD332) Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1. {ECO:0000269|PubMed:12529371, ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:15629145, ECO:0000269|PubMed:16384934, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19103595, ECO:0000269|PubMed:19387476, ECO:0000269|PubMed:19410646, ECO:0000269|PubMed:21596750, ECO:0000269|PubMed:8663044}.
P21802 FGFR2 Y657 psp Fibroblast growth factor receptor 2 (FGFR-2) (EC 2.7.10.1) (K-sam) (KGFR) (Keratinocyte growth factor receptor) (CD antigen CD332) Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1. {ECO:0000269|PubMed:12529371, ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:15629145, ECO:0000269|PubMed:16384934, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19103595, ECO:0000269|PubMed:19387476, ECO:0000269|PubMed:19410646, ECO:0000269|PubMed:21596750, ECO:0000269|PubMed:8663044}.
P22455 FGFR4 Y642 ochoa|psp Fibroblast growth factor receptor 4 (FGFR-4) (EC 2.7.10.1) (CD antigen CD334) Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645, ECO:0000269|PubMed:8663044}.
P22607 FGFR3 Y647 psp Fibroblast growth factor receptor 3 (FGFR-3) (EC 2.7.10.1) (CD antigen CD333) Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:14534538, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17145761, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:19286672, ECO:0000269|PubMed:8663044}.
P22607 FGFR3 Y648 psp Fibroblast growth factor receptor 3 (FGFR-3) (EC 2.7.10.1) (CD antigen CD333) Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:14534538, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17145761, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:19286672, ECO:0000269|PubMed:8663044}.
P23458 JAK1 Y1035 psp Tyrosine-protein kinase JAK1 (EC 2.7.10.2) (Janus kinase 1) (JAK-1) Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway (PubMed:16239216, PubMed:28111307, PubMed:32750333, PubMed:7615558, PubMed:8232552). Kinase partner for the interleukin (IL)-2 receptor (PubMed:11909529) as well as interleukin (IL)-10 receptor (PubMed:12133952). Kinase partner for the type I interferon receptor IFNAR2 (PubMed:16239216, PubMed:28111307, PubMed:32750333, PubMed:7615558, PubMed:8232552). In response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins (PubMed:7759950). Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors (PubMed:16239216, PubMed:32750333, PubMed:8232552). {ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:12133952, ECO:0000269|PubMed:16239216, ECO:0000269|PubMed:28111307, ECO:0000269|PubMed:32750333, ECO:0000269|PubMed:7615558, ECO:0000269|PubMed:7657660, ECO:0000269|PubMed:8232552}.
P29317 EPHA2 T771 ochoa Ephrin type-A receptor 2 (EC 2.7.10.1) (Epithelial cell kinase) (Tyrosine-protein kinase receptor ECK) Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:16236711, ECO:0000269|PubMed:18339848, ECO:0000269|PubMed:19573808, ECO:0000269|PubMed:20679435, ECO:0000269|PubMed:20861311, ECO:0000269|PubMed:23358419, ECO:0000269|PubMed:26158630, ECO:0000269|PubMed:27385333}.; FUNCTION: (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins. {ECO:0000269|PubMed:21516087}.; FUNCTION: Acts as a receptor for human cytomegalovirus (HCMV) to mediate viral entry and fusion in glioblastoma cells. {ECO:0000269|PubMed:37146061}.
P29323 EPHB2 Y780 ochoa Ephrin type-B receptor 2 (EC 2.7.10.1) (Developmentally-regulated Eph-related tyrosine kinase) (ELK-related tyrosine kinase) (EPH tyrosine kinase 3) (EPH-like kinase 5) (EK5) (hEK5) (Renal carcinoma antigen NY-REN-47) (Tyrosine-protein kinase TYRO5) (Tyrosine-protein kinase receptor EPH-3) [Cleaved into: EphB2/CTF1; EphB2/CTF2] Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. In addition to axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor. May be involved in the regulation of platelet activation and blood coagulation (PubMed:30213874). {ECO:0000269|PubMed:15300251, ECO:0000269|PubMed:30213874}.
P29597 TYK2 Y1055 psp Non-receptor tyrosine-protein kinase TYK2 (EC 2.7.10.2) Tyrosine kinase of the non-receptor type involved in numerous cytokines and interferons signaling, which regulates cell growth, development, cell migration, innate and adaptive immunity (PubMed:10542297, PubMed:10995743, PubMed:7657660, PubMed:7813427, PubMed:8232552). Plays both structural and catalytic roles in numerous interleukins and interferons (IFN-alpha/beta) signaling (PubMed:10542297). Associates with heterodimeric cytokine receptor complexes and activates STAT family members including STAT1, STAT3, STAT4 or STAT6 (PubMed:10542297, PubMed:7638186). The heterodimeric cytokine receptor complexes are composed of (1) a TYK2-associated receptor chain (IFNAR1, IL12RB1, IL10RB or IL13RA1), and (2) a second receptor chain associated either with JAK1 or JAK2 (PubMed:10542297, PubMed:25762719, PubMed:7526154, PubMed:7813427). In response to cytokine-binding to receptors, phosphorylates and activates receptors (IFNAR1, IL12RB1, IL10RB or IL13RA1), creating docking sites for STAT members (PubMed:7526154, PubMed:7657660). In turn, recruited STATs are phosphorylated by TYK2 (or JAK1/JAK2 on the second receptor chain), form homo- and heterodimers, translocate to the nucleus, and regulate cytokine/growth factor responsive genes (PubMed:10542297, PubMed:25762719, PubMed:7657660). Negatively regulates STAT3 activity by promototing phosphorylation at a specific tyrosine that differs from the site used for signaling (PubMed:29162862). {ECO:0000269|PubMed:10542297, ECO:0000269|PubMed:10995743, ECO:0000269|PubMed:25762719, ECO:0000269|PubMed:29162862, ECO:0000269|PubMed:7526154, ECO:0000269|PubMed:7638186, ECO:0000269|PubMed:7657660, ECO:0000269|PubMed:7813427, ECO:0000269|PubMed:8232552}.
P30530 AXL Y702 ochoa|psp Tyrosine-protein kinase receptor UFO (EC 2.7.10.1) (AXL oncogene) Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, AXL binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TNS2. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. {ECO:0000269|PubMed:10403904, ECO:0000269|PubMed:11484958, ECO:0000269|PubMed:12364394, ECO:0000269|PubMed:12490074, ECO:0000269|PubMed:15507525, ECO:0000269|PubMed:15733062, ECO:0000269|PubMed:1656220, ECO:0000269|PubMed:18840707}.; FUNCTION: (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope. {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:21501828, ECO:0000269|PubMed:22156524, ECO:0000269|PubMed:25277499}.; FUNCTION: (Microbial infection) Acts as a receptor for Ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope. {ECO:0000269|PubMed:22673088}.; FUNCTION: (Microbial infection) Promotes Zika virus entry in glial cells, Sertoli cells and astrocytes (PubMed:28076778, PubMed:29379210, PubMed:31311882). Additionally, Zika virus potentiates AXL kinase activity to antagonize type I interferon signaling and thereby promotes infection (PubMed:28076778). Interferon signaling inhibition occurs via an SOCS1-dependent mechanism (PubMed:29379210). {ECO:0000269|PubMed:28076778, ECO:0000269|PubMed:29379210, ECO:0000269|PubMed:31311882}.
P30530 AXL Y703 ochoa Tyrosine-protein kinase receptor UFO (EC 2.7.10.1) (AXL oncogene) Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, AXL binds and induces tyrosine phosphorylation of PI3-kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TNS2. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. {ECO:0000269|PubMed:10403904, ECO:0000269|PubMed:11484958, ECO:0000269|PubMed:12364394, ECO:0000269|PubMed:12490074, ECO:0000269|PubMed:15507525, ECO:0000269|PubMed:15733062, ECO:0000269|PubMed:1656220, ECO:0000269|PubMed:18840707}.; FUNCTION: (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope. {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:21501828, ECO:0000269|PubMed:22156524, ECO:0000269|PubMed:25277499}.; FUNCTION: (Microbial infection) Acts as a receptor for Ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope. {ECO:0000269|PubMed:22673088}.; FUNCTION: (Microbial infection) Promotes Zika virus entry in glial cells, Sertoli cells and astrocytes (PubMed:28076778, PubMed:29379210, PubMed:31311882). Additionally, Zika virus potentiates AXL kinase activity to antagonize type I interferon signaling and thereby promotes infection (PubMed:28076778). Interferon signaling inhibition occurs via an SOCS1-dependent mechanism (PubMed:29379210). {ECO:0000269|PubMed:28076778, ECO:0000269|PubMed:29379210, ECO:0000269|PubMed:31311882}.
P35916 FLT4 Y1068 ochoa|psp Vascular endothelial growth factor receptor 3 (VEGFR-3) (EC 2.7.10.1) (Fms-like tyrosine kinase 4) (FLT-4) (Tyrosine-protein kinase receptor FLT4) Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'. {ECO:0000269|PubMed:11532940, ECO:0000269|PubMed:15102829, ECO:0000269|PubMed:15474514, ECO:0000269|PubMed:16076871, ECO:0000269|PubMed:16452200, ECO:0000269|PubMed:17210781, ECO:0000269|PubMed:19610651, ECO:0000269|PubMed:19779139, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20431062, ECO:0000269|PubMed:20445537, ECO:0000269|PubMed:21273538, ECO:0000269|PubMed:7675451, ECO:0000269|PubMed:8700872, ECO:0000269|PubMed:9435229}.
P35968 KDR Y1059 ochoa|psp Vascular endothelial growth factor receptor 2 (VEGFR-2) (EC 2.7.10.1) (Fetal liver kinase 1) (FLK-1) (Kinase insert domain receptor) (KDR) (Protein-tyrosine kinase receptor flk-1) (CD antigen CD309) Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC. {ECO:0000269|PubMed:10102632, ECO:0000269|PubMed:10368301, ECO:0000269|PubMed:10600473, ECO:0000269|PubMed:11387210, ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:1417831, ECO:0000269|PubMed:15026417, ECO:0000269|PubMed:15215251, ECO:0000269|PubMed:15962004, ECO:0000269|PubMed:16966330, ECO:0000269|PubMed:17303569, ECO:0000269|PubMed:18529047, ECO:0000269|PubMed:19668192, ECO:0000269|PubMed:19834490, ECO:0000269|PubMed:20080685, ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20705758, ECO:0000269|PubMed:21893193, ECO:0000269|PubMed:25825981, ECO:0000269|PubMed:7929439, ECO:0000269|PubMed:9160888, ECO:0000269|PubMed:9804796, ECO:0000269|PubMed:9837777}.
P36888 FLT3 Y842 ochoa|psp Receptor-type tyrosine-protein kinase FLT3 (EC 2.7.10.1) (FL cytokine receptor) (Fetal liver kinase-2) (FLK-2) (Fms-like tyrosine kinase 3) (FLT-3) (Stem cell tyrosine kinase 1) (STK-1) (CD antigen CD135) Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways. {ECO:0000269|PubMed:10080542, ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:16627759, ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21067588, ECO:0000269|PubMed:21262971, ECO:0000269|PubMed:21516120, ECO:0000269|PubMed:7507245}.
P42680 TEC Y519 ochoa|psp Tyrosine-protein kinase Tec (EC 2.7.10.2) Non-receptor tyrosine kinase that contributes to signaling from many receptors and participates as a signal transducer in multiple downstream pathways, including regulation of the actin cytoskeleton. Plays a redundant role to ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. Required for TCR-dependent IL2 gene induction. Phosphorylates DOK1, one CD28-specific substrate, and contributes to CD28-signaling. Mediates signals that negatively regulate IL2RA expression induced by TCR cross-linking. Plays a redundant role to BTK in BCR-signaling for B-cell development and activation, especially by phosphorylating STAP1, a BCR-signaling protein. Required in mast cells for efficient cytokine production. Involved in both growth and differentiation mechanisms of myeloid cells through activation by the granulocyte colony-stimulating factor CSF3, a critical cytokine to promoting the growth, differentiation, and functional activation of myeloid cells. Participates in platelet signaling downstream of integrin activation. Cooperates with JAK2 through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. GRB10, a negative modifier of the FOS activation pathway, is another substrate of TEC. TEC is involved in G protein-coupled receptor- and integrin-mediated signalings in blood platelets. Plays a role in hepatocyte proliferation and liver regeneration and is involved in HGF-induced ERK signaling pathway. TEC also regulates FGF2 unconventional secretion (endoplasmic reticulum (ER)/Golgi-independent mechanism) under various physiological conditions through phosphorylation of FGF2 'Tyr-215'. May also be involved in the regulation of osteoclast differentiation. {ECO:0000269|PubMed:10518561, ECO:0000269|PubMed:19883687, ECO:0000269|PubMed:20230531, ECO:0000269|PubMed:9753425}.
P42681 TXK Y420 psp Tyrosine-protein kinase TXK (EC 2.7.10.2) (Protein-tyrosine kinase 4) (Resting lymphocyte kinase) Non-receptor tyrosine kinase that plays a redundant role with ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation leads to the recruitment of TXK to the cell membrane, where it is phosphorylated at Tyr-420. Phosphorylation leads to TXK full activation. Also contributes to signaling from many receptors and participates in multiple downstream pathways, including regulation of the actin cytoskeleton. Like ITK, can phosphorylate PLCG1, leading to its localization in lipid rafts and activation, followed by subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Plays a role in the positive regulation of IFNG transcription in T-helper 1 cells as part of an IFNG promoter-binding complex with PARP1 and EEF1A1 (PubMed:11859127, PubMed:17177976). Within the complex, phosphorylates both PARP1 and EEF1A1 (PubMed:17177976). Also phosphorylates key sites in LCP2 leading to the up-regulation of Th1 preferred cytokine IL-2. Phosphorylates 'Tyr-201' of CTLA4 which leads to the association of PI-3 kinase with the CTLA4 receptor. {ECO:0000269|PubMed:10523612, ECO:0000269|PubMed:11564877, ECO:0000269|PubMed:11859127, ECO:0000269|PubMed:17177976, ECO:0000269|PubMed:9813138}.
P42684 ABL2 Y439 ochoa|psp Tyrosine-protein kinase ABL2 (EC 2.7.10.2) (Abelson murine leukemia viral oncogene homolog 2) (Abelson tyrosine-protein kinase 2) (Abelson-related gene protein) (Tyrosine-protein kinase ARG) Non-receptor tyrosine-protein kinase that plays an ABL1-overlapping role in key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion and receptor endocytosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like MYH10 (involved in movement); CTTN (involved in signaling); or TUBA1 and TUBB (microtubule subunits). Binds directly F-actin and regulates actin cytoskeletal structure through its F-actin-bundling activity. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as CRK, CRKL, DOK1 or ARHGAP35. Adhesion-dependent phosphorylation of ARHGAP35 promotes its association with RASA1, resulting in recruitment of ARHGAP35 to the cell periphery where it inhibits RHO. Phosphorylates multiple receptor tyrosine kinases like PDGFRB and other substrates which are involved in endocytosis regulation such as RIN1. In brain, may regulate neurotransmission by phosphorylating proteins at the synapse. ABL2 also acts as a regulator of multiple pathological signaling cascades during infection. Pathogens can highjack ABL2 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Positively regulates chemokine-mediated T-cell migration, polarization, and homing to lymph nodes and immune-challenged tissues, potentially via activation of NEDD9/HEF1 and RAP1 (By similarity). {ECO:0000250|UniProtKB:Q4JIM5, ECO:0000269|PubMed:15735735, ECO:0000269|PubMed:15886098, ECO:0000269|PubMed:16678104, ECO:0000269|PubMed:17306540, ECO:0000269|PubMed:18945674}.
P42685 FRK Y387 ochoa Tyrosine-protein kinase FRK (EC 2.7.10.2) (FYN-related kinase) (Nuclear tyrosine protein kinase RAK) (Protein-tyrosine kinase 5) Non-receptor tyrosine-protein kinase that negatively regulates cell proliferation. Positively regulates PTEN protein stability through phosphorylation of PTEN on 'Tyr-336', which in turn prevents its ubiquitination and degradation, possibly by reducing its binding to NEDD4. May function as a tumor suppressor. {ECO:0000269|PubMed:19345329}.
P43403 ZAP70 Y493 ochoa|psp Tyrosine-protein kinase ZAP-70 (EC 2.7.10.2) (70 kDa zeta-chain associated protein) (Syk-related tyrosine kinase) Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Also contributes to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). {ECO:0000269|PubMed:11353765, ECO:0000269|PubMed:12051764, ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:20135127, ECO:0000269|PubMed:26903241, ECO:0000269|PubMed:38614099, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8702662, ECO:0000269|PubMed:9489702}.
P43405 SYK Y526 psp Tyrosine-protein kinase SYK (EC 2.7.10.2) (Spleen tyrosine kinase) (p72-Syk) Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development (PubMed:12387735, PubMed:33782605). Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include DEPTOR, VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK (PubMed:12456653, PubMed:15388330, PubMed:34634301, PubMed:8657103). Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition (PubMed:12456653). Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR also plays a role in T-cell receptor signaling. Also plays a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade (By similarity). Required for the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770). Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils (By similarity). Also functions downstream of receptors mediating cell adhesion (PubMed:12387735). Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Also plays a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (By similarity). {ECO:0000250|UniProtKB:P48025, ECO:0000269|PubMed:12387735, ECO:0000269|PubMed:12456653, ECO:0000269|PubMed:15123770, ECO:0000269|PubMed:15388330, ECO:0000269|PubMed:19909739, ECO:0000269|PubMed:33782605, ECO:0000269|PubMed:34634301, ECO:0000269|PubMed:8657103, ECO:0000269|PubMed:9535867}.
P49914 MTHFS Y83 ochoa 5-formyltetrahydrofolate cyclo-ligase (EC 6.3.3.2) (5,10-methenyl-tetrahydrofolate synthetase) (MTHFS) (Methenyl-THF synthetase) Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids. Catalyzes the irreversible conversion of 5-formyltetrahydrofolate (5-FTHF) to yield 5,10-methenyltetrahydrofolate. {ECO:0000269|PubMed:8522195}.
P51451 BLK Y389 ochoa|psp Tyrosine-protein kinase Blk (EC 2.7.10.2) (B lymphocyte kinase) (p55-Blk) Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling (By similarity). B-cell receptor (BCR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated coreceptors (By similarity). Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation (By similarity). Signaling through BLK plays an important role in transmitting signals through surface immunoglobulins and supports the pro-B to pre-B transition, as well as the signaling for growth arrest and apoptosis downstream of B-cell receptor (By similarity). Specifically binds and phosphorylates CD79A at 'Tyr-188'and 'Tyr-199', as well as CD79B at 'Tyr-196' and 'Tyr-207' (By similarity). Also phosphorylates the immunoglobulin G receptors FCGR2A, FCGR2B and FCGR2C (PubMed:8756631). With FYN and LYN, plays an essential role in pre-B-cell receptor (pre-BCR)-mediated NF-kappa-B activation (By similarity). Also contributes to BTK activation by indirectly stimulating BTK intramolecular autophosphorylation (By similarity). In pancreatic islets, acts as a modulator of beta-cells function through the up-regulation of PDX1 and NKX6-1 and consequent stimulation of insulin secretion in response to glucose (PubMed:19667185). Phosphorylates CGAS, promoting retention of CGAS in the cytosol (PubMed:30356214). {ECO:0000250|UniProtKB:P16277, ECO:0000269|PubMed:19667185, ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:8756631}.
P51813 BMX Y566 psp Cytoplasmic tyrosine-protein kinase BMX (EC 2.7.10.2) (Bone marrow tyrosine kinase gene in chromosome X protein) (Epithelial and endothelial tyrosine kinase) (ETK) (NTK38) Non-receptor tyrosine kinase that plays central but diverse modulatory roles in various signaling processes involved in the regulation of actin reorganization, cell migration, cell proliferation and survival, cell adhesion, and apoptosis. Participates in signal transduction stimulated by growth factor receptors, cytokine receptors, G-protein coupled receptors, antigen receptors and integrins. Induces tyrosine phosphorylation of BCAR1 in response to integrin regulation. Activation of BMX by integrins is mediated by PTK2/FAK1, a key mediator of integrin signaling events leading to the regulation of actin cytoskeleton and cell motility. Plays a critical role in TNF-induced angiogenesis, and implicated in the signaling of TEK and FLT1 receptors, 2 important receptor families essential for angiogenesis. Required for the phosphorylation and activation of STAT3, a transcription factor involved in cell differentiation. Also involved in interleukin-6 (IL6) induced differentiation. Also plays a role in programming adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts. May be involved in regulation of endocytosis through its interaction with an endosomal protein RUFY1. May also play a role in the growth and differentiation of hematopoietic cells; as well as in signal transduction in endocardial and arterial endothelial cells. {ECO:0000269|PubMed:10688651, ECO:0000269|PubMed:11331870, ECO:0000269|PubMed:12370298, ECO:0000269|PubMed:12832404, ECO:0000269|PubMed:15788485, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:9520419}.
P52333 JAK3 Y981 psp Tyrosine-protein kinase JAK3 (EC 2.7.10.2) (Janus kinase 3) (JAK-3) (Leukocyte janus kinase) (L-JAK) Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A and STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion. {ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:20440074, ECO:0000269|PubMed:7662955, ECO:0000269|PubMed:8022485}.
P54753 EPHB3 Y792 ochoa Ephrin type-B receptor 3 (EC 2.7.10.1) (EPH-like tyrosine kinase 2) (EPH-like kinase 2) (Embryonic kinase 2) (EK2) (hEK2) (Tyrosine-protein kinase TYRO6) Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Generally has an overlapping and redundant function with EPHB2. Like EPHB2, functions in axon guidance during development regulating for instance the neurons forming the corpus callosum and the anterior commissure, 2 major interhemispheric connections between the temporal lobes of the cerebral cortex. In addition to its role in axon guidance also plays an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and the formation of excitatory synapses. Controls other aspects of development through regulation of cell migration and positioning. This includes angiogenesis, palate development and thymic epithelium development for instance. Forward and reverse signaling through the EFNB2/EPHB3 complex also regulate migration and adhesion of cells that tubularize the urethra and septate the cloaca. Finally, plays an important role in intestinal epithelium differentiation segregating progenitor from differentiated cells in the crypt. {ECO:0000269|PubMed:15536074}.
P54760 EPHB4 Y774 ochoa|psp Ephrin type-B receptor 4 (EC 2.7.10.1) (Hepatoma transmembrane kinase) (Tyrosine-protein kinase TYRO11) Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 it is involved in the regulation of cell adhesion and migration, and plays a central role in heart morphogenesis, angiogenesis and blood vessel remodeling and permeability. EPHB4-mediated forward signaling controls cellular repulsion and segregation from EFNB2-expressing cells. {ECO:0000269|PubMed:12734395, ECO:0000269|PubMed:16424904, ECO:0000269|PubMed:27400125, ECO:0000269|PubMed:30578106}.
P54762 EPHB1 Y778 psp Ephrin type-B receptor 1 (EC 2.7.10.1) (ELK) (EPH tyrosine kinase 2) (EPH-like kinase 6) (EK6) (hEK6) (Neuronally-expressed EPH-related tyrosine kinase) (NET) (Tyrosine-protein kinase receptor EPH-2) Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. In addition to its role in axon guidance also plays an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively. Involved in the maintenance of the pool of satellite cells (muscle stem cells) by promoting their self-renewal and reducing their activation and differentiation (By similarity). {ECO:0000250|UniProtKB:Q8CBF3, ECO:0000269|PubMed:12223469, ECO:0000269|PubMed:12925710, ECO:0000269|PubMed:18034775, ECO:0000269|PubMed:9430661, ECO:0000269|PubMed:9499402}.
Q02763 TEK Y992 psp Angiopoietin-1 receptor (EC 2.7.10.1) (Endothelial tyrosine kinase) (Tunica interna endothelial cell kinase) (Tyrosine kinase with Ig and EGF homology domains-2) (Tyrosine-protein kinase receptor TEK) (Tyrosine-protein kinase receptor TIE-2) (hTIE2) (p140 TEK) (CD antigen CD202b) Tyrosine-protein kinase that acts as a cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of pro-inflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1. {ECO:0000269|PubMed:12816861, ECO:0000269|PubMed:14665640, ECO:0000269|PubMed:15284220, ECO:0000269|PubMed:15851516, ECO:0000269|PubMed:18366015, ECO:0000269|PubMed:18425119, ECO:0000269|PubMed:18425120, ECO:0000269|PubMed:19223473, ECO:0000269|PubMed:20651738, ECO:0000269|PubMed:9204896}.
Q04912 MST1R Y1238 ochoa|psp Macrophage-stimulating protein receptor (MSP receptor) (EC 2.7.10.1) (CDw136) (Protein-tyrosine kinase 8) (p185-Ron) (CD antigen CD136) [Cleaved into: Macrophage-stimulating protein receptor alpha chain; Macrophage-stimulating protein receptor beta chain] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to MST1 ligand. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces autophosphorylation of RON on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1 or the adapter GAB1. Recruitment of these downstream effectors by RON leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. RON signaling activates the wound healing response by promoting epithelial cell migration, proliferation as well as survival at the wound site. Also plays a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Alternatively, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligand. {ECO:0000269|PubMed:18836480, ECO:0000269|PubMed:7939629, ECO:0000269|PubMed:9764835}.
Q05397 PTK2 Y576 ochoa|psp Focal adhesion kinase 1 (FADK 1) (EC 2.7.10.2) (Focal adhesion kinase-related nonkinase) (FRNK) (Protein phosphatase 1 regulatory subunit 71) (PPP1R71) (Protein-tyrosine kinase 2) (p125FAK) (pp125FAK) Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Phosphorylates NEDD9 following integrin stimulation (PubMed:9360983). Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription. {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:11331870, ECO:0000269|PubMed:11980671, ECO:0000269|PubMed:15166238, ECO:0000269|PubMed:15561106, ECO:0000269|PubMed:15895076, ECO:0000269|PubMed:16919435, ECO:0000269|PubMed:16927379, ECO:0000269|PubMed:17395594, ECO:0000269|PubMed:17431114, ECO:0000269|PubMed:17968709, ECO:0000269|PubMed:18006843, ECO:0000269|PubMed:18206965, ECO:0000269|PubMed:18256281, ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:18497331, ECO:0000269|PubMed:18677107, ECO:0000269|PubMed:19138410, ECO:0000269|PubMed:19147981, ECO:0000269|PubMed:19224453, ECO:0000269|PubMed:20332118, ECO:0000269|PubMed:20495381, ECO:0000269|PubMed:21454698, ECO:0000269|PubMed:9360983}.; FUNCTION: [Isoform 6]: Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription. {ECO:0000269|PubMed:20109444}.
Q06187 BTK Y551 ochoa|psp Tyrosine-protein kinase BTK (EC 2.7.10.2) (Agammaglobulinemia tyrosine kinase) (ATK) (B-cell progenitor kinase) (BPK) (Bruton tyrosine kinase) Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling (PubMed:19290921). Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation (PubMed:19290921). After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members (PubMed:11606584). PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK (PubMed:11606584). BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways (PubMed:16517732, PubMed:17932028). Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway (PubMed:16517732). The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense (PubMed:16517732). Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells (PubMed:16517732, PubMed:17932028). Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation (PubMed:16415872). BTK also plays a critical role in transcription regulation (PubMed:19290921). Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes (PubMed:19290921). BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B (PubMed:19290921). Acts as an activator of NLRP3 inflammasome assembly by mediating phosphorylation of NLRP3 (PubMed:34554188). Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR (PubMed:9012831). GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression (PubMed:9012831). ARID3A and NFAT are other transcriptional target of BTK (PubMed:16738337). BTK is required for the formation of functional ARID3A DNA-binding complexes (PubMed:16738337). There is however no evidence that BTK itself binds directly to DNA (PubMed:16738337). BTK has a dual role in the regulation of apoptosis (PubMed:9751072). Plays a role in STING1-mediated induction of type I interferon (IFN) response by phosphorylating DDX41 (PubMed:25704810). {ECO:0000269|PubMed:11606584, ECO:0000269|PubMed:16415872, ECO:0000269|PubMed:16517732, ECO:0000269|PubMed:16738337, ECO:0000269|PubMed:17932028, ECO:0000269|PubMed:25704810, ECO:0000269|PubMed:34554188, ECO:0000269|PubMed:9012831, ECO:0000303|PubMed:19290921, ECO:0000303|PubMed:9751072}.
Q07912 TNK2 Y284 ochoa|psp Activated CDC42 kinase 1 (ACK-1) (EC 2.7.10.2) (EC 2.7.11.1) (Tyrosine kinase non-receptor protein 2) Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. Phosphorylates WASP (PubMed:20110370). {ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:11278436, ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:18262180, ECO:0000269|PubMed:18435854, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20110370, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20383201}.
Q08345 DDR1 Y796 ochoa|psp Epithelial discoidin domain-containing receptor 1 (Epithelial discoidin domain receptor 1) (EC 2.7.10.1) (CD167 antigen-like family member A) (Cell adhesion kinase) (Discoidin receptor tyrosine kinase) (HGK2) (Mammary carcinoma kinase 10) (MCK-10) (Protein-tyrosine kinase 3A) (Protein-tyrosine kinase RTK-6) (TRK E) (Tyrosine kinase DDR) (Tyrosine-protein kinase CAK) (CD antigen CD167a) Tyrosine kinase that functions as a cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11. {ECO:0000250, ECO:0000269|PubMed:12065315, ECO:0000269|PubMed:16234985, ECO:0000269|PubMed:16337946, ECO:0000269|PubMed:19401332, ECO:0000269|PubMed:20093046, ECO:0000269|PubMed:20432435, ECO:0000269|PubMed:20884741, ECO:0000269|PubMed:21044884, ECO:0000269|PubMed:9659899}.
Q08881 ITK Y512 ochoa|psp Tyrosine-protein kinase ITK/TSK (EC 2.7.10.2) (Interleukin-2-inducible T-cell kinase) (IL-2-inducible T-cell kinase) (Kinase EMT) (T-cell-specific kinase) (Tyrosine-protein kinase Lyk) Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation (PubMed:12186560, PubMed:12682224, PubMed:21725281). Required for TCR-mediated calcium response in gamma-delta T-cells, may also be involved in the modulation of the transcriptomic signature in the Vgamma2-positive subset of immature gamma-delta T-cells (By similarity). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity). {ECO:0000250|UniProtKB:Q03526, ECO:0000269|PubMed:12186560, ECO:0000269|PubMed:12682224, ECO:0000269|PubMed:21725281}.
Q12866 MERTK Y753 psp Tyrosine-protein kinase Mer (EC 2.7.10.1) (Proto-oncogene c-Mer) (Receptor tyrosine kinase MerTK) Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment (PubMed:32640697). Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:32640697}.
Q12866 MERTK Y754 psp Tyrosine-protein kinase Mer (EC 2.7.10.1) (Proto-oncogene c-Mer) (Receptor tyrosine kinase MerTK) Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment (PubMed:32640697). Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:17005688, ECO:0000269|PubMed:32640697}.
Q13470 TNK1 Y277 psp Non-receptor tyrosine-protein kinase TNK1 (EC 2.7.10.2) (CD38 negative kinase 1) Involved in negative regulation of cell growth. Has tumor suppressor properties. Plays a negative regulatory role in the Ras-MAPK pathway. May function in signaling pathways utilized broadly during fetal development and more selectively in adult tissues and in cells of the lymphohematopoietic system. Could specifically be involved in phospholipid signal transduction. {ECO:0000269|PubMed:10873601, ECO:0000269|PubMed:18974114}.
Q13882 PTK6 Y342 ochoa|psp Protein-tyrosine kinase 6 (EC 2.7.10.2) (Breast tumor kinase) (Tyrosine-protein kinase BRK) Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Phosphorylates the GTPase-activating protein ARAP1 following EGF stimulation which enhances EGFR signaling by delaying EGFR down-regulation (PubMed:20554524). Also associates with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways. {ECO:0000269|PubMed:20554524}.; FUNCTION: [Isoform 2]: Inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.
Q14004 CDK13 S867 ochoa Cyclin-dependent kinase 13 (EC 2.7.11.22) (EC 2.7.11.23) (CDC2-related protein kinase 5) (Cell division cycle 2-like protein kinase 5) (Cell division protein kinase 13) (hCDK13) (Cholinesterase-related cell division controller) Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, probably by phosphorylating SRSF1/SF2. Required during hematopoiesis. In case of infection by HIV-1 virus, interacts with HIV-1 Tat protein acetylated at 'Lys-50' and 'Lys-51', thereby increasing HIV-1 mRNA splicing and promoting the production of the doubly spliced HIV-1 protein Nef. {ECO:0000269|PubMed:16721827, ECO:0000269|PubMed:1731328, ECO:0000269|PubMed:18480452, ECO:0000269|PubMed:20952539}.
Q14289 PTK2B Y579 ochoa|psp Protein-tyrosine kinase 2-beta (EC 2.7.10.2) (Calcium-dependent tyrosine kinase) (CADTK) (Calcium-regulated non-receptor proline-rich tyrosine kinase) (Cell adhesion kinase beta) (CAK-beta) (CAKB) (Focal adhesion kinase 2) (FADK 2) (Proline-rich tyrosine kinase 2) (Related adhesion focal tyrosine kinase) (RAFTK) Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2. {ECO:0000269|PubMed:10022920, ECO:0000269|PubMed:12771146, ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:15050747, ECO:0000269|PubMed:15166227, ECO:0000269|PubMed:17634955, ECO:0000269|PubMed:18086875, ECO:0000269|PubMed:18339875, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18765415, ECO:0000269|PubMed:19086031, ECO:0000269|PubMed:19207108, ECO:0000269|PubMed:19244237, ECO:0000269|PubMed:19428251, ECO:0000269|PubMed:19648005, ECO:0000269|PubMed:19880522, ECO:0000269|PubMed:20001213, ECO:0000269|PubMed:20381867, ECO:0000269|PubMed:20521079, ECO:0000269|PubMed:21357692, ECO:0000269|PubMed:21533080, ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:8670418, ECO:0000269|PubMed:8849729}.
Q16288 NTRK3 Y709 psp NT-3 growth factor receptor (EC 2.7.10.1) (GP145-TrkC) (Trk-C) (Neurotrophic tyrosine kinase receptor type 3) (TrkC tyrosine kinase) Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation. {ECO:0000269|PubMed:25196463}.
Q16620 NTRK2 Y706 psp BDNF/NT-3 growth factors receptor (EC 2.7.10.1) (GP145-TrkB) (Trk-B) (Neurotrophic tyrosine kinase receptor type 2) (TrkB tyrosine kinase) (Tropomyosin-related kinase B) Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity (By similarity). Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2 (PubMed:15494731, PubMed:7574684). Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:15494731). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia. {ECO:0000250|UniProtKB:P15209, ECO:0000269|PubMed:15494731, ECO:0000269|PubMed:7574684}.
Q16620 NTRK2 Y707 psp BDNF/NT-3 growth factors receptor (EC 2.7.10.1) (GP145-TrkB) (Trk-B) (Neurotrophic tyrosine kinase receptor type 2) (TrkB tyrosine kinase) (Tropomyosin-related kinase B) Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity (By similarity). Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2 (PubMed:15494731, PubMed:7574684). Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:15494731). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia. {ECO:0000250|UniProtKB:P15209, ECO:0000269|PubMed:15494731, ECO:0000269|PubMed:7574684}.
Q16832 DDR2 Y740 psp Discoidin domain-containing receptor 2 (Discoidin domain receptor 2) (EC 2.7.10.1) (CD167 antigen-like family member B) (Discoidin domain-containing receptor tyrosine kinase 2) (Neurotrophic tyrosine kinase, receptor-related 3) (Receptor protein-tyrosine kinase TKT) (Tyrosine-protein kinase TYRO10) (CD antigen CD167b) Tyrosine kinase involved in the regulation of tissues remodeling (PubMed:30449416). It functions as a cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing. {ECO:0000269|PubMed:16186104, ECO:0000269|PubMed:16186108, ECO:0000269|PubMed:17665456, ECO:0000269|PubMed:18201965, ECO:0000269|PubMed:20004161, ECO:0000269|PubMed:20564243, ECO:0000269|PubMed:20734453, ECO:0000269|PubMed:30449416, ECO:0000269|PubMed:9659899}.
Q16832 DDR2 Y741 psp Discoidin domain-containing receptor 2 (Discoidin domain receptor 2) (EC 2.7.10.1) (CD167 antigen-like family member B) (Discoidin domain-containing receptor tyrosine kinase 2) (Neurotrophic tyrosine kinase, receptor-related 3) (Receptor protein-tyrosine kinase TKT) (Tyrosine-protein kinase TYRO10) (CD antigen CD167b) Tyrosine kinase involved in the regulation of tissues remodeling (PubMed:30449416). It functions as a cell surface receptor for fibrillar collagen and regulates cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation. Required for normal bone development. Regulates osteoblast differentiation and chondrocyte maturation via a signaling pathway that involves MAP kinases and leads to the activation of the transcription factor RUNX2. Regulates remodeling of the extracellular matrix by up-regulation of the collagenases MMP1, MMP2 and MMP13, and thereby facilitates cell migration and tumor cell invasion. Promotes fibroblast migration and proliferation, and thereby contributes to cutaneous wound healing. {ECO:0000269|PubMed:16186104, ECO:0000269|PubMed:16186108, ECO:0000269|PubMed:17665456, ECO:0000269|PubMed:18201965, ECO:0000269|PubMed:20004161, ECO:0000269|PubMed:20564243, ECO:0000269|PubMed:20734453, ECO:0000269|PubMed:30449416, ECO:0000269|PubMed:9659899}.
Q9H3Y6 SRMS Y380 psp Tyrosine-protein kinase Srms (EC 2.7.10.2) Non-receptor tyrosine-protein kinase which phosphorylates DOK1 on tyrosine residues (PubMed:23822091). Also phosphorylates KHDRBS1/SAM68 and VIM on tyrosine residues (PubMed:29496907). Phosphorylation of KHDRBS1 is EGF-dependent (PubMed:29496907). Phosphorylates OTUB1, promoting deubiquitination of RPTOR (PubMed:35927303). {ECO:0000269|PubMed:23822091, ECO:0000269|PubMed:29496907, ECO:0000269|PubMed:35927303}.
Q9NYV4 CDK12 S889 ochoa Cyclin-dependent kinase 12 (EC 2.7.11.22) (EC 2.7.11.23) (Cdc2-related kinase, arginine/serine-rich) (CrkRS) (Cell division cycle 2-related protein kinase 7) (CDC2-related protein kinase 7) (Cell division protein kinase 12) (hCDK12) Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors. {ECO:0000269|PubMed:11683387, ECO:0000269|PubMed:19651820, ECO:0000269|PubMed:20952539, ECO:0000269|PubMed:22012619, ECO:0000269|PubMed:24662513}.
Q9UM73 ALK Y1282 psp ALK tyrosine kinase receptor (EC 2.7.10.1) (Anaplastic lymphoma kinase) (CD antigen CD246) Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system (PubMed:11121404, PubMed:11387242, PubMed:16317043, PubMed:17274988, PubMed:30061385, PubMed:34646012, PubMed:34819673). Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response (PubMed:30061385, PubMed:33411331, PubMed:34646012, PubMed:34819673). In contrast, ALKAL1 is not a potent physiological ligand for ALK (PubMed:34646012). Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (PubMed:34819673). Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif (PubMed:15226403, PubMed:16878150). Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 (PubMed:15226403, PubMed:16878150). ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK) (PubMed:11278720, PubMed:11809760, PubMed:12107166, PubMed:12122009). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation (PubMed:11278720, PubMed:11809760, PubMed:12107166). MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction (PubMed:12122009). Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase (PubMed:15226403, PubMed:16878150). Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (PubMed:15226403, PubMed:16878150). {ECO:0000250|UniProtKB:P97793, ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:11387242, ECO:0000269|PubMed:11809760, ECO:0000269|PubMed:12107166, ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988, ECO:0000269|PubMed:30061385, ECO:0000269|PubMed:33411331, ECO:0000269|PubMed:34646012, ECO:0000269|PubMed:34819673}.
Q9UM73 ALK Y1283 psp ALK tyrosine kinase receptor (EC 2.7.10.1) (Anaplastic lymphoma kinase) (CD antigen CD246) Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system (PubMed:11121404, PubMed:11387242, PubMed:16317043, PubMed:17274988, PubMed:30061385, PubMed:34646012, PubMed:34819673). Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response (PubMed:30061385, PubMed:33411331, PubMed:34646012, PubMed:34819673). In contrast, ALKAL1 is not a potent physiological ligand for ALK (PubMed:34646012). Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (PubMed:34819673). Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif (PubMed:15226403, PubMed:16878150). Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 (PubMed:15226403, PubMed:16878150). ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK) (PubMed:11278720, PubMed:11809760, PubMed:12107166, PubMed:12122009). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation (PubMed:11278720, PubMed:11809760, PubMed:12107166). MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction (PubMed:12122009). Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase (PubMed:15226403, PubMed:16878150). Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (PubMed:15226403, PubMed:16878150). {ECO:0000250|UniProtKB:P97793, ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:11387242, ECO:0000269|PubMed:11809760, ECO:0000269|PubMed:12107166, ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988, ECO:0000269|PubMed:30061385, ECO:0000269|PubMed:33411331, ECO:0000269|PubMed:34646012, ECO:0000269|PubMed:34819673}.
O15146 MUSK Y755 Sugiyama Muscle, skeletal receptor tyrosine-protein kinase (EC 2.7.10.1) (Muscle-specific tyrosine-protein kinase receptor) (MuSK) (Muscle-specific kinase receptor) Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (PubMed:25537362). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation (By similarity). {ECO:0000250, ECO:0000269|PubMed:25537362}.
O15146 MUSK Y756 Sugiyama Muscle, skeletal receptor tyrosine-protein kinase (EC 2.7.10.1) (Muscle-specific tyrosine-protein kinase receptor) (MuSK) (Muscle-specific kinase receptor) Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (PubMed:25537362). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation (By similarity). {ECO:0000250, ECO:0000269|PubMed:25537362}.
P07949 RET S904 Sugiyama Proto-oncogene tyrosine-protein kinase receptor Ret (EC 2.7.10.1) (Cadherin family member 12) (Proto-oncogene c-Ret) [Cleaved into: Soluble RET kinase fragment; Extracellular cell-membrane anchored RET cadherin 120 kDa fragment] Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15) (PubMed:20064382, PubMed:20616503, PubMed:20702524, PubMed:21357690, PubMed:21454698, PubMed:24560924, PubMed:28846097, PubMed:28846099, PubMed:28953886, PubMed:31118272). In contrast to most receptor tyrosine kinases, RET requires not only its cognate ligands but also coreceptors, for activation (PubMed:21994944, PubMed:23333276, PubMed:28846097, PubMed:28846099, PubMed:28953886). GDNF ligands (GDNF, NRTN, ARTN, PSPN and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways (PubMed:21994944, PubMed:23333276, PubMed:24560924, PubMed:25242331, PubMed:28846097, PubMed:28846099, PubMed:28953886). Acts as a dependence receptor via the GDNF-GFRA1 signaling: in the presence of the ligand GDNF in somatotrophs within pituitary, promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF (PubMed:20616503, PubMed:21994944). Required for the molecular mechanisms orchestration during intestine organogenesis via the ARTN-GFRA3 signaling: involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue (By similarity). Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses (PubMed:28846097, PubMed:28846099, PubMed:28953886). Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner (PubMed:20702524, PubMed:21357690). Also active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage (PubMed:21357690). Triggers the differentiation of rapidly adapting (RA) mechanoreceptors (PubMed:20064382). Involved in the development of the neural crest (By similarity). Regulates nociceptor survival and size (By similarity). Phosphorylates PTK2/FAK1 (PubMed:21454698). {ECO:0000250|UniProtKB:P35546, ECO:0000269|PubMed:20064382, ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698, ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:24560924, ECO:0000269|PubMed:25242331, ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886, ECO:0000269|PubMed:31118272}.; FUNCTION: [Isoform 1]: Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL. {ECO:0000269|PubMed:28846099}.
P14616 INSRR Y1145 Sugiyama Insulin receptor-related protein (IRR) (EC 2.7.10.1) (IR-related receptor) [Cleaved into: Insulin receptor-related protein alpha chain; Insulin receptor-related protein beta chain] Receptor with tyrosine-protein kinase activity. Functions as a pH sensing receptor which is activated by increased extracellular pH. Activates an intracellular signaling pathway that involves IRS1 and AKT1/PKB. {ECO:0000269|PubMed:21641549}.
P17948 FLT1 Y1053 Sugiyama Vascular endothelial growth factor receptor 1 (VEGFR-1) (EC 2.7.10.1) (Fms-like tyrosine kinase 1) (FLT-1) (Tyrosine-protein kinase FRT) (Tyrosine-protein kinase receptor FLT) (FLT) (Vascular permeability factor receptor) Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. Acts as a positive regulator of postnatal retinal hyaloid vessel regression (By similarity). May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1 (PubMed:16685275). {ECO:0000250|UniProtKB:P35969, ECO:0000269|PubMed:11141500, ECO:0000269|PubMed:11312102, ECO:0000269|PubMed:11811792, ECO:0000269|PubMed:12796773, ECO:0000269|PubMed:14633857, ECO:0000269|PubMed:15735759, ECO:0000269|PubMed:16685275, ECO:0000269|PubMed:18079407, ECO:0000269|PubMed:18515749, ECO:0000269|PubMed:18583712, ECO:0000269|PubMed:18593464, ECO:0000269|PubMed:20512933, ECO:0000269|PubMed:20551949, ECO:0000269|PubMed:21752276, ECO:0000269|PubMed:7824266, ECO:0000269|PubMed:8248162, ECO:0000269|PubMed:8605350, ECO:0000269|PubMed:9299537, ECO:0000269|Ref.11}.; FUNCTION: [Isoform 1]: Phosphorylates PLCG. {ECO:0000269|PubMed:9299537}.; FUNCTION: [Isoform 2]: May function as decoy receptor for VEGFA. {ECO:0000269|PubMed:21752276}.; FUNCTION: [Isoform 3]: May function as decoy receptor for VEGFA. {ECO:0000269|PubMed:21752276}.; FUNCTION: [Isoform 4]: May function as decoy receptor for VEGFA. {ECO:0000269|PubMed:21752276}.; FUNCTION: [Isoform 7]: Has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion. {ECO:0000269|PubMed:20512933}.
P22455 FGFR4 Y643 GPS6|SIGNOR|EPSD|Sugiyama Fibroblast growth factor receptor 4 (FGFR-4) (EC 2.7.10.1) (CD antigen CD334) Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645, ECO:0000269|PubMed:8663044}.
Q08345 DDR1 Y797 Sugiyama Epithelial discoidin domain-containing receptor 1 (Epithelial discoidin domain receptor 1) (EC 2.7.10.1) (CD167 antigen-like family member A) (Cell adhesion kinase) (Discoidin receptor tyrosine kinase) (HGK2) (Mammary carcinoma kinase 10) (MCK-10) (Protein-tyrosine kinase 3A) (Protein-tyrosine kinase RTK-6) (TRK E) (Tyrosine kinase DDR) (Tyrosine-protein kinase CAK) (CD antigen CD167a) Tyrosine kinase that functions as a cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11. {ECO:0000250, ECO:0000269|PubMed:12065315, ECO:0000269|PubMed:16234985, ECO:0000269|PubMed:16337946, ECO:0000269|PubMed:19401332, ECO:0000269|PubMed:20093046, ECO:0000269|PubMed:20432435, ECO:0000269|PubMed:20884741, ECO:0000269|PubMed:21044884, ECO:0000269|PubMed:9659899}.
Q9UBE8 NLK S294 Sugiyama Serine/threonine-protein kinase NLK (EC 2.7.11.24) (Nemo-like kinase) (Protein LAK1) Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination (PubMed:12482967, PubMed:14960582, PubMed:15004007, PubMed:15764709, PubMed:20061393, PubMed:20874444, PubMed:21454679). Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2 (PubMed:15004007, PubMed:15764709). Negative regulator of the canonical Wnt/beta-catenin signaling pathway (PubMed:12482967). Binds to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the ubiquitination and subsequent proteolysis of LEF1 (PubMed:21454679). Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes (PubMed:12482967, PubMed:21454679). Negative regulator of the Notch signaling pathway (PubMed:20118921). Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1 (PubMed:20118921). Negative regulator of the MYB family of transcription factors (PubMed:15082531). Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP (PubMed:15082531). Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself (PubMed:15082531). Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1 (PubMed:15004007, PubMed:15764709). Upon IL1B stimulus, cooperates with ATF5 to activate the transactivation activity of C/EBP subfamily members (PubMed:25512613). Phosphorylates ATF5 but also stabilizes ATF5 protein levels in a kinase-independent manner (PubMed:25512613). Acts as an inhibitor of the mTORC1 complex in response to osmotic stress by mediating phosphorylation of RPTOR, thereby preventing recruitment of the mTORC1 complex to lysosomes (PubMed:26588989). {ECO:0000269|PubMed:12482967, ECO:0000269|PubMed:14960582, ECO:0000269|PubMed:15004007, ECO:0000269|PubMed:15082531, ECO:0000269|PubMed:15764709, ECO:0000269|PubMed:20061393, ECO:0000269|PubMed:20118921, ECO:0000269|PubMed:20874444, ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:25512613, ECO:0000269|PubMed:26588989}.
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reactome_id name p -log10_p
R-HSA-9006934 Signaling by Receptor Tyrosine Kinases 1.110223e-16 15.955
R-HSA-5663202 Diseases of signal transduction by growth factor receptors and second messengers 1.110223e-16 15.955
R-HSA-2219530 Constitutive Signaling by Aberrant PI3K in Cancer 1.110223e-16 15.955
R-HSA-5673001 RAF/MAP kinase cascade 1.110223e-16 15.955
R-HSA-5684996 MAPK1/MAPK3 signaling 1.110223e-16 15.955
R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling 1.110223e-16 15.955
R-HSA-162582 Signal Transduction 1.110223e-16 15.955
R-HSA-5683057 MAPK family signaling cascades 1.110223e-16 15.955
R-HSA-199418 Negative regulation of the PI3K/AKT network 1.110223e-16 15.955
R-HSA-2219528 PI3K/AKT Signaling in Cancer 1.110223e-16 15.955
R-HSA-1257604 PIP3 activates AKT signaling 1.110223e-16 15.955
R-HSA-9006925 Intracellular signaling by second messengers 1.110223e-16 15.955
R-HSA-1226099 Signaling by FGFR in disease 1.232348e-14 13.909
R-HSA-2428928 IRS-related events triggered by IGF1R 1.383560e-12 11.859
R-HSA-1433557 Signaling by SCF-KIT 2.021716e-12 11.694
R-HSA-2428924 IGF1R signaling cascade 2.174816e-12 11.663
R-HSA-74751 Insulin receptor signalling cascade 2.174816e-12 11.663
R-HSA-2404192 Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) 2.517764e-12 11.599
R-HSA-3928665 EPH-ephrin mediated repulsion of cells 4.211298e-12 11.376
R-HSA-109704 PI3K Cascade 7.049361e-12 11.152
R-HSA-112399 IRS-mediated signalling 2.122558e-11 10.673
R-HSA-512988 Interleukin-3, Interleukin-5 and GM-CSF signaling 5.651979e-11 10.248
R-HSA-2682334 EPH-Ephrin signaling 8.556056e-11 10.068
R-HSA-3928662 EPHB-mediated forward signaling 7.959555e-11 10.099
R-HSA-74752 Signaling by Insulin receptor 8.556056e-11 10.068
R-HSA-190236 Signaling by FGFR 1.710950e-10 9.767
R-HSA-422475 Axon guidance 6.121483e-10 9.213
R-HSA-9706374 FLT3 signaling through SRC family kinases 6.404524e-10 9.194
R-HSA-9669938 Signaling by KIT in disease 8.808747e-10 9.055
R-HSA-9670439 Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT m... 8.808747e-10 9.055
R-HSA-1643685 Disease 1.309333e-09 8.883
R-HSA-9675108 Nervous system development 1.798216e-09 8.745
R-HSA-1433559 Regulation of KIT signaling 2.694828e-09 8.569
R-HSA-3928664 Ephrin signaling 1.142743e-08 7.942
R-HSA-9705462 Inactivation of CSF3 (G-CSF) signaling 2.928971e-08 7.533
R-HSA-9020558 Interleukin-2 signaling 4.251943e-08 7.371
R-HSA-210990 PECAM1 interactions 4.251943e-08 7.371
R-HSA-9664407 Parasite infection 8.799351e-08 7.056
R-HSA-9664417 Leishmania phagocytosis 8.799351e-08 7.056
R-HSA-9664422 FCGR3A-mediated phagocytosis 8.799351e-08 7.056
R-HSA-3928663 EPHA-mediated growth cone collapse 9.463379e-08 7.024
R-HSA-9674555 Signaling by CSF3 (G-CSF) 1.333057e-07 6.875
R-HSA-9680350 Signaling by CSF1 (M-CSF) in myeloid cells 3.338721e-07 6.476
R-HSA-5654727 Negative regulation of FGFR2 signaling 3.338721e-07 6.476
R-HSA-1839126 FGFR2 mutant receptor activation 4.397114e-07 6.357
R-HSA-2029480 Fcgamma receptor (FCGR) dependent phagocytosis 5.727022e-07 6.242
R-HSA-8851708 Signaling by FGFR2 IIIa TM 5.981272e-07 6.223
R-HSA-912631 Regulation of signaling by CBL 5.981272e-07 6.223
R-HSA-389513 Co-inhibition by CTLA4 7.298231e-07 6.137
R-HSA-451927 Interleukin-2 family signaling 7.343543e-07 6.134
R-HSA-9607240 FLT3 Signaling 8.289086e-07 6.081
R-HSA-5655253 Signaling by FGFR2 in disease 2.449300e-06 5.611
R-HSA-194138 Signaling by VEGF 4.006689e-06 5.397
R-HSA-2029481 FCGR activation 5.411889e-06 5.267
R-HSA-8866910 TFAP2 (AP-2) family regulates transcription of growth factors and their receptor... 1.198385e-05 4.921
R-HSA-166520 Signaling by NTRKs 1.364383e-05 4.865
R-HSA-195399 VEGF binds to VEGFR leading to receptor dimerization 2.150516e-05 4.667
R-HSA-5654221 Phospholipase C-mediated cascade; FGFR2 2.359828e-05 4.627
R-HSA-194313 VEGF ligand-receptor interactions 2.150516e-05 4.667
R-HSA-69236 G1 Phase 2.475616e-05 4.606
R-HSA-69231 Cyclin D associated events in G1 2.475616e-05 4.606
R-HSA-5654738 Signaling by FGFR2 2.556822e-05 4.592
R-HSA-190241 FGFR2 ligand binding and activation 2.747039e-05 4.561
R-HSA-164944 Nef and signal transduction 3.047628e-05 4.516
R-HSA-9658195 Leishmania infection 2.745851e-05 4.561
R-HSA-9824443 Parasitic Infection Pathways 2.745851e-05 4.561
R-HSA-389356 Co-stimulation by CD28 3.513612e-05 4.454
R-HSA-9664323 FCGR3A-mediated IL10 synthesis 3.993969e-05 4.399
R-HSA-187015 Activation of TRKA receptors 4.160989e-05 4.381
R-HSA-9732724 IFNG signaling activates MAPKs 4.160989e-05 4.381
R-HSA-8854691 Interleukin-20 family signaling 4.189084e-05 4.378
R-HSA-5654695 PI-3K cascade:FGFR2 5.416008e-05 4.266
R-HSA-9032500 Activated NTRK2 signals through FYN 5.512358e-05 4.259
R-HSA-5654699 SHC-mediated cascade:FGFR2 6.886446e-05 4.162
R-HSA-112411 MAPK1 (ERK2) activation 7.123056e-05 4.147
R-HSA-5654700 FRS-mediated FGFR2 signaling 7.721630e-05 4.112
R-HSA-5654732 Negative regulation of FGFR3 signaling 7.721630e-05 4.112
R-HSA-1227986 Signaling by ERBB2 8.726140e-05 4.059
R-HSA-9020956 Interleukin-27 signaling 9.013979e-05 4.045
R-HSA-110056 MAPK3 (ERK1) activation 9.013979e-05 4.045
R-HSA-2424491 DAP12 signaling 9.609756e-05 4.017
R-HSA-1266738 Developmental Biology 1.022636e-04 3.990
R-HSA-354192 Integrin signaling 1.304148e-04 3.885
R-HSA-5654726 Negative regulation of FGFR1 signaling 1.304148e-04 3.885
R-HSA-5673000 RAF activation 1.577308e-04 3.802
R-HSA-8984722 Interleukin-35 Signalling 1.657072e-04 3.781
R-HSA-5654696 Downstream signaling of activated FGFR2 1.728363e-04 3.762
R-HSA-187687 Signalling to ERKs 1.728363e-04 3.762
R-HSA-114604 GPVI-mediated activation cascade 1.889596e-04 3.724
R-HSA-2033514 FGFR3 mutant receptor activation 1.978309e-04 3.704
R-HSA-1839130 Signaling by activated point mutants of FGFR3 1.978309e-04 3.704
R-HSA-6788467 IL-6-type cytokine receptor ligand interactions 1.978309e-04 3.704
R-HSA-1059683 Interleukin-6 signaling 1.978309e-04 3.704
R-HSA-4420097 VEGFA-VEGFR2 Pathway 2.051550e-04 3.688
R-HSA-2871809 FCERI mediated Ca+2 mobilization 2.051550e-04 3.688
R-HSA-201556 Signaling by ALK 2.438373e-04 3.613
R-HSA-391160 Signal regulatory protein family interactions 2.337392e-04 3.631
R-HSA-9662851 Anti-inflammatory response favouring Leishmania parasite infection 2.654337e-04 3.576
R-HSA-9664433 Leishmania parasite growth and survival 2.654337e-04 3.576
R-HSA-418885 DCC mediated attractive signaling 2.736163e-04 3.563
R-HSA-449147 Signaling by Interleukins 2.793524e-04 3.554
R-HSA-9656223 Signaling by RAF1 mutants 3.093358e-04 3.510
R-HSA-169893 Prolonged ERK activation events 3.176426e-04 3.498
R-HSA-194306 Neurophilin interactions with VEGF and VEGFR 3.249513e-04 3.488
R-HSA-9927418 Developmental Lineage of Mammary Gland Luminal Epithelial Cells 3.337225e-04 3.477
R-HSA-2172127 DAP12 interactions 3.865801e-04 3.413
R-HSA-8864260 Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors 3.865801e-04 3.413
R-HSA-5654741 Signaling by FGFR3 4.151360e-04 3.382
R-HSA-76009 Platelet Aggregation (Plug Formation) 4.151360e-04 3.382
R-HSA-6802946 Signaling by moderate kinase activity BRAF mutants 4.451672e-04 3.351
R-HSA-9649948 Signaling downstream of RAS mutants 4.451672e-04 3.351
R-HSA-6802955 Paradoxical activation of RAF signaling by kinase inactive BRAF 4.451672e-04 3.351
R-HSA-6802949 Signaling by RAS mutants 4.451672e-04 3.351
R-HSA-1839120 Signaling by FGFR1 amplification mutants 5.056015e-04 3.296
R-HSA-2023837 Signaling by FGFR2 amplification mutants 5.056015e-04 3.296
R-HSA-187042 TRKA activation by NGF 5.056015e-04 3.296
R-HSA-2033519 Activated point mutants of FGFR2 4.763638e-04 3.322
R-HSA-983695 Antigen activates B Cell Receptor (BCR) leading to generation of second messenge... 5.824571e-04 3.235
R-HSA-449836 Other interleukin signaling 5.387148e-04 3.269
R-HSA-2454202 Fc epsilon receptor (FCERI) signaling 6.269067e-04 3.203
R-HSA-1280215 Cytokine Signaling in Immune system 6.478434e-04 3.189
R-HSA-76002 Platelet activation, signaling and aggregation 6.723385e-04 3.172
R-HSA-109582 Hemostasis 6.906747e-04 3.161
R-HSA-9679191 Potential therapeutics for SARS 8.182675e-04 3.087
R-HSA-5654736 Signaling by FGFR1 8.361807e-04 3.078
R-HSA-112409 RAF-independent MAPK1/3 activation 8.396236e-04 3.076
R-HSA-912526 Interleukin receptor SHC signaling 9.284901e-04 3.032
R-HSA-164952 The role of Nef in HIV-1 replication and disease pathogenesis 9.284901e-04 3.032
R-HSA-9860931 Response of endothelial cells to shear stress 9.509740e-04 3.022
R-HSA-8849472 PTK6 Down-Regulation 9.826687e-04 3.008
R-HSA-9032759 NTRK2 activates RAC1 9.826687e-04 3.008
R-HSA-8939245 RUNX1 regulates transcription of genes involved in BCR signaling 9.826687e-04 3.008
R-HSA-212436 Generic Transcription Pathway 1.017854e-03 2.992
R-HSA-6783589 Interleukin-6 family signaling 1.023105e-03 2.990
R-HSA-5621575 CD209 (DC-SIGN) signaling 1.023105e-03 2.990
R-HSA-187024 NGF-independant TRKA activation 1.278097e-03 2.893
R-HSA-187706 Signalling to p38 via RIT and RIN 1.278097e-03 2.893
R-HSA-8874081 MET activates PTK2 signaling 1.230141e-03 2.910
R-HSA-9006115 Signaling by NTRK2 (TRKB) 1.342832e-03 2.872
R-HSA-5655332 Signaling by FGFR3 in disease 1.342832e-03 2.872
R-HSA-6802952 Signaling by BRAF and RAF1 fusions 1.354168e-03 2.868
R-HSA-8848021 Signaling by PTK6 1.223709e-03 2.912
R-HSA-9006927 Signaling by Non-Receptor Tyrosine Kinases 1.223709e-03 2.912
R-HSA-5674499 Negative feedback regulation of MAPK pathway 1.278097e-03 2.893
R-HSA-373755 Semaphorin interactions 1.223709e-03 2.912
R-HSA-375165 NCAM signaling for neurite out-growth 1.161902e-03 2.935
R-HSA-202733 Cell surface interactions at the vascular wall 1.455236e-03 2.837
R-HSA-9855142 Cellular responses to mechanical stimuli 1.420255e-03 2.848
R-HSA-8940973 RUNX2 regulates osteoblast differentiation 1.461814e-03 2.835
R-HSA-5654733 Negative regulation of FGFR4 signaling 1.587215e-03 2.799
R-HSA-9027283 Erythropoietin activates STAT5 1.610803e-03 2.793
R-HSA-186763 Downstream signal transduction 1.857765e-03 2.731
R-HSA-9924644 Developmental Lineages of the Mammary Gland 1.887250e-03 2.724
R-HSA-9603381 Activated NTRK3 signals through PI3K 1.980304e-03 2.703
R-HSA-428890 Role of ABL in ROBO-SLIT signaling 1.980304e-03 2.703
R-HSA-8849473 PTK6 Expression 1.980304e-03 2.703
R-HSA-9726840 SHOC2 M1731 mutant abolishes MRAS complex function 1.980304e-03 2.703
R-HSA-1839124 FGFR1 mutant receptor activation 2.155438e-03 2.666
R-HSA-9660537 Signaling by MRAS-complex mutants 2.386122e-03 2.622
R-HSA-9726842 Gain-of-function MRAS complexes activate RAF signaling 2.386122e-03 2.622
R-HSA-8985947 Interleukin-9 signaling 2.386122e-03 2.622
R-HSA-9020933 Interleukin-23 signaling 2.386122e-03 2.622
R-HSA-187037 Signaling by NTRK1 (TRKA) 2.454196e-03 2.610
R-HSA-170984 ARMS-mediated activation 2.827782e-03 2.549
R-HSA-9020958 Interleukin-21 signaling 2.827782e-03 2.549
R-HSA-430116 GP1b-IX-V activation signalling 2.827782e-03 2.549
R-HSA-8941326 RUNX2 regulates bone development 2.835741e-03 2.547
R-HSA-73857 RNA Polymerase II Transcription 2.950375e-03 2.530
R-HSA-6802948 Signaling by high-kinase activity BRAF mutants 3.024130e-03 2.519
R-HSA-8875878 MET promotes cell motility 3.220044e-03 2.492
R-HSA-6802957 Oncogenic MAPK signaling 3.234139e-03 2.490
R-HSA-9027277 Erythropoietin activates Phospholipase C gamma (PLCG) 3.304817e-03 2.481
R-HSA-202433 Generation of second messenger molecules 3.634823e-03 2.440
R-HSA-190377 FGFR2b ligand binding and activation 3.816759e-03 2.418
R-HSA-5674135 MAP2K and MAPK activation 4.080803e-03 2.389
R-HSA-5655302 Signaling by FGFR1 in disease 4.080803e-03 2.389
R-HSA-9702506 Drug resistance of FLT3 mutants 6.437812e-03 2.191
R-HSA-9700649 Drug resistance of ALK mutants 6.437812e-03 2.191
R-HSA-9669937 Drug resistance of KIT mutants 6.437812e-03 2.191
R-HSA-9674415 Drug resistance of PDGFR mutants 6.437812e-03 2.191
R-HSA-9669921 KIT mutants bind TKIs 6.437812e-03 2.191
R-HSA-9674428 PDGFR mutants bind TKIs 6.437812e-03 2.191
R-HSA-9702509 FLT3 mutants bind TKIs 6.437812e-03 2.191
R-HSA-9669914 Dasatinib-resistant KIT mutants 6.437812e-03 2.191
R-HSA-9674403 Regorafenib-resistant PDGFR mutants 6.437812e-03 2.191
R-HSA-9702581 crenolanib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9717316 alectinib-resistant ALK mutants 6.437812e-03 2.191
R-HSA-9703009 tamatinib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9717323 ceritinib-resistant ALK mutants 6.437812e-03 2.191
R-HSA-9669929 Regorafenib-resistant KIT mutants 6.437812e-03 2.191
R-HSA-9669936 Sorafenib-resistant KIT mutants 6.437812e-03 2.191
R-HSA-9702600 midostaurin-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9717301 NVP-TAE684-resistant ALK mutants 6.437812e-03 2.191
R-HSA-9717264 ASP-3026-resistant ALK mutants 6.437812e-03 2.191
R-HSA-9674396 Imatinib-resistant PDGFR mutants 6.437812e-03 2.191
R-HSA-9717319 brigatinib-resistant ALK mutants 6.437812e-03 2.191
R-HSA-9717326 crizotinib-resistant ALK mutants 6.437812e-03 2.191
R-HSA-9674401 Sunitinib-resistant PDGFR mutants 6.437812e-03 2.191
R-HSA-9717329 lorlatinib-resistant ALK mutants 6.437812e-03 2.191
R-HSA-9702596 lestaurtinib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9702636 tandutinib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9702614 ponatinib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9669924 Masitinib-resistant KIT mutants 6.437812e-03 2.191
R-HSA-9674404 Sorafenib-resistant PDGFR mutants 6.437812e-03 2.191
R-HSA-9669917 Imatinib-resistant KIT mutants 6.437812e-03 2.191
R-HSA-9702620 quizartinib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9702577 semaxanib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9702624 sorafenib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9702569 KW2449-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9702998 linifanib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9702605 pexidartinib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9702590 gilteritinib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9669934 Sunitinib-resistant KIT mutants 6.437812e-03 2.191
R-HSA-9702632 sunitinib-resistant FLT3 mutants 6.437812e-03 2.191
R-HSA-9669926 Nilotinib-resistant KIT mutants 6.437812e-03 2.191
R-HSA-1839122 Signaling by activated point mutants of FGFR1 4.363150e-03 2.360
R-HSA-9027276 Erythropoietin activates Phosphoinositide-3-kinase (PI3K) 4.943534e-03 2.306
R-HSA-190375 FGFR2c ligand binding and activation 5.557457e-03 2.255
R-HSA-399956 CRMPs in Sema3A signaling 6.204474e-03 2.207
R-HSA-5654227 Phospholipase C-mediated cascade; FGFR3 6.204474e-03 2.207
R-HSA-8847993 ERBB2 Activates PTK6 Signaling 6.204474e-03 2.207
R-HSA-170968 Frs2-mediated activation 5.557457e-03 2.255
R-HSA-389359 CD28 dependent Vav1 pathway 5.557457e-03 2.255
R-HSA-8983432 Interleukin-15 signaling 4.943534e-03 2.306
R-HSA-5654743 Signaling by FGFR4 4.558669e-03 2.341
R-HSA-877312 Regulation of IFNG signaling 4.943534e-03 2.306
R-HSA-373752 Netrin-1 signaling 4.809760e-03 2.318
R-HSA-75892 Platelet Adhesion to exposed collagen 5.557457e-03 2.255
R-HSA-983705 Signaling by the B Cell Receptor (BCR) 5.870057e-03 2.231
R-HSA-168249 Innate Immune System 5.853485e-03 2.233
R-HSA-8878171 Transcriptional regulation by RUNX1 5.401034e-03 2.268
R-HSA-453279 Mitotic G1 phase and G1/S transition 4.380255e-03 2.359
R-HSA-9027284 Erythropoietin activates RAS 6.884140e-03 2.162
R-HSA-190239 FGFR3 ligand binding and activation 6.884140e-03 2.162
R-HSA-399954 Sema3A PAK dependent Axon repulsion 6.884140e-03 2.162
R-HSA-1295596 Spry regulation of FGF signaling 6.884140e-03 2.162
R-HSA-9706369 Negative regulation of FLT3 7.596017e-03 2.119
R-HSA-354194 GRB2:SOS provides linkage to MAPK signaling for Integrins 7.596017e-03 2.119
R-HSA-399955 SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion 7.596017e-03 2.119
R-HSA-9700206 Signaling by ALK in cancer 7.637110e-03 2.117
R-HSA-9725370 Signaling by ALK fusions and activated point mutants 7.637110e-03 2.117
R-HSA-9734779 Developmental Cell Lineages of the Integumentary System 7.858740e-03 2.105
R-HSA-5621481 C-type lectin receptors (CLRs) 8.022900e-03 2.096
R-HSA-2892247 POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation 8.339671e-03 2.079
R-HSA-5621480 Dectin-2 family 8.845522e-03 2.053
R-HSA-372708 p130Cas linkage to MAPK signaling for integrins 9.114670e-03 2.040
R-HSA-5654219 Phospholipase C-mediated cascade: FGFR1 9.114670e-03 2.040
R-HSA-388841 Regulation of T cell activation by CD28 family 9.239684e-03 2.034
R-HSA-168256 Immune System 9.686311e-03 2.014
R-HSA-190242 FGFR1 ligand binding and activation 9.920588e-03 2.003
R-HSA-5654710 PI-3K cascade:FGFR3 1.075700e-02 1.968
R-HSA-186797 Signaling by PDGF 1.079578e-02 1.967
R-HSA-9734091 Drug-mediated inhibition of MET activation 1.283458e-02 1.892
R-HSA-1839128 FGFR4 mutant receptor activation 1.919055e-02 1.717
R-HSA-9603505 NTRK3 as a dependence receptor 1.919055e-02 1.717
R-HSA-2033515 t(4;14) translocations of FGFR3 1.919055e-02 1.717
R-HSA-8853334 Signaling by FGFR3 fusions in cancer 1.919055e-02 1.717
R-HSA-8853333 Signaling by FGFR2 fusions 1.919055e-02 1.717
R-HSA-9669935 Signaling by juxtamembrane domain KIT mutants 1.919055e-02 1.717
R-HSA-9680187 Signaling by extracellular domain mutants of KIT 1.919055e-02 1.717
R-HSA-9669933 Signaling by kinase domain mutants of KIT 1.919055e-02 1.717
R-HSA-5654704 SHC-mediated cascade:FGFR3 1.251966e-02 1.902
R-HSA-9034015 Signaling by NTRK3 (TRKC) 1.344507e-02 1.871
R-HSA-5654706 FRS-mediated FGFR3 signaling 1.344507e-02 1.871
R-HSA-9938206 Developmental Lineage of Mammary Stem Cells 1.439933e-02 1.842
R-HSA-5654688 SHC-mediated cascade:FGFR1 1.639279e-02 1.785
R-HSA-202430 Translocation of ZAP-70 to Immunological synapse 1.639279e-02 1.785
R-HSA-5654693 FRS-mediated FGFR1 signaling 1.743120e-02 1.759
R-HSA-9006335 Signaling by Erythropoietin 2.185359e-02 1.660
R-HSA-5654708 Downstream signaling of activated FGFR3 2.185359e-02 1.660
R-HSA-6806834 Signaling by MET 1.974459e-02 1.705
R-HSA-9671555 Signaling by PDGFR in disease 1.344507e-02 1.871
R-HSA-5654689 PI-3K cascade:FGFR1 1.439933e-02 1.842
R-HSA-912694 Regulation of IFNA/IFNB signaling 1.439933e-02 1.842
R-HSA-8876384 Listeria monocytogenes entry into host cells 1.344507e-02 1.871
R-HSA-982772 Growth hormone receptor signaling 1.538204e-02 1.813
R-HSA-400685 Sema4D in semaphorin signaling 1.743120e-02 1.759
R-HSA-167044 Signalling to RAS 1.251966e-02 1.902
R-HSA-9927432 Developmental Lineage of Mammary Gland Myoepithelial Cells 2.185359e-02 1.660
R-HSA-1266695 Interleukin-7 signaling 1.743120e-02 1.759
R-HSA-2029482 Regulation of actin dynamics for phagocytic cup formation 1.964544e-02 1.707
R-HSA-5218921 VEGFR2 mediated cell proliferation 1.743120e-02 1.759
R-HSA-9013695 NOTCH4 Intracellular Domain Regulates Transcription 1.251966e-02 1.902
R-HSA-389357 CD28 dependent PI3K/Akt signaling 1.958941e-02 1.708
R-HSA-9020591 Interleukin-12 signaling 1.749089e-02 1.757
R-HSA-9856530 High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR... 1.974459e-02 1.705
R-HSA-9830364 Formation of the nephric duct 1.743120e-02 1.759
R-HSA-9825892 Regulation of MITF-M-dependent genes involved in cell cycle and proliferation 1.344507e-02 1.871
R-HSA-9022699 MECP2 regulates neuronal receptors and channels 1.849687e-02 1.733
R-HSA-5663205 Infectious disease 1.316023e-02 1.881
R-HSA-74160 Gene expression (Transcription) 1.551465e-02 1.809
R-HSA-1500931 Cell-Cell communication 2.215718e-02 1.654
R-HSA-9833109 Evasion by RSV of host interferon responses 2.422073e-02 1.616
R-HSA-447115 Interleukin-12 family signaling 2.471126e-02 1.607
R-HSA-111465 Apoptotic cleavage of cellular proteins 2.544197e-02 1.594
R-HSA-9665230 Drug resistance in ERBB2 KD mutants 2.550599e-02 1.593
R-HSA-9024909 BDNF activates NTRK2 (TRKB) signaling 2.550599e-02 1.593
R-HSA-9025046 NTF3 activates NTRK2 (TRKB) signaling 2.550599e-02 1.593
R-HSA-9652282 Drug-mediated inhibition of ERBB2 signaling 2.550599e-02 1.593
R-HSA-9026357 NTF4 activates NTRK2 (TRKB) signaling 2.550599e-02 1.593
R-HSA-9034013 NTF3 activates NTRK3 signaling 2.550599e-02 1.593
R-HSA-9665250 Resistance of ERBB2 KD mutants to AEE788 2.550599e-02 1.593
R-HSA-9665249 Resistance of ERBB2 KD mutants to afatinib 2.550599e-02 1.593
R-HSA-9665737 Drug resistance in ERBB2 TMD/JMD mutants 2.550599e-02 1.593
R-HSA-9665247 Resistance of ERBB2 KD mutants to osimertinib 2.550599e-02 1.593
R-HSA-9665246 Resistance of ERBB2 KD mutants to neratinib 2.550599e-02 1.593
R-HSA-9665251 Resistance of ERBB2 KD mutants to lapatinib 2.550599e-02 1.593
R-HSA-9665244 Resistance of ERBB2 KD mutants to sapitinib 2.550599e-02 1.593
R-HSA-9665245 Resistance of ERBB2 KD mutants to tesevatinib 2.550599e-02 1.593
R-HSA-9665233 Resistance of ERBB2 KD mutants to trastuzumab 2.550599e-02 1.593
R-HSA-9927426 Developmental Lineage of Mammary Gland Alveolar Cells 2.925206e-02 1.534
R-HSA-9768919 NPAS4 regulates expression of target genes 2.925206e-02 1.534
R-HSA-5654687 Downstream signaling of activated FGFR1 3.056968e-02 1.515
R-HSA-9860927 Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZ... 3.056968e-02 1.515
R-HSA-9034793 Activated NTRK3 signals through PLCG1 3.178115e-02 1.498
R-HSA-167021 PLC-gamma1 signalling 3.178115e-02 1.498
R-HSA-8853336 Signaling by plasma membrane FGFR1 fusions 3.178115e-02 1.498
R-HSA-8875513 MET interacts with TNS proteins 3.178115e-02 1.498
R-HSA-8865999 MET activates PTPN11 3.178115e-02 1.498
R-HSA-198745 Signalling to STAT3 3.178115e-02 1.498
R-HSA-8875791 MET activates STAT3 3.178115e-02 1.498
R-HSA-8853659 RET signaling 3.191050e-02 1.496
R-HSA-2730905 Role of LAT2/NTAL/LAB on calcium mobilization 3.253936e-02 1.488
R-HSA-452723 Transcriptional regulation of pluripotent stem cells 3.466040e-02 1.460
R-HSA-9009391 Extra-nuclear estrogen signaling 3.647682e-02 1.438
R-HSA-9026527 Activated NTRK2 signals through PLCG1 3.801629e-02 1.420
R-HSA-1251932 PLCG1 events in ERBB2 signaling 3.801629e-02 1.420
R-HSA-1307965 betaKlotho-mediated ligand binding 3.801629e-02 1.420
R-HSA-1306955 GRB7 events in ERBB2 signaling 3.801629e-02 1.420
R-HSA-191650 Regulation of gap junction activity 3.801629e-02 1.420
R-HSA-9851151 MDK and PTN in ALK signaling 3.801629e-02 1.420
R-HSA-8853884 Transcriptional Regulation by VENTX 3.895072e-02 1.409
R-HSA-5675221 Negative regulation of MAPK pathway 4.042363e-02 1.393
R-HSA-1280218 Adaptive Immune System 4.272172e-02 1.369
R-HSA-74713 IRS activation 4.421166e-02 1.354
R-HSA-190374 FGFR1c and Klotho ligand binding and activation 4.421166e-02 1.354
R-HSA-9673768 Signaling by membrane-tethered fusions of PDGFRA or PDGFRB 4.421166e-02 1.354
R-HSA-9706377 FLT3 signaling by CBL mutants 4.421166e-02 1.354
R-HSA-8849468 PTK6 Regulates Proteins Involved in RNA Processing 4.421166e-02 1.354
R-HSA-8849474 PTK6 Activates STAT3 4.421166e-02 1.354
R-HSA-8866376 Reelin signalling pathway 4.421166e-02 1.354
R-HSA-202403 TCR signaling 4.505059e-02 1.346
R-HSA-75153 Apoptotic execution phase 4.809444e-02 1.318
R-HSA-6785807 Interleukin-4 and Interleukin-13 signaling 4.844460e-02 1.315
R-HSA-8849470 PTK6 Regulates Cell Cycle 5.036752e-02 1.298
R-HSA-8852405 Signaling by MST1 5.036752e-02 1.298
R-HSA-9758919 Epithelial-Mesenchymal Transition (EMT) during gastrulation 5.036752e-02 1.298
R-HSA-9725371 Nuclear events stimulated by ALK signaling in cancer 5.129979e-02 1.290
R-HSA-373760 L1CAM interactions 5.256584e-02 1.279
R-HSA-9766229 Degradation of CDH1 5.293060e-02 1.276
R-HSA-8878166 Transcriptional regulation by RUNX2 5.553079e-02 1.255
R-HSA-9645135 STAT5 Activation 5.648410e-02 1.248
R-HSA-8857538 PTK6 promotes HIF1A stabilization 5.648410e-02 1.248
R-HSA-6806942 MET Receptor Activation 5.648410e-02 1.248
R-HSA-9634815 Transcriptional Regulation by NPAS4 5.793190e-02 1.237
R-HSA-162909 Host Interactions of HIV factors 6.064637e-02 1.217
R-HSA-9032845 Activated NTRK2 signals through CDK5 6.256167e-02 1.204
R-HSA-8851907 MET activates PI3K/AKT signaling 6.256167e-02 1.204
R-HSA-190371 FGFR3b ligand binding and activation 6.256167e-02 1.204
R-HSA-418886 Netrin mediated repulsion signals 6.256167e-02 1.204
R-HSA-167590 Nef Mediated CD4 Down-regulation 6.256167e-02 1.204
R-HSA-177929 Signaling by EGFR 6.484344e-02 1.188
R-HSA-9764561 Regulation of CDH1 Function 6.661283e-02 1.176
R-HSA-8875656 MET receptor recycling 6.860046e-02 1.164
R-HSA-190370 FGFR1b ligand binding and activation 6.860046e-02 1.164
R-HSA-9028335 Activated NTRK2 signals through PI3K 6.860046e-02 1.164
R-HSA-8849469 PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 6.860046e-02 1.164
R-HSA-1253288 Downregulation of ERBB4 signaling 6.860046e-02 1.164
R-HSA-9700645 ALK mutants bind TKIs 7.460072e-02 1.127
R-HSA-428542 Regulation of commissural axon pathfinding by SLIT and ROBO 7.460072e-02 1.127
R-HSA-9820952 Respiratory Syncytial Virus Infection Pathway 7.842306e-02 1.106
R-HSA-8875555 MET activates RAP1 and RAC1 8.056269e-02 1.094
R-HSA-198203 PI3K/AKT activation 8.056269e-02 1.094
R-HSA-2586552 Signaling by Leptin 8.056269e-02 1.094
R-HSA-8934903 Receptor Mediated Mitophagy 8.056269e-02 1.094
R-HSA-74749 Signal attenuation 8.056269e-02 1.094
R-HSA-9830369 Kidney development 8.514450e-02 1.070
R-HSA-9034864 Activated NTRK3 signals through RAS 8.648663e-02 1.063
R-HSA-8876493 InlA-mediated entry of Listeria monocytogenes into host cells 8.648663e-02 1.063
R-HSA-8936459 RUNX1 regulates genes involved in megakaryocyte differentiation and platelet fun... 8.707566e-02 1.060
R-HSA-416550 Sema4D mediated inhibition of cell attachment and migration 9.237275e-02 1.034
R-HSA-9026519 Activated NTRK2 signals through RAS 9.237275e-02 1.034
R-HSA-4086398 Ca2+ pathway 9.692407e-02 1.014
R-HSA-8851805 MET activates RAS signaling 9.822132e-02 1.008
R-HSA-9634285 Constitutive Signaling by Overexpressed ERBB2 9.822132e-02 1.008
R-HSA-9028731 Activated NTRK2 signals through FRS2 and FRS3 9.822132e-02 1.008
R-HSA-2428933 SHC-related events triggered by IGF1R 9.822132e-02 1.008
R-HSA-1358803 Downregulation of ERBB2:ERBB3 signaling 9.822132e-02 1.008
R-HSA-9842663 Signaling by LTK 9.822132e-02 1.008
R-HSA-9013694 Signaling by NOTCH4 9.893059e-02 1.005
R-HSA-3000171 Non-integrin membrane-ECM interactions 1.009488e-01 0.996
R-HSA-190322 FGFR4 ligand binding and activation 1.040326e-01 0.983
R-HSA-190373 FGFR1c ligand binding and activation 1.040326e-01 0.983
R-HSA-383280 Nuclear Receptor transcription pathway 1.070717e-01 0.970
R-HSA-6783783 Interleukin-10 signaling 1.070717e-01 0.970
R-HSA-6796648 TP53 Regulates Transcription of DNA Repair Genes 1.070717e-01 0.970
R-HSA-877300 Interferon gamma signaling 1.074307e-01 0.969
R-HSA-5655291 Signaling by FGFR4 in disease 1.098067e-01 0.959
R-HSA-1170546 Prolactin receptor signaling 1.098067e-01 0.959
R-HSA-177504 Retrograde neurotrophin signalling 1.098067e-01 0.959
R-HSA-190372 FGFR3c ligand binding and activation 1.098067e-01 0.959
R-HSA-9734767 Developmental Cell Lineages 1.114945e-01 0.953
R-HSA-8875360 InlB-mediated entry of Listeria monocytogenes into host cell 1.155440e-01 0.937
R-HSA-9673770 Signaling by PDGFRA extracellular domain mutants 1.155440e-01 0.937
R-HSA-9673767 Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants 1.155440e-01 0.937
R-HSA-8964315 G beta:gamma signalling through BTK 1.155440e-01 0.937
R-HSA-5654228 Phospholipase C-mediated cascade; FGFR4 1.155440e-01 0.937
R-HSA-6785631 ERBB2 Regulates Cell Motility 1.155440e-01 0.937
R-HSA-171007 p38MAPK events 1.155440e-01 0.937
R-HSA-388844 Receptor-type tyrosine-protein phosphatases 1.212447e-01 0.916
R-HSA-1963640 GRB2 events in ERBB2 signaling 1.269089e-01 0.897
R-HSA-9702518 STAT5 activation downstream of FLT3 ITD mutants 1.269089e-01 0.897
R-HSA-1963642 PI3K events in ERBB2 signaling 1.325370e-01 0.878
R-HSA-164938 Nef-mediates down modulation of cell surface receptors by recruiting them to cla... 1.325370e-01 0.878
R-HSA-8986944 Transcriptional Regulation by MECP2 1.368395e-01 0.864
R-HSA-9665348 Signaling by ERBB2 ECD mutants 1.381292e-01 0.860
R-HSA-210993 Tie2 Signaling 1.381292e-01 0.860
R-HSA-432142 Platelet sensitization by LDL 1.381292e-01 0.860
R-HSA-180292 GAB1 signalosome 1.381292e-01 0.860
R-HSA-392517 Rap1 signalling 1.436857e-01 0.843
R-HSA-6807004 Negative regulation of MET activity 1.492067e-01 0.826
R-HSA-5654720 PI-3K cascade:FGFR4 1.492067e-01 0.826
R-HSA-373753 Nephrin family interactions 1.492067e-01 0.826
R-HSA-416572 Sema4D induced cell migration and growth-cone collapse 1.492067e-01 0.826
R-HSA-445144 Signal transduction by L1 1.492067e-01 0.826
R-HSA-5607764 CLEC7A (Dectin-1) signaling 1.523413e-01 0.817
R-HSA-5602498 MyD88 deficiency (TLR2/4) 1.546924e-01 0.811
R-HSA-9931295 PD-L1(CD274) glycosylation and translocation to plasma membrane 1.546924e-01 0.811
R-HSA-5654719 SHC-mediated cascade:FGFR4 1.601431e-01 0.795
R-HSA-5603041 IRAK4 deficiency (TLR2/4) 1.601431e-01 0.795
R-HSA-5654712 FRS-mediated FGFR4 signaling 1.655590e-01 0.781
R-HSA-9679506 SARS-CoV Infections 1.693909e-01 0.771
R-HSA-9830674 Formation of the ureteric bud 1.709403e-01 0.767
R-HSA-9634638 Estrogen-dependent nuclear events downstream of ESR-membrane signaling 1.709403e-01 0.767
R-HSA-9833110 RSV-host interactions 1.727433e-01 0.763
R-HSA-376176 Signaling by ROBO receptors 1.737494e-01 0.760
R-HSA-9665686 Signaling by ERBB2 TMD/JMD mutants 1.762873e-01 0.754
R-HSA-9703648 Signaling by FLT3 ITD and TKD mutants 1.762873e-01 0.754
R-HSA-418592 ADP signalling through P2Y purinoceptor 1 1.762873e-01 0.754
R-HSA-9620244 Long-term potentiation 1.816000e-01 0.741
R-HSA-525793 Myogenesis 1.868789e-01 0.728
R-HSA-8934593 Regulation of RUNX1 Expression and Activity 1.868789e-01 0.728
R-HSA-2871796 FCERI mediated MAPK activation 1.912319e-01 0.718
R-HSA-9730414 MITF-M-regulated melanocyte development 1.914459e-01 0.718
R-HSA-202427 Phosphorylation of CD3 and TCR zeta chains 1.921240e-01 0.716
R-HSA-1474244 Extracellular matrix organization 1.923153e-01 0.716
R-HSA-77387 Insulin receptor recycling 1.973356e-01 0.705
R-HSA-9638334 Iron assimilation using enterobactin 1.973356e-01 0.705
R-HSA-9664565 Signaling by ERBB2 KD Mutants 2.025139e-01 0.694
R-HSA-909733 Interferon alpha/beta signaling 2.029195e-01 0.693
R-HSA-9824446 Viral Infection Pathways 2.071229e-01 0.684
R-HSA-1227990 Signaling by ERBB2 in Cancer 2.076591e-01 0.683
R-HSA-5654716 Downstream signaling of activated FGFR4 2.076591e-01 0.683
R-HSA-1250196 SHC1 events in ERBB2 signaling 2.076591e-01 0.683
R-HSA-8863795 Downregulation of ERBB2 signaling 2.076591e-01 0.683
R-HSA-456926 Thrombin signalling through proteinase activated receptors (PARs) 2.076591e-01 0.683
R-HSA-9820960 Respiratory syncytial virus (RSV) attachment and entry 2.127714e-01 0.672
R-HSA-162906 HIV Infection 2.145927e-01 0.668
R-HSA-397795 G-protein beta:gamma signalling 2.228983e-01 0.652
R-HSA-5685938 HDR through Single Strand Annealing (SSA) 2.228983e-01 0.652
R-HSA-8939211 ESR-mediated signaling 2.314818e-01 0.635
R-HSA-392518 Signal amplification 2.328961e-01 0.633
R-HSA-5205647 Mitophagy 2.328961e-01 0.633
R-HSA-9682385 FLT3 signaling in disease 2.427665e-01 0.615
R-HSA-196757 Metabolism of folate and pterines 2.476545e-01 0.606
R-HSA-3858494 Beta-catenin independent WNT signaling 2.598540e-01 0.585
R-HSA-8941858 Regulation of RUNX3 expression and activity 2.621316e-01 0.581
R-HSA-5602358 Diseases associated with the TLR signaling cascade 2.621316e-01 0.581
R-HSA-5260271 Diseases of Immune System 2.621316e-01 0.581
R-HSA-1251985 Nuclear signaling by ERBB4 2.621316e-01 0.581
R-HSA-913531 Interferon Signaling 2.649001e-01 0.577
R-HSA-9705671 SARS-CoV-2 activates/modulates innate and adaptive immune responses 2.765653e-01 0.558
R-HSA-187577 SCF(Skp2)-mediated degradation of p27/p21 2.856494e-01 0.544
R-HSA-3214858 RMTs methylate histone arginines 2.856494e-01 0.544
R-HSA-9856651 MITF-M-dependent gene expression 2.956411e-01 0.529
R-HSA-437239 Recycling pathway of L1 2.994022e-01 0.524
R-HSA-9634597 GPER1 signaling 3.039279e-01 0.517
R-HSA-157858 Gap junction trafficking and regulation 3.084247e-01 0.511
R-HSA-109581 Apoptosis 3.241144e-01 0.489
R-HSA-8948751 Regulation of PTEN stability and activity 3.261259e-01 0.487
R-HSA-69278 Cell Cycle, Mitotic 3.296418e-01 0.482
R-HSA-5693565 Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at... 3.518396e-01 0.454
R-HSA-9764274 Regulation of Expression and Function of Type I Classical Cadherins 3.523000e-01 0.453
R-HSA-9764265 Regulation of CDH1 Expression and Function 3.523000e-01 0.453
R-HSA-983231 Factors involved in megakaryocyte development and platelet production 3.569614e-01 0.447
R-HSA-9793380 Formation of paraxial mesoderm 3.601930e-01 0.443
R-HSA-1660499 Synthesis of PIPs at the plasma membrane 3.643296e-01 0.439
R-HSA-5690714 CD22 mediated BCR regulation 3.725236e-01 0.429
R-HSA-5693606 DNA Double Strand Break Response 3.846188e-01 0.415
R-HSA-69202 Cyclin E associated events during G1/S transition 3.964830e-01 0.402
R-HSA-9856649 Transcriptional and post-translational regulation of MITF-M expression and activ... 4.003872e-01 0.398
R-HSA-3000178 ECM proteoglycans 4.003872e-01 0.398
R-HSA-9638482 Metal ion assimilation from the host 4.003872e-01 0.398
R-HSA-69656 Cyclin A:Cdk2-associated events at S phase entry 4.042663e-01 0.393
R-HSA-9759476 Regulation of Homotypic Cell-Cell Adhesion 4.051149e-01 0.392
R-HSA-1236394 Signaling by ERBB4 4.119503e-01 0.385
R-HSA-389948 Co-inhibition by PD-1 4.141009e-01 0.383
R-HSA-1169408 ISG15 antiviral mechanism 4.157553e-01 0.381
R-HSA-416482 G alpha (12/13) signalling events 4.270248e-01 0.370
R-HSA-216083 Integrin cell surface interactions 4.270248e-01 0.370
R-HSA-5357801 Programmed Cell Death 4.274544e-01 0.369
R-HSA-9707564 Cytoprotection by HMOX1 4.453309e-01 0.351
R-HSA-8939236 RUNX1 regulates transcription of genes involved in differentiation of HSCs 4.489219e-01 0.348
R-HSA-9006931 Signaling by Nuclear Receptors 4.508583e-01 0.346
R-HSA-6794362 Protein-protein interactions at synapses 4.524900e-01 0.344
R-HSA-418990 Adherens junctions interactions 4.558367e-01 0.341
R-HSA-9909615 Regulation of PD-L1(CD274) Post-translational modification 4.560352e-01 0.341
R-HSA-438064 Post NMDA receptor activation events 4.630575e-01 0.334
R-HSA-9663891 Selective autophagy 4.665349e-01 0.331
R-HSA-1236974 ER-Phagosome pathway 4.699900e-01 0.328
R-HSA-202424 Downstream TCR signaling 4.734229e-01 0.325
R-HSA-9705683 SARS-CoV-2-host interactions 4.771217e-01 0.321
R-HSA-9824439 Bacterial Infection Pathways 4.972392e-01 0.303
R-HSA-157118 Signaling by NOTCH 5.019956e-01 0.299
R-HSA-8878159 Transcriptional regulation by RUNX3 5.033448e-01 0.298
R-HSA-1640170 Cell Cycle 5.099367e-01 0.292
R-HSA-442755 Activation of NMDA receptors and postsynaptic events 5.192340e-01 0.285
R-HSA-1483255 PI Metabolism 5.192340e-01 0.285
R-HSA-421270 Cell-cell junction organization 5.241286e-01 0.281
R-HSA-418346 Platelet homeostasis 5.346195e-01 0.272
R-HSA-1236975 Antigen processing-Cross presentation 5.406363e-01 0.267
R-HSA-2672351 Stimuli-sensing channels 5.406363e-01 0.267
R-HSA-5693567 HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA) 5.582282e-01 0.253
R-HSA-2029485 Role of phospholipids in phagocytosis 5.667723e-01 0.247
R-HSA-5693538 Homology Directed Repair 5.751526e-01 0.240
R-HSA-446728 Cell junction organization 5.756296e-01 0.240
R-HSA-166058 MyD88:MAL(TIRAP) cascade initiated on plasma membrane 5.779102e-01 0.238
R-HSA-168188 Toll Like Receptor TLR6:TLR2 Cascade 5.779102e-01 0.238
R-HSA-168179 Toll Like Receptor TLR1:TLR2 Cascade 5.860772e-01 0.232
R-HSA-181438 Toll Like Receptor 2 (TLR2) Cascade 5.860772e-01 0.232
R-HSA-9851695 Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes 5.967235e-01 0.224
R-HSA-9841922 MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesi... 5.967235e-01 0.224
R-HSA-9818564 Epigenetic regulation of gene expression by MLL3 and MLL4 complexes 5.967235e-01 0.224
R-HSA-69206 G1/S Transition 5.967235e-01 0.224
R-HSA-6798695 Neutrophil degranulation 5.996084e-01 0.222
R-HSA-195721 Signaling by WNT 6.111226e-01 0.214
R-HSA-6807070 PTEN Regulation 6.366636e-01 0.196
R-HSA-1632852 Macroautophagy 6.413722e-01 0.193
R-HSA-2871837 FCERI mediated NF-kB activation 6.506088e-01 0.187
R-HSA-166016 Toll Like Receptor 4 (TLR4) Cascade 6.596098e-01 0.181
R-HSA-69242 S Phase 6.596098e-01 0.181
R-HSA-9758941 Gastrulation 6.618239e-01 0.179
R-HSA-5693532 DNA Double-Strand Break Repair 6.705386e-01 0.174
R-HSA-9917777 Epigenetic regulation by WDR5-containing histone modifying complexes 6.726823e-01 0.172
R-HSA-1169410 Antiviral mechanism by IFN-stimulated genes 6.726823e-01 0.172
R-HSA-9612973 Autophagy 6.769284e-01 0.169
R-HSA-9694516 SARS-CoV-2 Infection 6.913949e-01 0.160
R-HSA-418555 G alpha (s) signalling events 7.089899e-01 0.149
R-HSA-9909648 Regulation of PD-L1(CD274) expression 7.108857e-01 0.148
R-HSA-983712 Ion channel transport 7.413045e-01 0.130
R-HSA-168898 Toll-like Receptor Cascades 7.446679e-01 0.128
R-HSA-9640148 Infection with Enterobacteria 7.639579e-01 0.117
R-HSA-8953897 Cellular responses to stimuli 7.721519e-01 0.112
R-HSA-112314 Neurotransmitter receptors and postsynaptic signal transmission 7.789249e-01 0.109
R-HSA-196849 Metabolism of water-soluble vitamins and cofactors 8.035349e-01 0.095
R-HSA-3247509 Chromatin modifying enzymes 8.086240e-01 0.092
R-HSA-3700989 Transcriptional Regulation by TP53 8.250760e-01 0.084
R-HSA-4839726 Chromatin organization 8.265716e-01 0.083
R-HSA-112316 Neuronal System 8.277024e-01 0.082
R-HSA-416476 G alpha (q) signalling events 8.428508e-01 0.074
R-HSA-9711123 Cellular response to chemical stress 8.469300e-01 0.072
R-HSA-1483257 Phospholipid metabolism 8.718514e-01 0.060
R-HSA-212165 Epigenetic regulation of gene expression 8.934534e-01 0.049
R-HSA-112315 Transmission across Chemical Synapses 8.934534e-01 0.049
R-HSA-73894 DNA Repair 9.165596e-01 0.038
R-HSA-196854 Metabolism of vitamins and cofactors 9.187385e-01 0.037
R-HSA-983169 Class I MHC mediated antigen processing & presentation 9.288163e-01 0.032
R-HSA-418594 G alpha (i) signalling events 9.392874e-01 0.027
R-HSA-388396 GPCR downstream signalling 9.669275e-01 0.015
R-HSA-372790 Signaling by GPCR 9.794602e-01 0.009
R-HSA-199991 Membrane Trafficking 9.878813e-01 0.005
R-HSA-5653656 Vesicle-mediated transport 9.959000e-01 0.002
R-HSA-382551 Transport of small molecules 9.987460e-01 0.001
R-HSA-2262752 Cellular responses to stress 9.990284e-01 0.000
R-HSA-556833 Metabolism of lipids 9.999640e-01 0.000
R-HSA-1430728 Metabolism 1.000000e+00 0.000
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kinase JSD_mean pearson_surrounding kinase_max_IC_position max_position_JSD
EGFREGFR 0.753 0.362 1 0.731
SYKSYK 0.751 0.313 -1 0.789
ZAP70ZAP70 0.747 0.318 -1 0.792
MATKMATK 0.746 0.262 -1 0.784
BMPR2_TYRBMPR2_TYR 0.746 0.268 -1 0.752
METMET 0.744 0.266 3 0.641
FLT1FLT1 0.743 0.267 -1 0.811
WEE1_TYRWEE1_TYR 0.739 0.258 -1 0.659
BMXBMX 0.739 0.236 -1 0.682
KITKIT 0.737 0.212 3 0.668
TXKTXK 0.737 0.198 1 0.608
ABL2ABL2 0.735 0.170 -1 0.725
MUSKMUSK 0.735 0.284 1 0.695
KDRKDR 0.734 0.182 3 0.631
EPHB4EPHB4 0.734 0.168 -1 0.753
FLT3FLT3 0.733 0.178 3 0.722
ERBB2ERBB2 0.733 0.226 1 0.715
PDHK1_TYRPDHK1_TYR 0.732 0.154 -1 0.741
ITKITK 0.732 0.149 -1 0.594
ERBB4ERBB4 0.732 0.251 1 0.764
FGFR4FGFR4 0.731 0.240 -1 0.810
EPHA6EPHA6 0.731 0.141 -1 0.767
INSRRINSRR 0.731 0.155 3 0.647
PTK2PTK2 0.731 0.175 -1 0.709
JAK3JAK3 0.731 0.139 1 0.590
MAP2K6_TYRMAP2K6_TYR 0.731 0.149 -1 0.718
CSF1RCSF1R 0.730 0.128 3 0.676
EPHB2EPHB2 0.729 0.168 -1 0.755
FGRFGR 0.729 0.119 1 0.613
NTRK3NTRK3 0.729 0.224 -1 0.788
PINK1_TYRPINK1_TYR 0.728 0.085 1 0.629
ABL1ABL1 0.728 0.116 -1 0.695
FRKFRK 0.728 0.178 -1 0.650
MAP2K4_TYRMAP2K4_TYR 0.727 0.106 -1 0.712
FYNFYN 0.727 0.169 -1 0.606
EPHA8EPHA8 0.727 0.177 -1 0.746
FLT4FLT4 0.727 0.157 3 0.622
PDHK3_TYRPDHK3_TYR 0.726 0.034 4 0.704
MST1RMST1R 0.725 0.105 3 0.685
FERFER 0.725 0.132 1 0.636
PDHK4_TYRPDHK4_TYR 0.725 0.037 2 0.638
BLKBLK 0.725 0.110 -1 0.632
EPHB1EPHB1 0.724 0.107 1 0.635
ROS1ROS1 0.724 0.059 3 0.720
RETRET 0.723 0.031 1 0.613
CSKCSK 0.723 0.146 2 0.572
LCKLCK 0.723 0.105 -1 0.622
YES1YES1 0.723 0.082 -1 0.594
FGFR2FGFR2 0.723 0.116 3 0.643
PDGFRBPDGFRB 0.723 0.071 3 0.709
NTRK1NTRK1 0.722 0.161 -1 0.767
EPHA2EPHA2 0.722 0.188 -1 0.792
TYK2TYK2 0.722 0.039 1 0.592
PKMYT1_TYRPKMYT1_TYR 0.721 -0.017 3 0.721
EPHA4EPHA4 0.721 0.085 2 0.547
IGF1RIGF1R 0.721 0.159 3 0.568
FGFR3FGFR3 0.720 0.137 3 0.612
INSRINSR 0.719 0.103 3 0.633
EPHB3EPHB3 0.719 0.073 -1 0.727
SRCSRC 0.719 0.130 -1 0.605
TECTEC 0.719 0.069 -1 0.558
EPHA5EPHA5 0.718 0.138 2 0.523
JAK2JAK2 0.718 0.014 1 0.576
MAP2K7_TYRMAP2K7_TYR 0.718 -0.117 2 0.659
HCKHCK 0.717 0.046 -1 0.608
TNNI3K_TYRTNNI3K_TYR 0.717 0.092 1 0.626
NTRK2NTRK2 0.717 0.116 3 0.624
JAK1JAK1 0.716 0.059 1 0.526
TESK1_TYRTESK1_TYR 0.716 -0.103 3 0.764
SRMSSRMS 0.715 0.049 1 0.657
EPHA7EPHA7 0.715 0.065 2 0.565
TYRO3TYRO3 0.715 -0.028 3 0.732
ALKALK 0.715 0.054 3 0.633
PDGFRAPDGFRA 0.714 0.020 3 0.721
FGFR1FGFR1 0.714 0.063 3 0.635
LIMK1_TYRLIMK1_TYR 0.713 -0.046 2 0.699
BTKBTK 0.713 0.009 -1 0.524
PTK6PTK6 0.712 0.035 -1 0.598
EPHA3EPHA3 0.709 0.046 2 0.527
MERTKMERTK 0.708 0.017 3 0.615
LYNLYN 0.708 0.038 3 0.615
TEKTEK 0.707 -0.009 3 0.654
LTKLTK 0.707 0.022 3 0.623
LIMK2_TYRLIMK2_TYR 0.707 -0.098 -3 0.682
FESFES 0.702 0.130 -1 0.671
DDR1DDR1 0.702 -0.165 4 0.608
PTK2BPTK2B 0.699 0.002 -1 0.580
AXLAXL 0.697 -0.103 3 0.632
TNK2TNK2 0.695 -0.122 3 0.615
EPHA1EPHA1 0.693 -0.079 3 0.630
DDR2DDR2 0.693 -0.086 3 0.624
TNK1TNK1 0.688 -0.174 3 0.687
NEK10_TYRNEK10_TYR 0.688 -0.163 1 0.421
DSTYKDSTYK 0.684 0.391 2 0.747
COTCOT 0.684 0.334 2 0.706
GRK7GRK7 0.683 0.330 1 0.705
MLK4MLK4 0.678 0.291 2 0.685
EEF2KEEF2K 0.678 0.317 3 0.861
BMPR1BBMPR1B 0.676 0.247 1 0.621
ACVR2AACVR2A 0.676 0.325 -2 0.776
ACVR2BACVR2B 0.675 0.310 -2 0.770
MLK1MLK1 0.673 0.242 2 0.749
TTKTTK 0.673 0.338 -2 0.815
ALPHAK3ALPHAK3 0.672 0.322 -1 0.788
MLK3MLK3 0.669 0.231 2 0.745
NEK6NEK6 0.668 0.276 -2 0.755
PLK1PLK1 0.668 0.259 -2 0.776
TGFBR1TGFBR1 0.668 0.218 -2 0.719
ALK4ALK4 0.667 0.199 -2 0.725
TLK1TLK1 0.667 0.262 -2 0.755
BMPR1ABMPR1A 0.666 0.211 1 0.609
OSR1OSR1 0.666 0.237 2 0.668
HRIHRI 0.665 0.288 -2 0.744
ALK2ALK2 0.665 0.194 -2 0.731
BMPR2BMPR2 0.664 0.285 -2 0.711
MOSMOS 0.663 0.151 1 0.590
CLK3CLK3 0.663 0.151 1 0.589
NEK7NEK7 0.662 0.181 -3 0.650
TGFBR2TGFBR2 0.660 0.214 -2 0.794
PRPKPRPK 0.660 0.146 -1 0.705
PKRPKR 0.660 0.143 1 0.647
MST2MST2 0.660 0.194 1 0.558
GCN2GCN2 0.659 0.176 2 0.630
TAO3TAO3 0.659 0.163 1 0.565
GRK6GRK6 0.659 0.151 1 0.712
MEKK2MEKK2 0.659 0.138 2 0.690
MEKK3MEKK3 0.659 0.115 1 0.592
DLKDLK 0.658 0.091 1 0.664
GRK4GRK4 0.658 0.163 -2 0.705
GRK2GRK2 0.657 0.112 -2 0.570
TTBK2TTBK2 0.657 0.099 2 0.622
ANKRD3ANKRD3 0.657 0.099 1 0.603
PERKPERK 0.656 0.221 -2 0.752
VRK1VRK1 0.656 0.099 2 0.716
CHAK2CHAK2 0.656 0.067 -1 0.577
GRK3GRK3 0.656 0.147 -2 0.557
GRK5GRK5 0.656 0.094 -3 0.723
YSK4YSK4 0.656 0.132 1 0.540
ZAKZAK 0.654 0.085 1 0.618
CDK1CDK1 0.654 0.094 1 0.417
MST1MST1 0.653 0.146 1 0.561
NEK8NEK8 0.653 0.119 2 0.738
PLK2PLK2 0.653 0.188 -3 0.751
MEKK1MEKK1 0.652 0.081 1 0.588
MYO3AMYO3A 0.652 0.163 1 0.602
NEK9NEK9 0.651 0.070 2 0.731
TNIKTNIK 0.651 0.135 3 0.859
PLK3PLK3 0.651 0.158 2 0.540
MST3MST3 0.650 0.080 2 0.787
NIKNIK 0.650 -0.017 -3 0.694
TLK2TLK2 0.649 0.107 1 0.604
GRK1GRK1 0.647 0.093 -2 0.617
CDK2CDK2 0.647 0.133 1 0.545
RAF1RAF1 0.647 -0.056 1 0.579
PKN2PKN2 0.646 0.051 -3 0.631
ATMATM 0.646 0.057 1 0.504
TAO2TAO2 0.646 0.070 2 0.755
VRK2VRK2 0.646 -0.100 1 0.655
MST4MST4 0.646 0.075 2 0.733
IRE2IRE2 0.645 0.101 2 0.689
SRPK3SRPK3 0.645 0.108 -3 0.560
ULK2ULK2 0.645 0.002 2 0.654
GAKGAK 0.645 -0.032 1 0.551
GCKGCK 0.645 0.055 1 0.546
NEK5NEK5 0.645 0.005 1 0.581
PKCDPKCD 0.645 0.078 2 0.741
CHAK1CHAK1 0.644 0.029 2 0.697
CDKL1CDKL1 0.644 0.001 -3 0.614
PKCBPKCB 0.644 0.110 2 0.758
MINKMINK 0.644 0.054 1 0.538
KISKIS 0.643 0.070 1 0.408
MEK5MEK5 0.643 -0.060 2 0.675
CAMK1BCAMK1B 0.643 -0.060 -3 0.671
BRAFBRAF 0.643 -0.012 -4 0.717
MYO3BMYO3B 0.643 0.122 2 0.751
CAMK2GCAMK2G 0.643 -0.033 2 0.559
PASKPASK 0.642 0.040 -3 0.661
PKCHPKCH 0.642 0.076 2 0.733
TAK1TAK1 0.642 0.002 1 0.553
CDK5CDK5 0.642 0.062 1 0.415
IRE1IRE1 0.642 0.052 1 0.636
ATRATR 0.642 -0.063 1 0.558
MLK2MLK2 0.642 -0.020 2 0.713
PKCGPKCG 0.641 0.092 2 0.755
HGKHGK 0.641 0.063 3 0.861
MEK1MEK1 0.641 -0.084 2 0.648
PKN3PKN3 0.641 0.002 -3 0.624
NUAK2NUAK2 0.640 0.030 -3 0.635
PRP4PRP4 0.640 0.032 -3 0.664
MTORMTOR 0.640 -0.061 1 0.546
LRRK2LRRK2 0.639 -0.004 2 0.724
LATS1LATS1 0.639 0.036 -3 0.695
PKCAPKCA 0.639 0.096 2 0.747
PIM3PIM3 0.638 -0.022 -3 0.658
HASPINHASPIN 0.638 0.076 -1 0.461
SRPK1SRPK1 0.638 0.054 -3 0.575
NLKNLK 0.637 -0.075 1 0.553
CAMLCKCAMLCK 0.637 -0.090 -2 0.569
YSK1YSK1 0.636 0.032 2 0.746
ULK1ULK1 0.635 -0.041 -3 0.648
FAM20CFAM20C 0.635 0.036 2 0.371
KHS2KHS2 0.635 0.054 1 0.527
PINK1PINK1 0.635 -0.000 1 0.582
RIPK3RIPK3 0.635 -0.100 3 0.633
CK1ECK1E 0.635 0.054 -3 0.509
CDK3CDK3 0.635 0.104 1 0.344
P38GP38G 0.634 -0.004 1 0.329
PDHK4PDHK4 0.634 -0.227 1 0.600
TBK1TBK1 0.633 -0.089 1 0.482
CAMKK1CAMKK1 0.633 -0.079 -2 0.476
DRAK1DRAK1 0.633 0.010 1 0.586
DAPK2DAPK2 0.633 -0.132 -3 0.671
IKKBIKKB 0.633 -0.074 -2 0.493
CDC7CDC7 0.632 -0.083 1 0.566
TSSK2TSSK2 0.632 -0.051 -5 0.822
KHS1KHS1 0.632 0.004 1 0.518
SRPK2SRPK2 0.632 0.059 -3 0.509
PKCZPKCZ 0.632 0.019 2 0.745
WNK1WNK1 0.632 -0.072 -2 0.577
IKKEIKKE 0.631 -0.084 1 0.479
NEK1NEK1 0.631 -0.072 1 0.584
GSK3AGSK3A 0.631 0.040 4 0.393
STLK3STLK3 0.631 -0.008 1 0.574
NEK11NEK11 0.631 -0.112 1 0.546
MAP3K15MAP3K15 0.630 -0.081 1 0.559
CK1DCK1D 0.630 0.050 -3 0.466
JNK3JNK3 0.630 -0.030 1 0.391
PDK1PDK1 0.629 -0.087 1 0.529
HUNKHUNK 0.629 -0.127 2 0.662
CLK2CLK2 0.629 0.056 -3 0.583
HPK1HPK1 0.629 -0.031 1 0.525
ERK7ERK7 0.629 0.100 2 0.632
CK1A2CK1A2 0.628 0.046 -3 0.460
CDKL5CDKL5 0.628 -0.014 -3 0.598
PDHK1PDHK1 0.627 -0.202 1 0.585
ERK5ERK5 0.627 -0.096 1 0.465
CK2A2CK2A2 0.627 0.093 1 0.489
NEK2NEK2 0.627 -0.068 2 0.741
RIPK1RIPK1 0.626 -0.176 1 0.638
ICKICK 0.626 -0.065 -3 0.638
PIM1PIM1 0.625 -0.042 -3 0.603
P70S6KBP70S6KB 0.625 -0.051 -3 0.606
IRAK4IRAK4 0.625 -0.071 1 0.618
PKCEPKCE 0.625 0.071 2 0.764
NEK4NEK4 0.625 -0.116 1 0.549
IKKAIKKA 0.624 -0.039 -2 0.522
SKMLCKSKMLCK 0.624 -0.138 -2 0.582
SMMLCKSMMLCK 0.623 -0.078 -3 0.614
CAMK2BCAMK2B 0.623 -0.027 2 0.490
GSK3BGSK3B 0.623 -0.005 4 0.384
CDK8CDK8 0.622 -0.041 1 0.418
P38AP38A 0.621 -0.052 1 0.401
ASK1ASK1 0.621 -0.121 1 0.559
TAO1TAO1 0.621 0.014 1 0.500
MEKK6MEKK6 0.621 -0.148 1 0.558
AMPKA1AMPKA1 0.621 -0.120 -3 0.642
MAPKAPK2MAPKAPK2 0.621 0.008 -3 0.543
MPSK1MPSK1 0.621 -0.064 1 0.532
TTBK1TTBK1 0.620 -0.053 2 0.552
CLK1CLK1 0.619 -0.008 -3 0.552
WNK3WNK3 0.619 -0.230 1 0.582
CDK13CDK13 0.619 -0.035 1 0.374
MASTLMASTL 0.619 -0.301 -2 0.589
RSK2RSK2 0.618 -0.048 -3 0.581
CAMK1GCAMK1G 0.618 -0.044 -3 0.560
WNK4WNK4 0.618 -0.135 -2 0.588
PLK4PLK4 0.618 -0.043 2 0.461
CLK4CLK4 0.618 -0.040 -3 0.591
MAPKAPK3MAPKAPK3 0.617 -0.073 -3 0.565
BCKDKBCKDK 0.617 -0.144 -1 0.618
PKCTPKCT 0.617 -0.003 2 0.724
SLKSLK 0.617 -0.040 -2 0.472
LOKLOK 0.617 -0.059 -2 0.484
JNK2JNK2 0.617 -0.058 1 0.349
P38BP38B 0.617 -0.047 1 0.362
JNK1JNK1 0.616 -0.019 1 0.379
DYRK2DYRK2 0.616 -0.064 1 0.512
PHKG1PHKG1 0.616 -0.053 -3 0.627
RSK3RSK3 0.616 -0.057 -3 0.578
NDR2NDR2 0.615 -0.101 -3 0.654
NDR1NDR1 0.615 -0.115 -3 0.645
NUAK1NUAK1 0.615 -0.043 -3 0.596
CAMK2ACAMK2A 0.615 -0.053 2 0.542
CK2A1CK2A1 0.615 0.059 1 0.484
TSSK1TSSK1 0.614 -0.110 -3 0.654
CDK12CDK12 0.614 -0.038 1 0.357
CAMKK2CAMKK2 0.614 -0.200 -2 0.453
CAMK4CAMK4 0.614 -0.144 -3 0.618
HIPK4HIPK4 0.614 -0.072 1 0.596
CK1G1CK1G1 0.613 0.017 -3 0.557
DAPK3DAPK3 0.613 -0.093 -3 0.612
HIPK1HIPK1 0.613 -0.062 1 0.519
CDK17CDK17 0.613 -0.037 1 0.343
STK33STK33 0.613 -0.072 2 0.508
BIKEBIKE 0.613 -0.060 1 0.424
AURAAURA 0.613 -0.043 -2 0.385
MYLK4MYLK4 0.612 -0.087 -2 0.469
MEK2MEK2 0.612 -0.198 2 0.629
CDK18CDK18 0.612 -0.032 1 0.357
MARK4MARK4 0.612 -0.175 4 0.611
DCAMKL1DCAMKL1 0.612 -0.102 -3 0.583
ERK1ERK1 0.611 -0.054 1 0.331
ERK2ERK2 0.611 -0.087 1 0.408
CDK6CDK6 0.611 0.000 1 0.351
CDK19CDK19 0.611 -0.055 1 0.382
MNK1MNK1 0.610 -0.076 -2 0.504
CHK1CHK1 0.610 -0.097 -3 0.632
MSK2MSK2 0.610 -0.083 -3 0.561
AMPKA2AMPKA2 0.610 -0.123 -3 0.610
PKCIPKCI 0.610 -0.008 2 0.744
MNK2MNK2 0.610 -0.090 -2 0.487
P38DP38D 0.609 -0.038 1 0.271
PAK1PAK1 0.609 -0.123 -2 0.483
RSK4RSK4 0.609 -0.051 -3 0.559
P90RSKP90RSK 0.609 -0.094 -3 0.593
CDK16CDK16 0.608 -0.025 1 0.355
DAPK1DAPK1 0.608 -0.081 -3 0.597
AKT2AKT2 0.607 -0.055 -3 0.504
LKB1LKB1 0.607 -0.242 -3 0.636
CAMK2DCAMK2D 0.607 -0.173 -3 0.621
DCAMKL2DCAMKL2 0.607 -0.116 -3 0.606
CK1G2CK1G2 0.607 0.082 -3 0.465
PKACGPKACG 0.606 -0.124 -2 0.453
MELKMELK 0.606 -0.138 -3 0.590
SGK3SGK3 0.605 -0.093 -3 0.557
HIPK2HIPK2 0.605 -0.052 1 0.420
BUB1BUB1 0.605 -0.015 -5 0.759
PIM2PIM2 0.604 -0.074 -3 0.552
MAPKAPK5MAPKAPK5 0.604 -0.098 -3 0.518
CK1ACK1A 0.604 0.059 -3 0.408
PRKD2PRKD2 0.604 -0.087 -3 0.547
PHKG2PHKG2 0.604 -0.050 -3 0.588
PRKD3PRKD3 0.604 -0.084 -3 0.533
ROCK2ROCK2 0.603 -0.095 -3 0.595
IRAK1IRAK1 0.603 -0.232 -1 0.493
CHK2CHK2 0.602 -0.055 -3 0.449
SMG1SMG1 0.602 -0.165 1 0.510
DMPK1DMPK1 0.601 -0.082 -3 0.560
PAK2PAK2 0.601 -0.171 -2 0.471
DYRK3DYRK3 0.601 -0.069 1 0.545
QIKQIK 0.601 -0.195 -3 0.620
PAK3PAK3 0.601 -0.176 -2 0.466
DNAPKDNAPK 0.600 -0.146 1 0.385
NEK3NEK3 0.600 -0.142 1 0.516
CDK14CDK14 0.600 -0.076 1 0.401
PKG2PKG2 0.600 -0.093 -2 0.384
LATS2LATS2 0.600 -0.125 -5 0.619
RIPK2RIPK2 0.600 -0.190 1 0.518
CDK4CDK4 0.599 -0.045 1 0.362
PRKD1PRKD1 0.599 -0.148 -3 0.592
AAK1AAK1 0.598 -0.040 1 0.319
AKT1AKT1 0.598 -0.067 -3 0.512
CDK10CDK10 0.598 -0.033 1 0.380
PRKXPRKX 0.598 -0.047 -3 0.508
ROCK1ROCK1 0.598 -0.080 -3 0.561
DYRK1ADYRK1A 0.598 -0.094 1 0.470
PKACBPKACB 0.597 -0.080 -2 0.395
SIKSIK 0.597 -0.126 -3 0.571
CDK7CDK7 0.596 -0.108 1 0.388
AURBAURB 0.596 -0.108 -2 0.382
SNRKSNRK 0.596 -0.209 2 0.531
MSK1MSK1 0.596 -0.101 -3 0.565
NIM1NIM1 0.596 -0.229 3 0.645
CDK9CDK9 0.595 -0.102 1 0.380
MARK3MARK3 0.595 -0.141 4 0.544
PKN1PKN1 0.595 -0.047 -3 0.517
HIPK3HIPK3 0.595 -0.116 1 0.464
YANK3YANK3 0.595 -0.046 2 0.303
MOKMOK 0.594 -0.040 1 0.530
AURCAURC 0.594 -0.100 -2 0.386
CAMK1DCAMK1D 0.594 -0.101 -3 0.497
DYRK4DYRK4 0.593 -0.083 1 0.412
QSKQSK 0.593 -0.165 4 0.577
MARK2MARK2 0.592 -0.170 4 0.511
DYRK1BDYRK1B 0.592 -0.102 1 0.440
MRCKBMRCKB 0.592 -0.101 -3 0.544
PBKPBK 0.592 -0.176 1 0.426
P70S6KP70S6K 0.592 -0.095 -3 0.515
PAK6PAK6 0.591 -0.077 -2 0.386
MRCKAMRCKA 0.591 -0.111 -3 0.569
MAKMAK 0.590 -0.042 -2 0.555
MARK1MARK1 0.590 -0.178 4 0.566
SSTKSSTK 0.590 -0.161 4 0.575
BRSK1BRSK1 0.589 -0.144 -3 0.590
SGK1SGK1 0.586 -0.079 -3 0.443
CAMK1ACAMK1A 0.584 -0.083 -3 0.464
CK1G3CK1G3 0.583 0.005 -3 0.373
YANK2YANK2 0.583 -0.045 2 0.322
BRSK2BRSK2 0.582 -0.200 -3 0.605
PKACAPKACA 0.582 -0.093 -2 0.339
AKT3AKT3 0.579 -0.069 -3 0.447
PAK5PAK5 0.576 -0.120 -2 0.347
CRIKCRIK 0.570 -0.129 -3 0.502
PAK4PAK4 0.570 -0.114 -2 0.364
SBKSBK 0.559 -0.106 -3 0.393
PKG1PKG1 0.555 -0.134 -2 0.290