BioPAX pathway converted from "Signaling by VEGF" in the Reactome database. Signaling by VEGF Signaling by Vascular Epithelial Growth Factors (VEGF) In normal development vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development during embryogenesis (vasculogenesis) and blood-vessel formation in the adult (angiogenesis). In tumor progression, activation of VEGF pathways promotes tumor vascularization, facilitating tumor growth and metastasis. Abnormal VEGF function is also associated with inflammatory diseases including atherosclerosis, and hyperthyroidism. The members of the VEGF and VEGF-receptor protein families have distinct but overlapping ligand-receptor specificities, cell-type expression, and function. VEGF-receptor activation in turn regulates a network of signaling processes in the body that promote endothelial cell growth, migration and survival (Hicklin and Ellis, 2005; Shibuya and Claesson-Welsh, 2006).<br>Molecular features of the VGF signaling cascades are outlined in the figure below (from Olsson et al. 2006; Nature Publishing Group). Tyrosine residues in the intracellular domains of VEGF receptors 1, 2,and 3 are indicated by dark blue boxes; residues susceptible to phosphorylation are numbered. A circled R indicates that phosphorylation is regulated by cell state (VEGFR2), by ligand binding (VEGFR1), or by heterodimerization (VEGFR3). Specific phosphorylation sites (boxed numbers) bind signaling molecules (dark blue ovals), whose interaction with other cytosolic signaling molecules (light blue ovals) leads to specific cellular (pale blue boxes) and tissue-level (pink boxes) responses in vivo. Signaling cascades whose molecular details are unclear are indicated by dashed arrows. DAG, diacylglycerol; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; FAK, focal adhesion kinase; HPC, hematopoietic progenitor cell; HSP27, heat-shock protein-27; MAPK, mitogen-activated protein kinase; MEK, MAPK and ERK kinase; PI3K, phosphatidylinositol 3' kinase; PKC, protein kinase C; PLCgamma, phospholipase C-gamma; Shb, SH2 and beta-cells; TSAd, T-cell-specific adaptor.<br>In the current release, the first events in these cascades - the interactions between VEGF proteins and their receptors - are annotated. Authored: Garapati, P V, 2013-08-30 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 Edited: Garapati, P V, 2013-08-30 VEGF ligand-receptor interactions The VEGF family is encoded by seven genes (VEGF-A, B, C, D, E: PLGF (Placenta Growth Factor)-1, 2). Six isoforms of VEGF-A protein, containing 121, 145, 165, 183, 189, and 206 amino acid residues, and two isoforms of VEGF-B (167 and 186 residues) are specified by alternatively spliced mRNAs. The active form of each of these proteins is a homodimer.<br>The specificities of the three VEGF tyrosine kinase receptors, VEGFR-1, VEGFR-2 and VEGFR-3, for these ligands are shown in the figure (Hicklin and Ellis 2005). All VEGF-A isoforms bind both VEGFR-1 and VEGFR-2; PLGF-1 and -2, and VEGF-B isoforms bind only VEGFR-1; VEGF-E binds VEGFR-2; and VEGF-C and -D bind both VEGFR-2 and -3. VEGF-D undergoes a complex series of post-translational modifications that results in secreted forms with increased activity toward VEGFR-3 and VEGFR-2. <br>Two co-receptor proteins in the cell membrane, neuropilin (NRP)-1 and NRP-2, interact with VEGFR proteins to increase the affinity of the latter for their ligands (Neufeld et al.,2002). They differ from VEGFR proteins in not having intracellular signaling domains. Authored: Garapati, P V, 2013-08-30 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 Edited: Garapati, P V, 2013-08-30 LEFT-TO-RIGHT Homodimerization of VEGF proteins VEGF proteins bind their receptors as homodimers. Heterodimers with PLGF and among different VEGF proteins have been observed but have no known function. Authored: Garapati, P V, 2013-08-30 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 Edited: Garapati, P V, 2013-08-30 Converted from EntitySet in Reactome VEGF Reactome DB_ID: 195361 VEGFA Vascular endothelial growth factor A VEGFA_HUMAN Reactome DB_ID: 2975974 extracellular region GENE ONTOLOGY GO:0005576 UniProt:P15692 VEGFA VEGFA VEGF FUNCTION Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth. Binding to NRP1 receptor initiates a signaling pathway needed for motor neuron axon guidance and cell body migration, including for the caudal migration of facial motor neurons from rhombomere 4 to rhombomere 6 during embryonic development (By similarity). Also binds the DEAR/FBXW7-AS1 receptor (PubMed:17446437).SUBUNIT Homodimer; disulfide-linked (By similarity). Also found as heterodimer with PGF (By similarity). Interacts with NRP1 (PubMed:26503042). Interacts with isoform 2 of BSG (PubMed:25825981).TISSUE SPECIFICITY Isoform VEGF189, isoform VEGF165 and isoform VEGF121 are widely expressed. Isoform VEGF206 and isoform VEGF145 are not widely expressed. A higher level expression seen in pituitary tumors as compared to the pituitary gland.INDUCTION By hypoxia. Regulated by growth factors, cytokines, gonadotropins, nitric oxide, hypoglycemia and oncogenic mutations.SIMILARITY Belongs to the PDGF/VEGF growth factor family. Homo sapiens NCBI Taxonomy 9606 UniProt P15692 27 EQUAL 232 EQUAL Reactome Database ID Release 83 2975974 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2975974 Reactome R-HSA-2975974 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2975974.1 Reactome http://www.reactome.org VEGFB Vascular endothelial growth factor B VEGFB_HUMAN Reactome DB_ID: 2975973 UniProt:P49765 VEGFB VEGFB VRF FUNCTION Growth factor for endothelial cells. VEGF-B167 binds heparin and neuropilin-1 whereas the binding to neuropilin-1 of VEGF-B186 is regulated by proteolysis.SUBUNIT Homodimer; disulfide-linked. Can also form heterodimer with VEGF.TISSUE SPECIFICITY Expressed in all tissues except liver. Highest levels found in heart, skeletal muscle and pancreas.PTM VEGF-B186 is O-glycosylated.SIMILARITY Belongs to the PDGF/VEGF growth factor family. UniProt P49765 22 EQUAL 207 EQUAL Reactome Database ID Release 83 2975973 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2975973 Reactome R-HSA-2975973 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2975973.1 VRP VEGFC Vascular endothelial growth factor C precursor Vascular endothelial growth factor related protein Flt4 ligand Flt4- L Reactome DB_ID: 139887 UniProt:P49767 VEGFC VEGFC FUNCTION Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in angiogenesis of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates KDR/VEGFR2 and FLT4/VEGFR3 receptors.SUBUNIT Homodimer; non-covalent and antiparallel (PubMed:20145116). Interacts with FLT4/VEGFR3; the interaction is required for FLT4/VEGFR3 homodimarization and activation (PubMed:23878260).TISSUE SPECIFICITY Spleen, lymph node, thymus, appendix, bone marrow, heart, placenta, ovary, skeletal muscle, prostate, testis, colon and small intestine and fetal liver, lung and kidney, but not in peripheral blood lymphocyte.PTM Undergoes a complex proteolytic maturation which generates a variety of processed secreted forms with increased activity toward VEGFR-3, but only the fully processed form could activate VEGFR-2. VEGF-C first form an antiparallel homodimer linked by disulfide bonds. Before secretion, a cleavage occurs between Arg-227 and Ser-228 producing a heterotetramer. The next extracellular step of the processing removes the N-terminal propeptide. Finally the mature VEGF-C is composed mostly of two VEGF homology domains (VHDs) bound by non-covalent interactions.SIMILARITY Belongs to the PDGF/VEGF growth factor family. UniProt P49767 112 EQUAL 227 EQUAL Reactome Database ID Release 83 139887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=139887 Reactome R-HSA-139887 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-139887.1 FIGF VEGFD Vascular endothelial growth factor D precursor c-fos induced growth factor Reactome DB_ID: 139888 UniProt:O43915 VEGFD VEGFD FIGF FUNCTION Growth factor active in angiogenesis, lymphangiogenesis and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in the formation of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates VEGFR-2 (KDR/FLK1) and VEGFR-3 (FLT4) receptors.SUBUNIT Homodimer; non-covalent and antiparallel.TISSUE SPECIFICITY Highly expressed in lung, heart, small intestine and fetal lung, and at lower levels in skeletal muscle, colon, and pancreas.PTM Undergoes a complex proteolytic maturation which generates a variety of processed secreted forms with increased activity toward VEGFR-3 and VEGFR-2. VEGF-D first form an antiparallel homodimer linked by disulfide bonds before secretion. The fully processed VEGF-D is composed mostly of two VEGF homology domains (VHDs) bound by non-covalent interactions.SIMILARITY Belongs to the PDGF/VEGF growth factor family. UniProt O43915 89 EQUAL 205 EQUAL Reactome Database ID Release 83 139888 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=139888 Reactome R-HSA-139888 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-139888.1 PGF Placenta growth factor PLGF_HUMAN Reactome DB_ID: 3009042 UniProt:P49763 PGF PGF PGFL PLGF FUNCTION Growth factor active in angiogenesis and endothelial cell growth, stimulating their proliferation and migration. It binds to the receptor FLT1/VEGFR-1. Isoform PlGF-2 binds NRP1/neuropilin-1 and NRP2/neuropilin-2 in a heparin-dependent manner. Also promotes cell tumor growth.SUBUNIT Antiparallel homodimer; disulfide-linked. Also found as heterodimer with VEGFA/VEGF. Isoform PlGF-3 is found both as homodimer and as monomer.TISSUE SPECIFICITY While the three isoforms are present in most placental tissues, PlGF-2 is specific to early (8 week) placenta and only PlGF-1 is found in the colon and mammary carcinomas.DOMAIN Isoform PlGF-2 contains a basic insert which acts as a cell retention signal.PTM N-glycosylated.SIMILARITY Belongs to the PDGF/VEGF growth factor family. UniProt P49763 19 EQUAL 221 EQUAL Reactome Database ID Release 83 3009042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3009042 Reactome R-HSA-3009042 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3009042.1 Reactome Database ID Release 83 195361 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195361 Reactome R-HSA-195361 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195361.1 2 Converted from EntitySet in Reactome VEGF dimer Reactome DB_ID: 195376 VEGFA dimer Reactome DB_ID: 195364 2 Reactome Database ID Release 83 195364 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195364 Reactome R-HSA-195364 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195364.1 ComplexPortal CPX-1977 additional information MI MI:0361 VEGFB dimer Reactome DB_ID: 195367 2 Reactome Database ID Release 83 195367 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195367 Reactome R-HSA-195367 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195367.1 ComplexPortal CPX-7402 VEGFC dimer Reactome DB_ID: 195360 2 Reactome Database ID Release 83 195360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195360 Reactome R-HSA-195360 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195360.1 ComplexPortal CPX-7403 VEGFD dimer Reactome DB_ID: 195355 2 Reactome Database ID Release 83 195355 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195355 Reactome R-HSA-195355 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195355.1 PGF dimer Reactome DB_ID: 195352 2 Reactome Database ID Release 83 195352 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195352 Reactome R-HSA-195352 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195352.1 Reactome Database ID Release 83 195376 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195376 Reactome R-HSA-195376 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195376.1 Reactome Database ID Release 83 195378 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195378 Reactome R-HSA-195378 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195378.1 16633338 Pubmed 2006 VEGF receptor signalling - in control of vascular function Olsson, AK Dimberg, A Kreuger, J Claesson-Welsh, Lena Nat Rev Mol Cell Biol 7:359-71 16835467 Pubmed 2006 Signal transduction via vascular endothelial growth factor (VEGF) receptors and their roles in atherogenesis Matsumoto, T Mugishima, H J Atheroscler Thromb 13:130-5 VEGF binds to VEGFR leading to receptor dimerization The binding of VEGF ligands to VEGFR receptors in the cell membrane induces dimerization and activation of the latter, initiating intracellular signaling cascades that result in proliferation, survival, migration and increased permeability of vascular endothelial cells (Matsumoto and Mugishima, 2006). The receptors predominantly form homodimers but heterodimers between VEGFR-1 and -2 have been observed. Although both VEGFR-1 and -2 are expressed in the vascular endothelium, the angiogenic activities of VEGFs are transduced mainly through VEGFR-2 in vivo. Authored: Garapati, P V, 2013-08-30 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 Edited: Garapati, P V, 2013-08-30 LEFT-TO-RIGHT VEGFA,B,PLGF bind to VEGFR1 leading to receptor dimerization VEGFR-1 binds VEGF-A, VEGF-B, and PLGF homodimers. This interaction is required for normal angiogenesis and hematopoiesis, although many of the detailed molecular steps from binding to these physiological consequences remain unclear (Hickins and Ellis, 2005). VEGFR-1 is made up of 1338 aa and has three regions: an extracellular region consisting of 7 immunoglobin-like domains, a transmembrane (TM) domain and a cytosolic tyrosine kinase (TK) domain. An alternatively spliced form, soluble VEGFR-1 (sVEGFR1), also binds VEGF proteins and may serve in the body to down-regulate VEGF activation of membrane-bound receptors. Overexpression of sVEGFR1 (VEGF121) is associated with preeclampsia, a major disorder of pregnancy (Shibuya and Claesson-Welsh 2006; Levine et al. 2004). Authored: Garapati, P V, 2013-08-30 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 Edited: Garapati, P V, 2013-08-30 Converted from EntitySet in Reactome VEGFA,VEGFB,PGF dimers Reactome DB_ID: 195389 Reactome Database ID Release 83 195389 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195389 Reactome R-HSA-195389 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195389.1 FLT1 VEGFR1 Vascular endothelial growth factor receptor 1 VGFR1_HUMAN Reactome DB_ID: 3004464 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:P17948 FLT1 FLT1 FLT FRT VEGFR1 FUNCTION 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 (Ref.11). 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).ACTIVITY REGULATION Present in an inactive conformation in the absence of bound ligand. Binding of VEGFA, VEGFB or PGF leads to dimerization and activation by autophosphorylation on tyrosine residues.SUBUNIT Interacts with VEGFA, VEGFB and PGF. Monomer in the absence of bound VEGFA, VEGFB or PGF. Homodimer in the presence of bound VEGFA, VEGFB and PGF. Can also form a heterodimer with KDR. Interacts (when tyrosine phosphorylated) with CBL, CRK, GRB2, NCK1, PIK3R1, PLCG, PSEN1 and PTPN11. Probably interacts also with PTPRB. Interacts with RACK1. Identified in a complex with CBL and CD2AP.TISSUE SPECIFICITY Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform 2 is strongly expressed in placenta. Isoform 3 is expressed in corneal epithelial cells (at protein level). Isoform 3 is expressed in vascular smooth muscle cells (VSMC).INDUCTION Up-regulated in coculture of VSMC/endothelial cell (EC) or by direct exposure to VEGF of VSMC monoculture. Up-regulated from the second trimester of pregnancy to the term and in the placenta of women with preeclampsia (PE). Up-regulated in monocytes exposed to bacterial lipopolysaccharide (LPS).DOMAIN The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFA binding.PTM N-glycosylated.PTM Ubiquitinated after VEGFA-mediated autophosphorylation, leading to proteolytic degradation.PTM Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-1169 is important for interaction with PLCG. Phosphorylation at Tyr-1213 is important for interaction with PIK3R1, PTPN11, GRB2, and PLCG. Phosphorylation at Tyr-1333 is important for endocytosis and for interaction with CBL, NCK1 and CRK. Is probably dephosphorylated by PTPRB.DISEASE Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages.DISEASE Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. UniProt P17948 27 EQUAL 1338 EQUAL Reactome Database ID Release 83 3004464 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3004464 Reactome R-HSA-3004464 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3004464.1 2 VEGFR1 dimer:VEGFA, VEGFB, PGF dimers Reactome DB_ID: 195396 1 VEGFR1 dimer Reactome DB_ID: 195398 2 Reactome Database ID Release 83 195398 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195398 Reactome R-HSA-195398 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195398.1 1 Reactome Database ID Release 83 195396 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195396 Reactome R-HSA-195396 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195396.1 Reactome Database ID Release 83 194311 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194311 Reactome R-HSA-194311 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194311.2 11387210 Pubmed 2001 A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells Takahashi, T Yamaguchi, S Chida, K Shibuya, M EMBO J 20:2768-78 12871269 Pubmed 2003 Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders Autiero, M Luttun, A Tjwa, M Carmeliet, P J Thromb Haemost 1:1356-70 2479986 Pubmed 1989 Vascular endothelial growth factor is a secreted angiogenic mitogen Leung, DW Cachianes, G Kuang, WJ Goeddel, DV Ferrara, N Science 246:1306-9 9722576 Pubmed 1998 Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules Ito, N Wernstedt, C Engstrom, U Claesson-Welsh, Lena J Biol Chem 273:23410-8 8637916 Pubmed 1996 Vascular endothelial growth factor B, a novel growth factor for endothelial cells Olofsson, B Pajusola, K Kaipainen, A von Euler, G Joukov, V Saksela, O Orpana, A Pettersson, RF Alitalo, K Eriksson, U Proc Natl Acad Sci U S A 93:2576-81 15585754 Pubmed 2005 Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis Hicklin, DJ Ellis, LM J Clin Oncol 23:1011-27 9207067 Pubmed 1997 Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site Muller, YA Li, B Christinger, HW Wells, JA Cunningham, BC de Vos, AM Proc Natl Acad Sci U S A 94:7192-7 14764923 Pubmed 2004 Circulating angiogenic factors and the risk of preeclampsia Levine, RJ Maynard, SE Qian, C Lim, KH England, LJ Yu, KF Schisterman, EF Thadhani, R Sachs, BP Epstein, FH Sibai, BM Sukhatme, VP Karumanchi, SA N Engl J Med 350:672-83 16336962 Pubmed 2006 Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis Shibuya, M Claesson-Welsh, Lena Exp Cell Res 312:549-60 LEFT-TO-RIGHT VEGF-A,C,D bind to VEGFR2 leading to receptor dimerization VEGFR-2 binds VEGF-A, -C, -D, and -E homodimers. VEGFR-2 is the primary mediator of the physiological effects of VEGF-A in angiogenesis, including microvascular permeability, endothelial cell proliferation, invasion, migration, and survival. In endothelial cells, these effects are mediated via activation of a phospholipase gamma-protein kinase C-Raf-MAPK signaling pathway for proliferation and PI3K and focal adhesion kinase for survival and migration. VEGFR-2 is the important receptor among VEGFR protiens and its activation and signaling may be positively or negatively regulated by co-expression and activation of various factors and other VEGF receptors like VEGFR-1 (Hicklin and Ellis 2005).The regulatory events of this receptor will be annotated in subsequent modules. Authored: Garapati, P V, 2013-08-30 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 Edited: Garapati, P V, 2013-08-30 KDR VEGFR2 Kinase insert domain receptor Reactome DB_ID: 195382 UniProt:P35968 KDR KDR FLK1 VEGFR2 FUNCTION 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.ACTIVITY REGULATION Present in an inactive conformation in the absence of bound ligand. Binding of VEGFA, VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by the small molecule PTK inhibitor SU5614 ((3Z)-5-Chloro-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one). May be regulated by hydrogen sulfide (H(2)S) levels via a H(2)S-sensitive intracellular disulfide bond.SUBUNIT Homodimer in the presence of bound dimeric VEGFA, VEGFC or VEGFD ligands; monomeric in the absence of bound ligands. Can also form heterodimers with FLT1/VEGFR1 and KDR/VEGFR2. Interacts (tyrosine phosphorylated) with LFYN, NCK1, PLCG1. Interacts (tyrosine-phosphorylated active form preferentially) with DAB2IP (via C2 domain and active form preferentially); the interaction occurs at the late phase of VEGFA response and inhibits KDR/VEGFR2 activity. Interacts with SHBSH2D2A/TSAD, GRB2, MYOF, CBL and PDCD6. Interacts (via C-terminus domain) with ERN1 (via kinase domain); the interaction is facilitated in a XBP1 isoform 1- and vascular endothelial growth factor (VEGF)-dependent manner in endothelial cells (PubMed:23529610). Interacts (via juxtamembrane region) with chaperone PDCL3 (via thioredoxin fold region); the interaction leads to increased KDR/VEGFR2 abundance through inhibition of its ubiquitination and degradation (PubMed:23792958, PubMed:26059764). Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the KDR/VEGFR2 C-terminal region (PubMed:25187647). Interacts with isoform 2 of BSG (PubMed:25825981).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.TISSUE SPECIFICITY Detected in cornea (at protein level). Widely expressed.DOMAIN The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding.PTM N-glycosylated.PTM Ubiquitinated. Tyrosine phosphorylation of the receptor promotes its poly-ubiquitination, leading to its degradation via the proteasome or lysosomal proteases.PTM Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-951 is important for interaction with SH2D2A/TSAD and VEGFA-mediated reorganization of the actin cytoskeleton. Phosphorylation at Tyr-1175 is important for interaction with PLCG1 and SHB. Phosphorylation at Tyr-1214 is important for interaction with NCK1 and FYN. Dephosphorylated by PTPRB. Dephosphorylated by PTPRJ at Tyr-951, Tyr-996, Tyr-1054, Tyr-1059, Tyr-1175 and Tyr-1214.PTM The inhibitory disulfide bond between Cys-1024 and Cys-1045 may serve as a specific molecular switch for H(2)S-induced modification that regulates KDR/VEGFR2 function.DISEASE Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. UniProt P35968 20 EQUAL 1356 EQUAL Reactome Database ID Release 83 195382 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195382 Reactome R-HSA-195382 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195382.1 2 Converted from EntitySet in Reactome VEGFA,C,D dimers Reactome DB_ID: 195393 Reactome Database ID Release 83 195393 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195393 Reactome R-HSA-195393 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195393.1 VEGFR2:VEGFA,C,D Reactome DB_ID: 215139 VEGFR2 dimer Reactome DB_ID: 195403 2 Reactome Database ID Release 83 195403 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195403 Reactome R-HSA-195403 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195403.1 1 1 Reactome Database ID Release 83 215139 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=215139 Reactome R-HSA-215139 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-215139.1 Reactome Database ID Release 83 194310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194310 Reactome R-HSA-194310 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194310.2 11004490 Pubmed 2000 Identification of a novel platelet-derived growth factor-like gene, fallotein, in the human reproductive tract Tsai, YJ Lee, RK Lin, SP Chen, YH Biochim Biophys Acta 1492:196-202 7824266 Pubmed 1995 A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF Seetharam, L Gotoh, N Maru, Y Neufeld, G Yamaguchi, S Shibuya, M Oncogene 10:135-47 9435229 Pubmed 1998 Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) Achen, MG Jeltsch, M Kukk, E Makinen, T Vitali, A Wilks, AF Alitalo, K Stacker, SA Proc Natl Acad Sci U S A 95:548-53 8617204 Pubmed 1996 A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases Joukov, V Pajusola, K Kaipainen, A Chilov, D Lahtinen, I Kukk, E Saksela, O Kalkkinen, N Alitalo, K EMBO J 15:290-98 1417831 Pubmed 1992 Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor Terman, BI Dougher-Vermazen, M Carrion, ME Dimitrov, D Armellino, DC Gospodarowicz, D Bohlen, P Biochem Biophys Res Commun 187:1579-86 12881528 Pubmed 2003 Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites Dixelius, J Makinen, T Wirzenius, M Karkkainen, MJ Wernstedt, C Alitalo, K Claesson-Welsh, Lena J Biol Chem 278:40973-9 LEFT-TO-RIGHT VEGF-C,D bind to VEGFR3 leading to receptor dimerization VEGFR-3 preferentially binds VEGF-C and -D. Mutations of the VEGFR-3 tyrosine kinase domain are seen in human lymphedema. VEGFR-3 expression has been correlated with transient lymphangiogenesis in wound healing and may modulate VEGFR-2 signaling in maintaining vascular integrity (Hicklin and Ellis 2005). Authored: Garapati, P V, 2013-08-30 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 Edited: Garapati, P V, 2013-08-30 Converted from EntitySet in Reactome VEGFC,VEGFD dimers Reactome DB_ID: 195391 Reactome Database ID Release 83 195391 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195391 Reactome R-HSA-195391 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195391.1 FLT4 VEGFR3 Reactome DB_ID: 195359 UniProt:P35916 FLT4 FLT4 VEGFR3 FUNCTION 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'.ACTIVITY REGULATION Present in an inactive conformation in the absence of bound ligand. Binding of VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by MAZ51.SUBUNIT Interacts with VEGFC and VEGFD. Monomer in the absence of bound VEGFC or VEGFD. Homodimer in the presence of bound VEGFC or VEGFD. Can also form a heterodimer with KDR. Interacts with PTPN14; the interaction is enhanced by stimulation with VEGFC. Interacts with CRK, GRB2, PTK2/FAK1, SHC1, PIK3R1 and PTPN11/SHP-2. Identified in a complex with SRC and ITGB1.TISSUE SPECIFICITY Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney.DOMAIN The first and second Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding (PubMed:23878260). The fourth and fifth Ig-like C2-type domains are sufficient for homodimerization (PubMed:23878260). The fifth and seventh Ig-like C2-type domains are required for autophosphorylation and further activation (PubMed:23878260).PTM Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation in response to H(2)O(2) is mediated by a process that requires SRC and PRKCD activity. Phosphorylation at Tyr-1068 is required for autophosphorylation at additional tyrosine residues. Phosphorylation at Tyr-1063 and Tyr-1337 is important for interaction with CRK and subsequent activation of MAPK8. Phosphorylation at Tyr-1230, Tyr-1231 and Tyr-1337 is important for interaction with GRB2 and subsequent activation of the AKT1 and MAPK1/ERK2 and/or MAPK3/ERK1 signaling pathways. In response to endothelial cell adhesion onto collagen, can also be phosphorylated in the absence of FLT4 kinase activity by SRC at Tyr-830, Tyr-833, Tyr-853, Tyr-1063, Tyr-1333, and Tyr-1337.DISEASE Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. UniProt P35916 25 EQUAL 1363 EQUAL Reactome Database ID Release 83 195359 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195359 Reactome R-HSA-195359 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195359.2 2 VEGFR3 dimer:VEGFC, VEGFD dimers Reactome DB_ID: 215140 VEGFR3 dimer Reactome DB_ID: 195405 2 Reactome Database ID Release 83 195405 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195405 Reactome R-HSA-195405 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195405.1 1 1 Reactome Database ID Release 83 215140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=215140 Reactome R-HSA-215140 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-215140.1 Reactome Database ID Release 83 194308 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194308 Reactome R-HSA-194308 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194308.2 8700872 Pubmed 1996 Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4 Lee, J Gray, A Yuan, J Luoh, SM Avraham, H Wood, WI Proc Natl Acad Sci U S A 93:1988-92 11532940 Pubmed 2001 Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3 Makinen, T Veikkola, T Mustjoki, S Karpanen, T Catimel, B Nice, EC Wise, L Mercer, A Kowalski, H Kerjaschki, D Stacker, SA Achen, MG Alitalo, K EMBO J 20:4762-73 Reactome Database ID Release 83 195399 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195399 Reactome R-HSA-195399 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195399.1 13678960 Pubmed 2003 VEGF-receptor signal transduction Cross, MJ Dixelius, J Matsumoto, T Claesson-Welsh, Lena Trends Biochem Sci 28:488-94 Reactome Database ID Release 83 194313 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194313 Reactome R-HSA-194313 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194313.1 17002866 Pubmed 2006 Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis Shibuya, M J Biochem Mol Biol 39:469-78 12613545 Pubmed 2002 The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors for VEGF Neufeld, G Kessler, O Herzog, Y Adv Exp Med Biol 515:81-90 GENE ONTOLOGY GO:0048010 gene ontology term for cellular process MI MI:0359 VEGFA-VEGFR2 Pathway Angiogenesis is the formation of new blood vessels from preexisting vasculature. One of the most important proangiogenic factors is vascular endothelial growth factor (VEGF). VEGF exerts its biologic effect through interaction with transmembrane tyrosine kinase receptors VEGFR, selectively expressed on vascular endothelial cells. VEGFA signaling through VEGFR2 is the major pathway that activates angiogenesis by inducing the proliferation, survival, sprouting and migration of endothelial cells (ECs), and also by increasing endothelial permeability (Lohela et al. 2009, Shibuya & Claesson-Welsh 2006, Claesson-Welsh & Welsh, 2013). The critical role of VEGFR2 in vascular development is highlighted by the fact that VEGFR2-/- mice die at E8.5-9.5 due to defective development of blood islands, endothelial cells and haematopoietic cells (Shalaby et al. 1995). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 LEFT-TO-RIGHT VEGFA-165 dimer binds VEGFR2 dimer Binding of vascular endothelial growth factor A dimer (VEGFA dimer) to vascular endothelial growth factor receptor 2 dimer (VEGFR2, aka KDR, FLK1) (Ruch et al. 2007) induces receptor dimerization and autophosphorylation, leading to the recruitment of downstream signalling molecules. VEGFA isoform 4 (VEGFA-165) is widely expressed. Signaling through VEGFR2 is the major pathway that activates angiogenesis by inducing the proliferation, survival, sprouting and migration of endothelial cells (ECs), and also by increasing endothelial permeability (Lohela et al. 2009, Shibuya & Claesson-Welsh 2006, Claesson-Welsh & Welsh, 2013). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Jassal, Bijay, 2020-06-10 VEGFA-165 dimer Reactome DB_ID: 4420158 VEGFA-165 Vascular endothelial growth factor A VEGFA_HUMAN Reactome DB_ID: 4420127 UniProt:P15692-4 VEGFA VEGFA VEGF FUNCTION Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth. Binding to NRP1 receptor initiates a signaling pathway needed for motor neuron axon guidance and cell body migration, including for the caudal migration of facial motor neurons from rhombomere 4 to rhombomere 6 during embryonic development (By similarity). Also binds the DEAR/FBXW7-AS1 receptor (PubMed:17446437).SUBUNIT Homodimer; disulfide-linked (By similarity). Also found as heterodimer with PGF (By similarity). Interacts with NRP1 (PubMed:26503042). Interacts with isoform 2 of BSG (PubMed:25825981).TISSUE SPECIFICITY Isoform VEGF189, isoform VEGF165 and isoform VEGF121 are widely expressed. Isoform VEGF206 and isoform VEGF145 are not widely expressed. A higher level expression seen in pituitary tumors as compared to the pituitary gland.INDUCTION By hypoxia. Regulated by growth factors, cytokines, gonadotropins, nitric oxide, hypoglycemia and oncogenic mutations.SIMILARITY Belongs to the PDGF/VEGF growth factor family. UniProt Isoform P15692-4 27 EQUAL 191 EQUAL Reactome Database ID Release 83 4420127 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420127 Reactome R-HSA-4420127 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420127.1 2 Reactome Database ID Release 83 4420158 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420158 Reactome R-HSA-4420158 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420158.1 ComplexPortal CPX-1977 VEGFA-165 dimer:VEGFR2 Reactome DB_ID: 195402 1 1 Reactome Database ID Release 83 195402 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195402 Reactome R-HSA-195402 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195402.2 Reactome Database ID Release 83 9691215 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9691215 Reactome R-HSA-9691215 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9691215.1 23216836 Pubmed 2013 VEGFA and tumour angiogenesis Claesson-Welsh, Lena Welsh, Michael J. Intern. Med. 273:114-27 19230644 Pubmed 2009 VEGFs and receptors involved in angiogenesis versus lymphangiogenesis Lohela, Marja Bry, Maija Tammela, Tuomas Alitalo, K Curr. Opin. Cell Biol. 21:154-65 17293873 Pubmed 2007 Structure of a VEGF-VEGF receptor complex determined by electron microscopy Ruch, Claudia Skiniotis, Georgios Steinmetz, Michel O Walz, Thomas Ballmer-Hofer, Kurt Nat. Struct. Mol. Biol. 14:249-50 INHIBITION Reactome Database ID Release 83 9691216 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9691216 VEGFA-165 dimer:VEGFA inhibitors Reactome DB_ID: 9679453 1 Converted from EntitySet in Reactome VEGFA inhibitors Reactome DB_ID: 9679456 aflibercept Reactome DB_ID: 9679475 aflibercept [Guide to Pharmacology:6786] aflibercept AVE0005 Eylea&reg; VEGF Trap Zaltrap&reg; ziv-aflibercept Guide to Pharmacology 6786 Reactome Database ID Release 83 9679475 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679475 Reactome R-ALL-9679475 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9679475.1 bevacizumab Reactome DB_ID: 9679458 bevacizumab [Guide to Pharmacology:6771] bevacizumab Avastin&reg; rhuMAb-VEGF Guide to Pharmacology 6771 Reactome Database ID Release 83 9679458 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679458 Reactome R-ALL-9679458 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9679458.1 brolucizumab Reactome DB_ID: 9679482 brolucizumab [Guide to Pharmacology:8713] brolucizumab Beovu&reg; brolucizumab-dbll ESBA1008 ESBA-1008 RTH258 Guide to Pharmacology 8713 Reactome Database ID Release 83 9679482 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679482 Reactome R-ALL-9679482 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9679482.1 pegaptanib Reactome DB_ID: 9679463 pegaptanib [Guide to Pharmacology:6836] pegaptanib EYEOO1 Macugen&reg; NX183 pegaptanib sodium Guide to Pharmacology 6836 Reactome Database ID Release 83 9679463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679463 Reactome R-ALL-9679463 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9679463.1 ranibizumab Reactome DB_ID: 9679464 ranibizumab [Guide to Pharmacology:6779] ranibizumab Fab-12 variant Y0317 Lucentis&reg; muMAb VEGF A.4.6.1 rhuFab V2 Guide to Pharmacology 6779 Reactome Database ID Release 83 9679464 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679464 Reactome R-ALL-9679464 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9679464.1 vanucizumab Reactome DB_ID: 9679469 vanucizumab [Guide to Pharmacology:9132] vanucizumab RG7221 RG-7221 RO5520985 Guide to Pharmacology 9132 Reactome Database ID Release 83 9679469 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679469 Reactome R-ALL-9679469 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9679469.1 abicipar pegol Reactome DB_ID: 9679474 abicipar pegol [Guide to Pharmacology:8371] abicipar pegol AGN-150998 MP0112 Guide to Pharmacology 8371 Reactome Database ID Release 83 9679474 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679474 Reactome R-ALL-9679474 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9679474.1 Reactome Database ID Release 83 9679456 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679456 Reactome R-ALL-9679456 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9679456.1 1 Reactome Database ID Release 83 9679453 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679453 Reactome R-HSA-9679453 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9679453.2 LEFT-TO-RIGHT VEGFA-165 dimer binds VEGFA inhibitors In normal development vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development during embryogenesis (vasculogenesis) and blood-vessel formation in the adult (angiogenesis). In tumor progression, activation of VEGF pathways promotes tumor vascularization, facilitating tumor growth and metastasis. Abnormal VEGF function is also associated with inflammatory diseases including atherosclerosis, and hyperthyroidism. Inhibition of this process may provide clinical benefits to patients suffering from cancer, diabetic macular edema (DME) and age-related macular degeneration (AMD). VEGFA inhibitors are therapeutic options for these diseases (Melincovici et al. 2018, Aguilar-Cazares et al. 2019, Kim et al. 2019).<br><br>Aflibercept is a recombinant protein which is indicated for DME, AMD and part of a combined treatment for metastatic colorectal cancer (Chu 2009, Tang & Moore 2013).<br><br>Abicipar Pegol (MP0112) is an investigational compound that has been used in trials studying the treatment of DME and AMD (Campochiaro et al. 2013).<br><br>Brolucizumab (RTH258, ESBA1008,4) is a monoclonal antibody indicated to treat AMD (Yannuzzi et al. 2019).<br><br>Pegaptanib is a polynucleotide aptamer used to treat AMD (Gragoudas et al. 2004, Vinores 2006).<br><br>Ranibizumab is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. It is indicated for the treatment of DME and AMD (Nguyen et al. 2006, Ferrara et al. 2006).<br><br>Vanucizumab is an investigational monoclonal antibody that has been used in trials studying the treatment of colorectal cancer and advanced/metastatic solid tumours (Hidalgo et al. 2018, Bendell et al. 2019).<br><br>Bevacizumab (Avastin) is a humanized monoclonal IgG antibody, and inhibits angiogenesis by binding and inhibiting VEGFA (Papachristos et al. 2019). Researchers have identified higher VEGF expression in patients with COVID-19, which may contribute to lung pathologies. Bevacizumab is being investigated for the treatment of lung complications associated with severe cases of COVID-19 (Phase 2/3 NCT04275414) (Rosa & Santos 2020). Authored: Jassal, Bijay, 2020-03-24 Reviewed: Shoichet, Brian, 2020-05-14 Edited: Jassal, Bijay, 2020-03-24 Reactome Database ID Release 83 9679477 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9679477 Reactome R-HSA-9679477 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9679477.2 30173249 Pubmed 2018 Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis Melincovici, Carmen Stanca Boşca, Adina Bianca Şuşman, Sergiu Mărginean, Mariana Mihu, Carina Istrate, Mihnea Moldovan, Ioana Maria Roman, Alexandra Livia Mihu, Carmen Mihaela Rom J Morphol Embryol 59:455-467 15625332 Pubmed 2004 Pegaptanib for neovascular age-related macular degeneration Gragoudas, Evangelos S Adamis, Anthony P Cunningham, Emmett T Feinsod, Matthew Guyer, David R N. Engl. J. Med. 351:2805-16 17046701 Pubmed 2006 Vascular endothelial growth factor is a critical stimulus for diabetic macular edema Nguyen, Quan Dong Tatlipinar, Sinan Shah, Syed Mahmood Haller, Julia A Quinlan, Edward Sung, Jennifer Zimmer-Galler, Ingrid Do, Diana V Campochiaro, Peter A Am. J. Ophthalmol. 142:961-9 31413539 Pubmed 2019 Brolucizumab: evidence to date in the treatment of neovascular age-related macular degeneration Yannuzzi, Nicolas A Freund, K Bailey Clin Ophthalmol 13:1323-1329 23218689 Pubmed 2013 Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study Campochiaro, Peter A Channa, Roomasa Berger, Brian B Heier, Jeffrey S Brown, David M Fiedler, Ulrike Hepp, Julia Stumpp, Michael T Am. J. Ophthalmol. 155:697-704, 704.e1-2 17031284 Pubmed 2006 Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration Ferrara, Napoleone Damico, Lisa Shams, Naveed Lowman, Henry Kim, Robert Retina (Philadelphia, Pa.) 26:859-70 31570519 Pubmed 2019 The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC) Bendell, Johanna C Sauri, Tamara Gracián, Antonio Cubillo Alvarez, Rafael López-López, Carlos García-Alfonso, Pilar Hussein, Maen Miron, Maria-Luisa Limon Cervantes, Andrés Montagut, Clara Vivas, Cristina Santos Bessudo, Alberto Plezia, Patricia Moons, Veerle Andel, Johannes Bennouna, Jaafar van der Westhuizen, Andre Samuel, Leslie Rossomanno, Simona Boetsch, Christophe Lahr, Angelika Franjkovic, Izolda Heil, Florian Lechner, Katharina Krieter, Oliver Hurwitz, Herbert Oncologist 31921656 Pubmed 2019 Contribution of Angiogenesis to Inflammation and Cancer Aguilar-Cazares, Dolores Chavez-Dominguez, Rodolfo Carlos-Reyes, Angeles Lopez-Camarillo, César Hernadez de la Cruz, Olga N Lopez-Gonzalez, Jose S Front Oncol 9:1399 31359157 Pubmed 2019 Treatment of Diabetic Macular Edema Kim, Eric J Lin, Weijie V Rodriguez, Sean M Chen, Ariel Loya, Asad Weng, Christina Y Curr. Diab. Rep. 19:68 31752122 Pubmed 2019 <i>VEGF-A</i> and <i>ICAM-1</i> Gene Polymorphisms as Predictors of Clinical Outcome to First-Line Bevacizumab-Based Treatment in Metastatic Colorectal Cancer Papachristos, Apostolos Kemos, Polychronis Katsila, Theodora Panoilia, Eirini Patrinos, George P Kalofonos, Haralabos Sivolapenko, Gregory B Int J Mol Sci 20: 29217526 Pubmed 2018 First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors Hidalgo, Manuel Martinez-Garcia, Maria Le Tourneau, Christophe Massard, Christophe Garralda, Elena Boni, Valentina Taus, Alvaro Albanell, Joan Sablin, Marie-Paule Alt, Marie Bahleda, Ratislav Varga, Andrea Boetsch, Christophe Franjkovic, Izolda Heil, Florian Lahr, Angelika Lechner, Katharina Morel, Anthony Nayak, Tapan Rossomanno, Simona Smart, Kevin Stubenrauch, Kay Krieter, Oliver Clin. Cancer Res. 24:1536-1545 24179482 Pubmed 2013 Aflibercept in the treatment of patients with metastatic colorectal cancer: latest findings and interpretations Tang, Patricia A Moore, Malcom J Therap Adv Gastroenterol 6:459-73 19236257 Pubmed 2009 Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors Chu, Quincy Siu-Chung Expert Opin Biol Ther 9:263-71 32256547 Pubmed 2020 Clinical trials on drug repositioning for COVID-19 treatment Rosa, Sandro G Viveiros Santos, Wilson C Rev. Panam. Salud Publica 44:e40 17717967 Pubmed 2006 Pegaptanib in the treatment of wet, age-related macular degeneration Vinores, Stanley A Int J Nanomedicine 1:263-8 LEFT-TO-RIGHT 2.7.10.2 VEGFR2 autophosphorylates Binding of VEGFA to VEGFR2 induces receptor dimerization and autophosphorylation, leading to the recruitment of downstream signalling molecules. Once the two VEGFR2 receptors are cross-linked to each other, via simultaneous interaction with VEGFA dimer, their membrane-proximal Ig-like domain 7s are held in close proximity so that low-affinity homotypic interactions between these domains further stabilise the receptor dimers. This allows for the exact positioning of the intracellular kinase domains resulting in VEGFR2 autophosphorylation (Ruch et al. 2007, Holmes at al. 2007). The major tyrosine residues known to be autophosphorylated are Y801 and Y951 in the kinase-insert domain, Y1054 and Y1059 within the kinase domain, and Y1175 and Y1214 in the C-terminal tail of VEGFR (Dougher-Vermazen et al. 1994, Cunningham et al. 2007, Kendall et al. 1999, Matsumoto et al. 2005). The Y1175 (mice Y1173) is crucial for endothelial and haemopoietic cell development. Mice with muatation Y1173F die between E8.5 and E9.5 from lack of endothelial and haemopoietic development (Sakurai et al. 2005). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 cytosol GENE ONTOLOGY GO:0005829 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 83 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 12 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 83 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 12 VEGFA dimer:p-6Y-VEGFR2 dimer Reactome DB_ID: 4420101 1 p-6Y-VEGFR2 dimer Reactome DB_ID: 4420096 p-6Y-VEGFR2 p-Y951,Y1054,Y1059,Y1175,Y1214-KDR Kinase insert domain receptor p-Y951,Y1054,Y1059,Y1175,Y1214-VEGFR2 Reactome DB_ID: 4420103 1214 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1054 EQUAL 1059 EQUAL 1175 EQUAL 951 EQUAL 801 EQUAL 20 EQUAL 1356 EQUAL Reactome Database ID Release 83 4420103 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420103 Reactome R-HSA-4420103 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420103.1 2 Reactome Database ID Release 83 4420096 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420096 Reactome R-HSA-4420096 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420096.1 1 Reactome Database ID Release 83 4420101 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420101 Reactome R-HSA-4420101 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420101.1 ACTIVATION activeUnit: #Protein8 GENE ONTOLOGY GO:0004713 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 83 4420144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420144 Reactome Database ID Release 83 4420117 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420117 Reactome R-HSA-4420117 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420117.4 9398617 Pubmed 1997 Interactions of FLT-1 and KDR with phospholipase C gamma: identification of the phosphotyrosine binding sites Cunningham, S A Arrate, M P Brock, T A Waxham, M N Biochem. Biophys. Res. Commun. 240:635-9 10037737 Pubmed 1999 Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues Kendall, R L Rutledge, R Z Mao, X Tebben, A J Hungate, R W Thomas, K A J. Biol. Chem. 274:6453-60 7999104 Pubmed 1994 Biological activity and phosphorylation sites of the bacterially expressed cytosolic domain of the KDR VEGF-receptor Dougher-Vermazen, M Hulmes, J D Böhlen, P Terman, B I Biochem. Biophys. Res. Commun. 205:728-38 15644447 Pubmed 2005 Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice Sakurai, Yoshiko Ohgimoto, Kaori Kataoka, Yuki Yoshida, Nobuaki Shibuya, Masabumi Proc. Natl. Acad. Sci. U.S.A. 102:1076-81 15962004 Pubmed 2005 VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis Matsumoto, Taro Bohman, Svante Dixelius, Johan Berge, Tone Dimberg, Anna Magnusson, Peetra Wang, Ling Wikner, Charlotte Qi, Jian Hua Wernstedt, Christer Wu, Jiong Bruheim, Skjalg Mugishima, Hideo Mukhopadhyay, Debrabata Spurkland, Anne Claesson-Welsh, Lena EMBO J. 24:2342-53 LEFT-TO-RIGHT p-6Y-VEGFR2 binds SHB The adaptor protein SHB (Src homology 2 domain-containing adapter protein B) binds to phosphorylated tyrosine Y1175 in VEGFR2 and regulates the PTK2/FAK activity and endothelial cell migration. The SH2 domain located in the C-terminus of SHB interacts with the phosphotyrosine residue in VEGFR2 (Holmqvist et al. 2004). SHB is not required for vascular development, but SHB-deficient mice shows diffects in vessel functionality (Christoffersson et al. 2012) and impaired tumor growth (Funa et al. 2009). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 SHB SH2 domain-containing adapter protein B SHB_HUMAN Reactome DB_ID: 4420213 UniProt:Q15464 SHB SHB FUNCTION Adapter protein which regulates several signal transduction cascades by linking activated receptors to downstream signaling components. May play a role in angiogenesis by regulating FGFR1, VEGFR2 and PDGFR signaling. May also play a role in T-cell antigen receptor/TCR signaling, interleukin-2 signaling, apoptosis and neuronal cells differentiation by mediating basic-FGF and NGF-induced signaling cascades. May also regulate IRS1 and IRS2 signaling in insulin-producing cells.SUBUNIT Interacts with PTPN11 (By similarity). Interacts with phosphorylated 'Tyr-720' of the ligand-activated receptor PDGFRA via its SH2 domain. Interacts with the ligand-activated receptors PDGFRB, FGFR1, KDR/VEGFR2, IL2RB and IL2RG. Interacts with EPS8 and V-SRC. Interacts with GRB2 and GRAP. Interacts with CD3Z. Interacts with tyrosine-phosphorylated LAT upon T-cell antigen receptor activation. Interacts with PLCG1. Interacts with ZAP70, LCP2/SLP-76, VAV1 and GRAP2. Interacts with JAK1 and JAK3. Interacts with PTK2/FAK1. Interacts with CRK/CrKII. Interacts with IRS2.TISSUE SPECIFICITY Widely expressed.DOMAIN The SH2 domain preferentially binds phosphopeptides with the consensus sequence Y-[TVI]-X-L and mediates interaction with PDGFRA, PDGFRB, FGRFR1, IL2RB, IL2RG, CD3Z and CRK/CrKII.PTM Phosphorylated upon PDGFRA, PDGFRB, TCR, IL2 receptor, FGFR1 or VEGFR2 activation. UniProt Q15464 1 EQUAL 509 EQUAL Reactome Database ID Release 83 4420213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420213 Reactome R-HSA-4420213 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420213.1 VEGFA dimer:p-6Y-VEGFR2 dimer:SHB Reactome DB_ID: 4420196 1 1 Reactome Database ID Release 83 4420196 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420196 Reactome R-HSA-4420196 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420196.1 Reactome Database ID Release 83 4420099 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420099 Reactome R-HSA-4420099 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420099.2 22562363 Pubmed 2012 Vascular adaptation to a dysfunctional endothelium as a consequence of Shb deficiency Christoffersson, Gustaf Zang, Guangxiang Zhuang, Zhen W Vågesjö, Evelina Simons, Michael Phillipson, Mia Welsh, Michael Angiogenesis 15:469-80 15026417 Pubmed 2004 The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration Holmqvist, Kristina Cross, Michael J Rolny, Charlotte Hägerkvist, Robert Rahimi, Nader Matsumoto, Taro Claesson-Welsh, Lena Welsh, Michael J. Biol. Chem. 279:22267-75 19223532 Pubmed 2009 Dysfunctional microvasculature as a consequence of shb gene inactivation causes impaired tumor growth Funa, Nina S Kriz, Vitezslav Zang, Guangxiang Calounova, Gabriela Akerblom, Björn Mares, Jaroslav Larsson, Erik Sun, Ying Betsholtz, Christer Welsh, Michael Cancer Res. 69:2141-8 LEFT-TO-RIGHT 2.7.10.2 SRC-1 phosphorylates SHB Association of SHB with VEGFR2 leads to its Src-dependent tyrosine phosphorylation and activation (Holmqvist et al. 2003, Holmqvist et al. 2004). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA dimer:p-6Y-VEGFR2 dimer:p-S-SHB Reactome DB_ID: 4420164 1 pS-SHB Reactome DB_ID: 5228991 O-phospho-L-serine MOD MOD:00046 1 EQUAL 509 EQUAL Reactome Database ID Release 83 5228991 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5228991 Reactome R-HSA-5228991 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5228991.1 1 Reactome Database ID Release 83 4420164 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420164 Reactome R-HSA-4420164 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420164.1 ACTIVATION activeUnit: #Protein21 SRC1 SRC-1 Proto-oncogene tyrosine-protein kinase SRC (EC 2.7.1.112) (p60-SRC) (C-SRC) Proto-oncogene tyrosine-protein kinase Src p60-Src c-Src SRC isoform 1 Reactome DB_ID: 354153 UniProt:P12931-1 SRC SRC SRC1 FUNCTION 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. 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). 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:8755529, PubMed:14585963). 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 DDX58/RIG-I-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).ACTIVITY REGULATION Phosphorylation by CSK at Tyr-530 inhibits kinase activity. Inhibitory phosphorylation at Tyr-530 is enhanced by heme. Further phosphorylation by CDK1 partially reactivates CSK-inactivated SRC and facilitates complete reactivation by protein tyrosine phosphatase PTPRC. Integrin engagement stimulates kinase activity. Phosphorylation by PTK2/FAK1 enhances kinase activity. Butein and pseudosubstrate-based peptide inhibitors like CIYKYYF act as inhibitors. Phosphorylation at Tyr-419 increases kinase activity.SUBUNIT Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Interacts with DDEF1/ASAP1; via the SH3 domain (By similarity). Interacts with CCPG1 (By similarity). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (By similarity). Interacts with ERBB2, STAT1 and PNN (By similarity). Interacts with DDR1, DDR2 and DAB2 (By similarity). Interacts with CDCP1, TGFB1I1 and TOM1L2 (PubMed:15851033, PubMed:16479011, PubMed:17202804). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (PubMed:11152665). Interacts with RALGPS1; via the SH3 domain (PubMed:10747847). Interacts with CAV2 (tyrosine phosphorylated form) (PubMed:12091389, PubMed:15504032). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus (By similarity). Interacts with ARRB1 and ARRB2 (PubMed:10753943, PubMed:9924018). Interacts with SRCIN1 (PubMed:17525734). Interacts with NDFIP2 and more weakly with NDFIP1 (PubMed:20534535). Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1 and ESR1 (dimethylated on arginine) (PubMed:18657504, PubMed:21411625). Interacts with FASLG (PubMed:19807924). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:14585963). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (By similarity). Interacts with PDGFRA (tyrosine phosphorylated) (By similarity). Interacts with CSF1R (By similarity). Interacts (via SH2 and SH3 domain) with TNK2 (PubMed:21309750). Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain) (PubMed:20100835). Interacts with TRAF3 (via RING-type zinc finger domain) (PubMed:19419966). Interacts with DDX58, MAVS and TBK1 (PubMed:19419966). Interacts (via SH2 domain) with RACK1; the interaction is enhanced by tyrosine phosphorylation of RACK1 and inhibits SRC activity (PubMed:9584165, PubMed:11279199). Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Interacts with FCAMR (PubMed:8759729). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (PubMed:18024423). Interacts with AMOTL2; this interaction regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (PubMed:17293535). Interacts with TRAP1 (PubMed:23564345). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at Tyr-419 (PubMed:14661060, PubMed:22888118). Interacts with ARHGEF5 (By similarity). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (PubMed:7478590). Interacts with MPP2 (PubMed:19665017). Interacts with PRR7 (PubMed:21460222). Interacts (via kinase domain and to a lesser extent the SH2 domain) directly with PDLIM4; this interaction results in PTPN13-mediated dephosphorylation of this protein leading to its inactivation (PubMed:19307596). Interacts with P85 (PIK3R1 or PIK3R2) (PubMed:28903391). Interacts with HNRNPA2B1 (PubMed:31320558). Interacts with IL6ST/gp130 (PubMed:25731159). Interacts (via SH3 domain) with PELP1 in the presence of 17-beta-estradiol. Interacts with AMBRA1 (By similarity).SUBUNIT (Microbial infection) Interacts with HEV ORF3 protein; via the SH3 domain.SUBUNIT (Microbial infection) Interacts (via SH2 domain) with HCV non-structural protein 5A (via N-terminus).TISSUE SPECIFICITY Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues.DOMAIN The SH2 and SH3 domains are important for the intramolecular and intermolecular interactions that regulate catalytic activity, localization, and substrate recruitment.PTM Myristoylated at Gly-2, and this is essential for targeting to membranes.PTM Dephosphorylated at Tyr-530 by PTPRJ (By similarity). Phosphorylated on Tyr-530 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src. Dephosphorylated by PTPRJ at Tyr-419. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-530, the SH3 domain engaged with the SH2-kinase linker, and Tyr-419 dephosphorylated. Dephosphorylation of Tyr-530 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-530, Tyr-419 can then become autophosphorylated, resulting in SRC activation. Phosphorylation of Tyr-530 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-75 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. Phosphorylated by PTK2/FAK1; this enhances kinase activity. Phosphorylated by PTK2B/PYK2; this enhances kinase activity. Upon activation of IL6ST by IL6, Tyr-419 is phosphorylated and Tyr-530 dephosphorylated (PubMed:25731159).PTM S-nitrosylation is important for activation of its kinase activity.PTM Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-419 and may lead to lysosomal degradation.DISEASE SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt Isoform P12931-1 2 EQUAL 536 EQUAL Reactome Database ID Release 83 354153 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=354153 Reactome R-HSA-354153 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-354153.2 Reactome Database ID Release 83 210268 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210268 p-Y419-SRC Active SRC (p-Y419) Reactome DB_ID: 377592 419 EQUAL 2 EQUAL 536 EQUAL Reactome Database ID Release 83 377592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377592 Reactome R-HSA-377592 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377592.1 Reactome Database ID Release 83 4420128 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420128 Reactome R-HSA-4420128 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420128.2 12464388 Pubmed 2003 The Shb adaptor protein causes Src-dependent cell spreading and activation of focal adhesion kinase in murine brain endothelial cells Holmqvist, Kristina Cross, Michael Riley, Debbie Welsh, Michael Cell. Signal. 15:171-9 LEFT-TO-RIGHT PTK2 binds p-S-SHB and is recruited to p-6Y-VEGFR2 SHB binds focal adhesion kinase 1 (FAK1; also known as PTK2) via its PTB domain in a phosphotyrosine-dependent manner. This regulates FAK1 phosphorylation, leading to Src dependent enhanced cell spreading (Holmqvist et al. 2003). During vascular development, FAK1 is involved in the control of endothelial cell migration (Holmquist et al. 2004), vascular permeability (Chen et al. 2012) and tube formation (Bohnsack & Hirshi, 2003). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 FAK PTK2 FAK1 FADK1 Focal adhesion kinase 1 Reactome DB_ID: 201621 UniProt:Q05397 PTK2 PTK2 FAK FAK1 FUNCTION 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.ACTIVITY REGULATION Subject to autoinhibition, mediated by interactions between the FERM domain and the kinase domain. Activated by autophosphorylation at Tyr-397. This promotes interaction with SRC and phosphorylation at Tyr-576 and Tyr-577 in the kinase activation loop. Phosphorylation at Tyr-576 and Tyr-577 is required for maximal kinase activity. Inhibited by TAC544, TAE226, PF-573,228 and PF-562,271.SUBUNIT Interacts (via first Pro-rich region) with CAS family members (via SH3 domain), including BCAR1, BCAR3, and CASS4. Interacts with NEDD9 (via SH3 domain) (PubMed:9360983). Interacts with GIT1. Interacts with SORBS1. Interacts with ARHGEF28. Interacts with SHB. Part of a complex composed of THSD1, PTK2/FAK1, TLN1 and VCL (PubMed:29069646). Interacts with PXN and TLN1. Interacts with STAT1. Interacts with DCC. Interacts with WASL. Interacts with ARHGEF7. Interacts with GRB2 and GRB7 (By similarity). Component of a complex that contains at least FER, CTTN and PTK2/FAK1. Interacts with BMX. Interacts with TGFB1I1. Interacts with STEAP4. Interacts with ZFYVE21. Interacts with ESR1. Interacts with PIK3R1 or PIK3R2. Interacts with SRC, FGR, FLT4 and RET. Interacts with EPHA2 in resting cells; activation of EPHA2 recruits PTPN11, leading to dephosphorylation of PTK2/FAK1 and dissociation of the complex. Interacts with EPHA1 (kinase activity-dependent). Interacts with CD4; this interaction requires the presence of HIV-1 gp120. Interacts with PIAS1. Interacts with ARHGAP26 and SHC1. Interacts with RB1CC1; this inhibits PTK2/FAK1 activity and activation of downstream signaling pathways. Interacts with P53/TP53 and MDM2. Interacts with LPXN (via LD motif 3). Interacts with MISP. Interacts with CIB1 isoform 2. Interacts with CD36. Interacts with EMP2; regulates PTK2 activation and localization (PubMed:19494199). Interacts with DSCAM (By similarity). Interacts with AMBRA1 (By similarity).TISSUE SPECIFICITY Detected in B and T-lymphocytes. Isoform 1 and isoform 6 are detected in lung fibroblasts (at protein level). Ubiquitous. Expressed in epithelial cells (at protein level) (PubMed:31630787).DOMAIN The Pro-rich regions interact with the SH3 domain of CAS family members, such as BCAR1 and NEDD9, and with the GTPase activating protein ARHGAP26.DOMAIN The C-terminal region is the site of focal adhesion targeting (FAT) sequence which mediates the localization of FAK1 to focal adhesions.PTM Phosphorylated on tyrosine residues upon activation, e.g. upon integrin signaling. Tyr-397 is the major autophosphorylation site, but other kinases can also phosphorylate this residue. Phosphorylation at Tyr-397 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-576, Tyr-577 and at additional tyrosine residues. FGR promotes phosphorylation at Tyr-397 and Tyr-576. FER promotes phosphorylation at Tyr-577, Tyr-861 and Tyr-925, even when cells are not adherent. Tyr-397, Tyr-576 and Ser-722 are phosphorylated only when cells are adherent. Phosphorylation at Tyr-397 is important for interaction with BMX, PIK3R1 and SHC1. Phosphorylation at Tyr-925 is important for interaction with GRB2. Dephosphorylated by PTPN11; PTPN11 is recruited to PTK2 via EPHA2 (tyrosine phosphorylated). Microtubule-induced dephosphorylation at Tyr-397 is crucial for the induction of focal adhesion disassembly; this dephosphorylation could be catalyzed by PTPN11 and regulated by ZFYVE21. Phosphorylation on tyrosine residues is enhanced by NTN1 (By similarity).PTM Sumoylated; this enhances autophosphorylation.DISEASE Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily. UniProt Q05397 2 EQUAL 1052 EQUAL Reactome Database ID Release 83 201621 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201621 Reactome R-HSA-201621 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201621.2 VEGFA:p-6Y-VEGFR2:p-SHB:PTK2 Reactome DB_ID: 4420141 1 1 Reactome Database ID Release 83 4420141 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420141 Reactome R-HSA-4420141 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420141.2 Reactome Database ID Release 83 4420083 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420083 Reactome R-HSA-4420083 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420083.2 9182576 Pubmed 1997 Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells Abedi, H Zachary, I J. Biol. Chem. 272:15442-51 22264731 Pubmed 2012 VEGF-induced vascular permeability is mediated by FAK Chen, Xiao Lei Nam, Ju-Ock Jean, Christine Lawson, Christine Walsh, Colin T Goka, Erik Lim, Ssang-Taek Tomar, Alok Tancioni, Isabelle Uryu, Sean Guan, Jun-Lin Acevedo, Lisette M Weis, Sara M Cheresh, David A Schlaepfer, David D Dev. Cell 22:146-57 12595334 Pubmed 2003 The FAKs about blood vessel assembly Bohnsack, Brenda L Hirschi, Karen K Circ. Res. 92:255-7 LEFT-TO-RIGHT 2.7.10.2 PTK2 autophosphorylates Six tyrosine phosphorylation sites in focal adhesion kinase 1 (FAK1) serve to modulate FAK1 kinase activity or mediate FAK1 interaction with SH2-domain containing proteins. These are Y397, Y407, Y576, Y577, Y861 and Y925 (Mitra et al. 2005). They are differentially phosphorylated by diverse agonists and implicated in transmitting different signals and effects (Ciccimaro et al. 2006, Le Boeuf et al. 2004,2006). Y397 is the major autophosphorylation site present upstream of the FAK kinase domain (Schaller et al. 1994). In response to VEGF stimulation FAK1 is recruited and autophosphorylated at Y397. This phosphorylated tyrosine then creates a binding site for other signaling proteins that link FAK1 to downstream signaling pathways and the actin cytoskeleton (Toutant et al. 2002). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA:p-6Y-VEGFR2:p-SHB:p-Y397-PTK2 Reactome DB_ID: 5218639 1 p-Y397-PTK2 p-Y397-FAK1 auto phosphorylated FAK 1 Reactome DB_ID: 354068 397 EQUAL 2 EQUAL 1052 EQUAL Reactome Database ID Release 83 354068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=354068 Reactome R-HSA-354068 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-354068.1 1 Reactome Database ID Release 83 5218639 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218639 Reactome R-HSA-5218639 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218639.2 ACTIVATION activeUnit: #Protein22 Reactome Database ID Release 83 5218644 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218644 Reactome Database ID Release 83 5218642 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218642 Reactome R-HSA-5218642 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218642.3 16760434 Pubmed 2006 Phosphorylation of focal adhesion kinase (FAK) on Ser732 is induced by rho-dependent kinase and is essential for proline-rich tyrosine kinase-2-mediated phosphorylation of FAK on Tyr407 in response to vascular endothelial growth factor Le Boeuf, Fabrice Houle, François Sussman, Mark Huot, Jacques Mol. Biol. Cell 17:3508-20 17117420 Pubmed 2006 Analysis of phosphorylation sites on focal adhesion kinase using nanospray liquid chromatography/multiple reaction monitoring mass spectrometry Ciccimaro, Eugene Hevko, John Blair, Ian A Rapid Commun. Mass Spectrom. 20:3681-92 15688067 Pubmed 2005 Focal adhesion kinase: in command and control of cell motility Mitra, SK Hanson, DA Schlaepfer, DD Nat Rev Mol Cell Biol 6:56-68 12391143 Pubmed 2002 Alternative splicing controls the mechanisms of FAK autophosphorylation Toutant, Madeleine Costa, Alicia Studler, Jeanne-Marie Kadaré, Gress Carnaud, Michèle Girault, Jean-Antoine Mol. Cell. Biol. 22:7731-43 15247219 Pubmed 2004 Regulation of vascular endothelial growth factor receptor 2-mediated phosphorylation of focal adhesion kinase by heat shock protein 90 and Src kinase activities Le Boeuf, Fabrice Houle, François Huot, Jacques J. Biol. Chem. 279:39175-85 LEFT-TO-RIGHT SRC-1 binds p-Y397-PTK2 Autophosphorylation of Y397 on FAK1 provides a high affinity binding site for the Src homology 2 (SH2) domain of Src family kinases (SFKs) allowing their recruitment, activation and subsequent transphosphorylation of FAK1 at additional sites (Calalb et al. 1995). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA:p-6Y-VEGFR2:p-SHB:p-Y397-PTK2:SRC-1 Reactome DB_ID: 5218641 1 1 Reactome Database ID Release 83 5218641 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218641 Reactome R-HSA-5218641 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218641.2 Reactome Database ID Release 83 5218645 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218645 Reactome R-HSA-5218645 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218645.2 7529876 Pubmed 1995 Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases Calalb, MB Polte, TR Hanks, SK Mol Cell Biol 15:954-63 7509446 Pubmed 1994 Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src Schaller, MD Hildebrand, JD Shannon, JD Fox, JW Vines, RR Parsons, JT Mol Cell Biol 14:1680-8 LEFT-TO-RIGHT 2.7.10.2 SRC-1 phosphorylates p-Y397-PTK2 Src family kinases (SFKs) induce transphosphorylation of tyrosyl residues Y576, Y577, Y861 and Y925. Phosphorylation of Y576 and Y577 within the catalytic domain confers maximal FAK1 enzymatic activity and signaling in response to adhesion (Calalb et al. 1995, Brunton et al. 2005). Y576 and Y861 are both phosphorylated in a Src-dependent manner in response to VEGF (Abu-Ghazaleh et al. 2001, Le Boeuf et al. 2006, 2004). Phosphorylation of FAK on Y861 contributes to the recruitment of vinculin to FAK1 (Le Boeuf et al. 2004). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 5 5 VEGFA:p-6Y-VEGFR2:p-SHB:p-5Y-PTK2:SRC-1 VEGFA:p-6Y-VEGFR2:p-SHB:p-5Y-FAK1:SRC-1 Reactome DB_ID: 5218636 1 VEGFA:p-6Y-VEGFR2:p-SHB:p-5Y-PTK2 VEGFA:p-6Y-VEGFR2:p-SHB:p-5Y-FAK1 Reactome DB_ID: 5218635 1 p-5Y-PTK2 p-5Y-FAK1 p(Y397,576,577,861,925)-FAK 1 Reactome DB_ID: 5218711 576 EQUAL 577 EQUAL 861 EQUAL 925 EQUAL 2 EQUAL 1052 EQUAL Reactome Database ID Release 83 5218711 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218711 Reactome R-HSA-5218711 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218711.2 1 Reactome Database ID Release 83 5218635 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218635 Reactome R-HSA-5218635 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218635.2 1 Reactome Database ID Release 83 5218636 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218636 Reactome R-HSA-5218636 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218636.2 ACTIVATION activeUnit: #Protein20 Reactome Database ID Release 83 5218648 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218648 Reactome Database ID Release 83 5218640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218640 Reactome R-HSA-5218640 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218640.3 15735019 Pubmed 2005 Identification of Src-specific phosphorylation site on focal adhesion kinase: dissection of the role of Src SH2 and catalytic functions and their consequences for tumor cell behavior Brunton, VG Avizienyte, Egle Fincham, Valerie J Serrels, Bryan Metcalf, Chester A Sawyer, Tomi K Frame, Margaret C Cancer Res. 65:1335-42 11696015 Pubmed 2001 Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells Abu-Ghazaleh, R Kabir, J Jia, H Lobo, M Zachary, I Biochem. J. 360:255-64 LEFT-TO-RIGHT Integrin alphaVbeta3 binds p-6Y-VEGFR2 Several receptor tyrosine kinases (RTKs) are known to associate with integrins, and it has been suggested that focal adhesion kinase (FAK) is at the crossroads of these signaling pathways. On endothelial cells integrin alphaVbeta3 acts as a regulator of VEGFR2 signaling and shown to be necessary for angiogenic response (Hood et al. 2003). In mouse endothelial cells VEGF stimulated complex formation between VEGFR2 and beta3 integrin. This association between alphaVbeta3 with VEGFR2 appears to be synergistic, because VEGFR2 activation induces beta3 integrin tyrosine phosphorylation, which, in turn, enhances the phosphorylation of VEGFR2 and mediates the activation of mitogenic pathways involving focal adhesion kinase (FAK) and stress-activated protein kinase-2/p38 (SAPK2/p38) (Masson-Gadais et al. 2003, Mahabaleshwar et al. 2006, Somanath et al. 2009). This promotes activation of alphaVbeta3 and results in the increase of ligand binding ability (integrin activation), integrin ligation, and phosphorylation of beta3 integrin by cSrc. Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 Integrin alphaVbeta3 Reactome DB_ID: 210216 ITGB3 Integrin beta3 Platelet membrane glycoprotein IIIa GPIIIa CD61 antigen Reactome DB_ID: 57600 UniProt:P05106 ITGB3 ITGB3 GP3A FUNCTION Integrin alpha-V/beta-3 (ITGAV:ITGB3) is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor. Integrin alpha-IIb/beta-3 (ITGA2B:ITGB3) is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3 recognize the sequence R-G-D in a wide array of ligands. Integrin alpha-IIb/beta-3 recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial surface. Fibrinogen binding enhances SELP expression in activated platelets (By similarity). ITGAV:ITGB3 binds to fractalkine (CX3CL1) and acts as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415, PubMed:24789099). ITGAV:ITGB3 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling (PubMed:20682778). ITGAV:ITGB3 binds to FGF1 and this binding is essential for FGF1 signaling (PubMed:18441324). ITGAV:ITGB3 binds to FGF2 and this binding is essential for FGF2 signaling (PubMed:28302677). ITGAV:ITGB3 binds to IGF1 and this binding is essential for IGF1 signaling (PubMed:19578119). ITGAV:ITGB3 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464). ITGAV:ITGB3 binds to IL1B and this binding is essential for IL1B signaling (PubMed:29030430). ITGAV:ITGB3 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGAV:ITGB3 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887). In brain, plays a role in synaptic transmission and plasticity. Involved in the regulation of the serotonin neurotransmission, is required to localize to specific compartments within the synapse the serotonin receptor SLC6A4 and for an appropriate reuptake of serotonin. Controls excitatory synaptic strength by regulating GRIA2-containing AMPAR endocytosis, which affects AMPAR abundance and composition (By similarity). ITGAV:ITGB3 act as a receptor for CD40LG (PubMed:31331973).FUNCTION (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Herpes virus 8/HHV-8.FUNCTION (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Coxsackievirus A9.FUNCTION (Microbial infection) Acts as a receptor for Hantaan virus.FUNCTION (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Cytomegalovirus/HHV-5.FUNCTION (Microbial infection) Integrin ITGA5:ITGB3 acts as a receptor for Human metapneumovirus.FUNCTION (Microbial infection) Integrin ITGAV:ITGB3 acts aP05556s a receptor for Human parechovirus 1.FUNCTION (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for West nile virus.FUNCTION (Microbial infection) In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.SUBUNIT Heterodimer of an alpha and a beta subunit. Beta-3 (ITGB3) associates with either alpha-IIb (ITGA2B) or alpha-V (ITGAV). Isoform Beta-3C interacts with FLNB. Interacts with COMP. Interacts with PDIA6 following platelet stimulation. Interacts with SYK; upon activation by ITGB3 promotes platelet adhesion. Interacts with MYO10. Interacts with DAB2. Interacts with FERMT2. Interacts with EMP2; regulates the levels of the heterodimer ITGA5:ITGB3 integrin expression on the plasma membrane (PubMed:16216233). Integrin ITGAV:ITGB3 interacts with FBLN5 (via N-terminus) (By similarity). ITGAV:ITGB3 interacts with CCN3 (PubMed:12695522). ITGAV:ITGB3 is found in a ternary complex with CX3CR1 and CX3CL1 (PubMed:23125415). ITGAV:ITGB3 is found in a ternary complex with NRG1 and ERBB3 (PubMed:20682778). ITGAV:ITGB3 is found in a ternary complex with FGF1 and FGFR1 (PubMed:18441324). ITGAV:ITGB3 interacts with FGF2; it is likely that FGF2 can simultaneously bind ITGAV:ITGB3 and FGF receptors (PubMed:28302677). ITGAV:ITGB3 binds to IL1B (PubMed:29030430). ITGAV:ITGB3 is found in a ternary complex with IGF1 and IGF1R (PubMed:19578119). ITGAV:ITGB3 interacts with IGF2 (PubMed:28873464). ITGAV:ITGB3 interacts with FBN1 (PubMed:12807887). ITGAV:ITGB3 interacts with CD9, CD81 and CD151 (via second extracellular domain) (PubMed:27993971). Interacts (via the allosteric site (site 2)) with CXCL12 in a CXCR4-independent manner (PubMed:29301984). Interacts with MXRA8/DICAM; the interaction inhibits ITGAV:ITGB3 heterodimer formation (PubMed:22492581). ITGAV:ITGB3 interacts with PTN (PubMed:19141530). Forms a complex with PTPRZ1 and PTN that stimulates endothelial cell migration through ITGB3 Tyr-773 phosphorylation (PubMed:19141530). ITGAV:ITGB3 interacts with SLC6A4 (By similarity). ITGA2B:ITGB3 interacts with PPIA/CYPA; the interaction is ROS and PPIase activity-dependent and is increased in the presence of thrombin (By similarity).SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with herpes virus 8/HHV-8 glycoprotein B.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with coxsackievirus A9 capsid proteins.SUBUNIT (Microbial infection) Interacts with Hantaan virus glycoprotein G.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with cytomegalovirus/HHV-5 gH:gL proteins.SUBUNIT (Microbial infection) Integrin ITGA5:ITGB3 interacts with human metapneumovirus fusion protein.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with human parechovirus 1 capsid proteins.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with west nile virus envelope protein E.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat (PubMed:10397733). ITGAV:ITGB3 interacts with AGRA2 (PubMed:16982628).TISSUE SPECIFICITY Isoform beta-3A and isoform beta-3C are widely expressed. Isoform beta-3A is specifically expressed in osteoblast cells; isoform beta-3C is specifically expressed in prostate and testis.PTM Phosphorylated on tyrosine residues in response to thrombin-induced platelet aggregation. Probably involved in outside-in signaling. A peptide (AA 740-762) is capable of binding GRB2 only when both Tyr-773 and Tyr-785 are phosphorylated. Phosphorylation of Thr-779 inhibits SHC binding.POLYMORPHISM Position 59 is associated with platelet-specific alloantigen HPA-1 (ZW or PL(A)). HPA-1A/ZW(A)/PL(A1) has Leu-59 and HPA-1B/ZW(B)/PL(A2) has Pro-59. HPA-1A is involved in fetal-maternal alloimmune thromobocytopenia (FMAIT) as well as in neonatal alloimmune thrombocytopenia (NAIT).POLYMORPHISM Position 169 is associated with platelet-specific alloantigen HPA-4 (PEN or YUK). HPA-4A/PEN(A)/YUK(A) has Arg-169 and HPA-4B/PEN(B)/YUK(B) has Gln-169. HPA-4B is involved in neonatal alloimmune thrombocytopenia (NAIT or NATP).POLYMORPHISM Position 433 is associated with platelet-specific alloantigen MO. MO(-) has Pro-433 and MO(+) has Ala-433. MO(+) is involved in NAIT.POLYMORPHISM Position 515 is associated with platelet-specific alloantigen CA/TU. CA(-)/TU(-) has Arg-515 and CA(+)/TU(+) has Gln-515. CA(+) is involved in NAIT.POLYMORPHISM Position 662 is associated with platelet-specific alloantigen SR(A). SR(A)(-) has Arg-662 and SR(A)(+) has Cys-662.SIMILARITY Belongs to the integrin beta chain family. UniProt P05106 27 EQUAL 788 EQUAL Reactome Database ID Release 83 57600 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=57600 Reactome R-HSA-57600 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-57600.1 1 CD51 antigen ITGAV(31-1048) Integrin alpha-V Reactome DB_ID: 210013 UniProt:P06756 ITGAV ITGAV MSK8 VNRA VTNR FUNCTION The alpha-V (ITGAV) integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. ITGAV:ITGB3 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415). ITGAV:ITGB3 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling (PubMed:20682778). ITGAV:ITGB3 binds to FGF1 and this binding is essential for FGF1 signaling (PubMed:18441324). ITGAV:ITGB3 binds to FGF2 and this binding is essential for FGF2 signaling (PubMed:28302677). ITGAV:ITGB3 binds to IGF1 and this binding is essential for IGF1 signaling (PubMed:19578119). ITGAV:ITGB3 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464). ITGAV:ITGB3 binds to IL1B and this binding is essential for IL1B signaling (PubMed:29030430). ITGAV:ITGB3 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGAV:ITGB3 and ITGAV:ITGB6 act as receptors for fibrillin-1 (FBN1) and mediate R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). Integrin alpha-V/beta-6 or alpha-V/beta-8 (ITGAV:ITGB6 or ITGAV:ITGB8) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation (PubMed:15184403, PubMed:22278742, PubMed:28117447). ITGAV:ITGB3 acts as a receptor for CD40LG (PubMed:31331973).FUNCTION (Microbial infection) Integrin ITGAV:ITGB5 acts as a receptor for Adenovirus type C.FUNCTION (Microbial infection) Integrin ITGAV:ITGB5 and ITGAV:ITGB3 act as receptors for Coxsackievirus A9 and B1.FUNCTION (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Herpes virus 8/HHV-8.FUNCTION (Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for herpes simplex 1/HHV-1.FUNCTION (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Human parechovirus 1.FUNCTION (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for West nile virus.FUNCTION (Microbial infection) In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.SUBUNIT Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond. Alpha-V (ITGAV) associates with either beta-1 (ITGB1), beta-3 (ITGB3), beta-5 (ITGB5), beta-6 (ITGB6) or beta-8 (ITGB8). Interacts with CIB1 (PubMed:24011356). Interacts with RAB25 (PubMed:17925226). Integrins ITGAV:ITGB3 and ITGAV:ITGB5 interact with FBLN5 (via N-terminus) (By similarity). ITGAV:ITGB3 and ITGAV:ITGB5 interact with CCN3 (PubMed:12695522). ITGAV:ITGB3 interacts with ADGRA2 (PubMed:16982628). ITGAV:ITGB3 interacts with FGF2; it is likely that FGF2 can simultaneously bind ITGAV:ITGB3 and FGF receptors (PubMed:28302677). ITGAV:ITGB3 interacts with IL1B (PubMed:29030430). ITGAV:ITGB3 is found in a ternary complex with CX3CR1 and CX3CL1 (PubMed:23125415). ITGAV:ITGB3 is found in a ternary complex with NRG1 and ERBB3 (PubMed:20682778). ITGAV:ITGB3 is found in a ternary complex with FGF1 and FGFR1 (PubMed:18441324). ITGAV:ITGB3 is found in a ternary complex with IGF1 and IGF1R (PubMed:19578119). ITGAV:ITGB3 interacts with IGF2 (PubMed:28873464). ITGAV:ITGB3 and ITGAV:ITGB6 interact with FBN1 (PubMed:12807887, PubMed:17158881). ITGAV:ITGB3 interacts with CD9, CD81 and CD151 (via second extracellular domain) (PubMed:27993971). ITGAV:ITGB6 interacts with TGFB1 (PubMed:22278742, PubMed:28117447). ITGAV:ITGB3 interacts with PTN (PubMed:19141530). Forms a complex with PTPRZ1 and PTN that stimulates endothelial cell migration through ITGB3 'Tyr-773' phosphorylation (PubMed:19141530).SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with herpes virus 8/HHV-8 envelope glycoprotein B.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 and ITGAV:ITGB6 bind to coxsackievirus A9 and coxsackievirus B1 capsid proteins (PubMed:9426447, PubMed:15194773, PubMed:7519807).SUBUNIT (Microbial infection) Integrin ITGAV:ITGB6 interacts with herpes simplex 1/HHV-1 envelope glycoprotein H.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with Herpes simplex 2/HHV-2 envelope glycoprotein H.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB5 interacts with adenovirus type C penton protein.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with Human parechovirus 1 capsid proteins.SUBUNIT (Microbial infection) Integrin ITGAV:ITGB3 interacts with West nile virus envelope protein E.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.SIMILARITY Belongs to the integrin alpha chain family. UniProt P06756 31 EQUAL 1048 EQUAL Reactome Database ID Release 83 210013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210013 Reactome R-HSA-210013 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210013.1 1 Reactome Database ID Release 83 210216 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210216 Reactome R-HSA-210216 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210216.1 ComplexPortal CPX-1795 VEGFA:p-6Y-VEGFR2:Integrin alphaVbeta3 Reactome DB_ID: 5218779 1 1 Reactome Database ID Release 83 5218779 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218779 Reactome R-HSA-5218779 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218779.1 Reactome Database ID Release 83 5218818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218818 Reactome R-HSA-5218818 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218818.1 12952943 Pubmed 2003 Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis Hood, John D Frausto, Ricardo Kiosses, William B Schwartz, Martin A Cheresh, David A J. Cell Biol. 162:933-43 19267251 Pubmed 2009 Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis Somanath, Payaningal R Malinin, Nikolay L Byzova, Tatiana V Angiogenesis 12:177-85 12820653 Pubmed 2003 Integrin alphavbeta3, requirement for VEGFR2-mediated activation of SAPK2/p38 and for Hsp90-dependent phosphorylation of focal adhesion kinase in endothelial cells activated by VEGF Masson-Gadais, Bénédicte Houle, François Laferrière, Julie Huot, Jacques Cell Stress Chaperones 8:37-52 17030947 Pubmed 2006 Integrin signaling is critical for pathological angiogenesis Mahabeleshwar, Ganapati H Feng, Weiyi Phillips, David R Byzova, Tatiana V J. Exp. Med. 203:2495-507 LEFT-TO-RIGHT HSP90AA1 binds p-6Y-VEGFR2 Heat-shock protein of 90 kDa (HSP90) a molecular chaperone, associates with VEGFR2 in response to VEGF. The last 130 amino acids of VEGFR2 C-terminal portion are involved in the association of VEGFR2 with HSP90. HSP90 associated with VEGFR2 is involved in regulating the activity of a Rho-associated protein kinase (ROCK) that is required to phosphorylate FAK on residue S732 (Le Bouef et al. 2004, 2006). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 HSP90 HSP90AA1 Reactome DB_ID: 192864 UniProt:P07900 HSP90AA1 HSP90AA1 HSP90A HSPC1 HSPCA FUNCTION Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity which is essential for its chaperone activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:11274138, PubMed:15577939, PubMed:15937123, PubMed:27353360, PubMed:29127155, PubMed:12526792). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself (PubMed:29127155). Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:27295069, PubMed:26991466). Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 (PubMed:12526792). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels (PubMed:25973397). In the first place, they alter the steady-state levels of certain transcription factors in response to various physiological cues(PubMed:25973397). Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment (PubMed:25973397). Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Mediates the association of TOMM70 with IRF3 or TBK1 in mitochondrial outer membrane which promotes host antiviral response (PubMed:20628368, PubMed:25609812).FUNCTION (Microbial infection) Seems to interfere with N.meningitidis NadA-mediated invasion of human cells. Decreasing HSP90 levels increases adhesion and entry of E.coli expressing NadA into human Chang cells; increasing its levels leads to decreased adhesion and invasion.ACTIVITY REGULATION In the resting state, through the dimerization of its C-terminal domain, HSP90 forms a homodimer which is defined as the open conformation (PubMed:18400751). Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation (PubMed:18400751). After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state (PubMed:18400751). Co-chaperone TSC1 promotes ATP binding and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Binding to phosphorylated AHSA1 promotes HSP90AA1 ATPase activity (PubMed:29127155). Inhibited by geldanamycin, Ganetespib (STA-9090) and SNX-2112 (PubMed:29127155, PubMed:12526792).SUBUNIT Homodimer (PubMed:7588731, PubMed:8289821, PubMed:18400751, PubMed:29127155). Identified in NR3C1/GCR steroid receptor-chaperone complexes formed at least by NR3C1, HSP90AA1 and a variety of proteins containing TPR repeats such as FKBP4, FKBP5, PPID, PPP5C or STIP1 (PubMed:15383005, PubMed:9195923). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (PubMed:29127155). The closed form interacts (via the middle domain and TPR repeat-binding motif) with co-chaperone TSC1 (via C-terminus) (PubMed:29127155). Interacts with TOM34 (PubMed:9660753). Interacts with TERT; the interaction, together with PTGES3, is required for correct assembly and stabilization of the TERT holoenzyme complex (PubMed:11274138, PubMed:9817749). Interacts with CHORDC1 and DNAJC7 (PubMed:12853476, PubMed:19875381). Interacts with STUB1 and UBE2N; may couple the chaperone and ubiquitination systems (PubMed:16307917, PubMed:27353360). Interacts (via TPR repeat-binding motif) with PPP5C (via TPR repeats); the interaction is direct and activates PPP5C phosphatase activity (PubMed:15383005, PubMed:15577939, PubMed:16531226, PubMed:27353360). Following LPS binding, may form a complex with CXCR4, GDF5 and HSPA8 (PubMed:11276205). Interacts with KSR1 (PubMed:10409742). Interacts with co-chaperone CDC37 (via C-terminus); the interaction inhibits HSP90AA1 ATPase activity (PubMed:23569206, PubMed:27353360). May interact with NWD1 (PubMed:24681825). Interacts with FNIP1 and FNIP2; the interaction inhibits HSP90AA1 ATPase activity (PubMed:17028174, PubMed:27353360). Interacts with co-chaperone AHSA1 (phosphorylated on 'Tyr-223'); the interaction activates HSP90AA1 ATPase activity and results in the dissociation of TSC1 from HSP90AA1 (PubMed:12604615, PubMed:27353360, PubMed:29127155). Interacts with FLCN in the presence of FNIP1 (PubMed:27353360). Interacts with HSP70, STIP1 and PTGES3 (PubMed:27353360). Interacts with SMYD3; this interaction enhances SMYD3 histone-lysine N-methyltransferase (PubMed:15235609, PubMed:25738358). Interacts with SGTA (via TPR repeats) (PubMed:15708368). Interacts with TTC1 (via TPR repeats) (PubMed:15708368). Interacts with HSF1 in an ATP-dependent manner (PubMed:11583998. PubMed:26517842). Interacts with MET; the interaction suppresses MET kinase activity (PubMed:26517842). Interacts with ERBB2 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity (PubMed:26517842). Interacts with HIF1A, KEAP1 and RHOBTB2 (PubMed:26517842). Interacts with HSF1; this interaction is decreased in a IER5-dependent manner, promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-binding activities (PubMed:26754925). Interacts with STUB1 and SMAD3 (PubMed:24613385). Interacts with HSP90AB1; interaction is constitutive (PubMed:20353823). Interacts with HECTD1 (via N-terminus) (By similarity). Interacts with NR3C1 (via domain NR LBD) and NR1D1 (via domain NR LBD) (By similarity). Interacts with NLPR12 (PubMed:30559449, PubMed:17947705). Interacts with PDCL3 (By similarity). Interacts with TOMM70; the interaction is required for preprotein mitochondrial import (PubMed:12526792). Interacts with TOMM70, IRF3 and TBK1; the interactions are direct and mediate the association of TOMM70 with IRF3 and TBK1 (PubMed:20628368). Forms a complex with ASL, ASS1 and NOS2; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction inhibits TBK1-induced interferon production.SUBUNIT (Microbial infection) Interacts with N.meningitidis serogroup B adhesin A (nadA). Interaction is stabilized by ADP and 17-AAG (17-N-allylamino-17-demethoxygeldanamycin) and inhibited by ATP. Decreasing HSP90 levels increases adhesion and entry of bacterial into human Chang cells; increasing its levels leads to decreased adhseion and invasion.DOMAIN The TPR repeat-binding motif mediates interaction with TPR repeat-containing proteins like the co-chaperone STUB1.PTM ISGylated.PTM S-nitrosylated; negatively regulates the ATPase activity and the activation of eNOS by HSP90AA1.PTM Ubiquitinated via 'Lys-63'-linked polyubiquitination by HECTD1. Ubiquitination promotes translocation into the cytoplasm away from the membrane and secretory pathways.SIMILARITY Belongs to the heat shock protein 90 family. UniProt P07900 2 EQUAL 732 EQUAL Reactome Database ID Release 83 192864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=192864 Reactome R-HSA-192864 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-192864.1 VEGFA:p-6Y-VEGFR2:p-SHB:p-5Y-PTK2:SRC-1:HSP90AA1 Reactome DB_ID: 5218637 1 1 Reactome Database ID Release 83 5218637 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218637 Reactome R-HSA-5218637 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218637.2 Reactome Database ID Release 83 5218643 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218643 Reactome R-HSA-5218643 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218643.1 LEFT-TO-RIGHT RHOA:GTP:Mg2+ binds ROCK1,ROCK2 RHOA propagates downstream signals by binding to effector proteins such as Rho-associated, coiled-coil containing protein kinases (ROCKs). ROCKs consist of an amino-terminal kinase domain, followed by a Rho-binding domain (RBD) and a carboxy terminal cysteine-rich domain (CRD) located within the pleckstrin homology (PH) motif. RHOA:GTP interacts with the RBD domain and activates the phosphotransferase activity (Ishizaki et al. 1996, Amano et al. 2000). Heat-shock protein of 90 kDa (HSP90) recruited to VEGFR2 initiates the activation of Rho-dependent kinase (ROCK) (Le Boeuf et al. 2004, 2006). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 RHOA:GTP Reactome DB_ID: 5665993 GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 29438 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 83 29438 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29438 Reactome R-ALL-29438 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29438.4 COMPOUND C00044 1 RHOA RhoA Transforming protein RhoA RHOA_HUMAN Reactome DB_ID: 194510 UniProt:P61586 RHOA RHOA ARH12 ARHA RHO12 FUNCTION Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers (PubMed:8910519, PubMed:9121475, PubMed:31570889). Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (PubMed:16236794, PubMed:12900402). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:20974804, PubMed:23940119). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (PubMed:31888991). May be an activator of PLCE1 (PubMed:16103226). In neurons, involved in the inhibition of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity).FUNCTION (Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague.ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR (PubMed:23940119, PubMed:12221096). Inhibited by GAPs such as ARHGAP30 (PubMed:21565175). Inhibited by GDP dissociation inhibitors such as ARHGDIA (PubMed:20400958).SUBUNIT Interacts with ARHGEF28 (By similarity). Interacts (via GTP-bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases (PubMed:27807006). Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:25588844). Binds PRKCL1, ROCK1 and ROCK2 (PubMed:10388627, PubMed:8617235, PubMed:8641286). Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN (PubMed:10940294, PubMed:12221096, PubMed:9857026). Interacts with PLCE1 and AKAP13 (PubMed:11696353, PubMed:12900402). Interacts with DIAPH1 (PubMed:23325789). Interacts (in the constitutively activated, GTP-bound form) with DGKQ (PubMed:10066731). Interacts with RACK1; enhances RHOA activation (PubMed:20499158). Interacts with PKP4; the interaction is detected at the midbody (PubMed:17115030). Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2 (PubMed:20974804, PubMed:9121475). Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA (PubMed:20400958). Interacts with ARHGDIB. Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain) (PubMed:9635436). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2 (PubMed:31888991). Interacts with RAP1GDS1; the interaction is direct and in a 1:1 stoichiometry (PubMed:28630045, PubMed:30190425, PubMed:20709748, PubMed:12551911).SUBUNIT (Microbial infection) Interacts with yopT from Yersinia pestis.SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein F; this interaction facilitates virus-induced syncytium formation.DOMAIN (Microbial infection) The basic-rich region is essential for yopT recognition and cleavage.PTM (Microbial infection) Substrate for botulinum ADP-ribosyltransferase.PTM (Microbial infection) Cleaved by yopT protease when the cell is infected by some Yersinia pathogens. This removes the lipid attachment, and leads to its displacement from plasma membrane and to subsequent cytoskeleton cleavage.PTM (Microbial infection) AMPylation at Tyr-34 and Thr-37 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:7777059, PubMed:7775453, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-37 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).PTM (Microbial infection) Stearoylated By S.flexneri N-epsilon-fatty acyltransferase IcsB, thereby disrupting the host actin cytoskeleton.PTM Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (PubMed:11162591). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (By similarity).PTM Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons.PTM Serotonylation of Gln-63 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P61586 1 EQUAL 190 EQUAL Reactome Database ID Release 83 194510 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194510 Reactome R-HSA-194510 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194510.1 1 Reactome Database ID Release 83 5665993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665993 Reactome R-HSA-5665993 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665993.1 Converted from EntitySet in Reactome ROCK1,ROCK2 Reactome DB_ID: 419057 ROCK1 Rock1 p160 ROCK Reactome DB_ID: 212509 UniProt:Q13464 ROCK1 ROCK1 FUNCTION Protein kinase which is a key regulator of the actin cytoskeleton and cell polarity (PubMed:10436159, PubMed:10652353, PubMed:11018042, PubMed:11283607, PubMed:17158456, PubMed:18573880, PubMed:19131646, PubMed:8617235, PubMed:9722579). Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, TPPP, PFN1 and PPP1R12A (PubMed:10436159, PubMed:10652353, PubMed:11018042, PubMed:11283607, PubMed:17158456, PubMed:18573880, PubMed:19131646, PubMed:8617235, PubMed:9722579, PubMed:23093407, PubMed:23355470). Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing (PubMed:18694941). Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress (PubMed:19036714). Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability (By similarity). Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation (PubMed:19181962). Required for centrosome positioning and centrosome-dependent exit from mitosis (By similarity). Plays a role in terminal erythroid differentiation (PubMed:21072057). Inhibits podocyte motility via regulation of actin cytoskeletal dynamics and phosphorylation of CFL1 (By similarity). Promotes keratinocyte terminal differentiation (PubMed:19997641). Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization (By similarity). May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles (By similarity).ACTIVITY REGULATION Activated by RHOA binding. Inhibited by Y-27632.SUBUNIT Homodimer. Interacts with RHOB, RHOC, MYLC2B and PTEN. Interacts with ITGB1BP1 (via N-terminus and PTB domain) (By similarity). Interacts with RHOA (activated by GTP), CHORDC1, DAPK3, GEM, JIP3, RHOE, PPP1R12A, PFN1, LIMK1, LIMK2 and TSG101. Interacts with FHOD1 in a Src-dependent manner. Interacts with SHROOM3 (PubMed:22493320).TISSUE SPECIFICITY Detected in blood platelets.DOMAIN The C-terminal auto-inhibitory domain interferes with kinase activity. RHOA binding leads to a conformation change and activation of the kinase. Truncated ROCK1 is constitutively activated.PTM Autophosphorylated on serine and threonine residues.PTM Cleaved by caspase-3 during apoptosis. This leads to constitutive activation of the kinase and membrane blebbing.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. UniProt Q13464 2 EQUAL 1354 EQUAL Reactome Database ID Release 83 212509 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212509 Reactome R-HSA-212509 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212509.1 ROCK2 Rho-associated protein kinase 2 ROCK2_HUMAN Reactome DB_ID: 419058 UniProt:O75116 ROCK2 ROCK2 KIAA0619 FUNCTION Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation.ACTIVITY REGULATION Activated by RHOA binding. Inhibited by Y-27632 (By similarity).SUBUNIT Homodimer (By similarity). Interacts with IRS1 (By similarity). Interacts with RAF1 (By similarity). Interacts with RHOA (activated by GTP), RHOB and RHOC (By similarity). Interacts with PPP1R12A (PubMed:10579722, PubMed:19131646). Interacts with EP300 (PubMed:16574662). Interacts with CHORDC1 (PubMed:20230755). Interacts with BRCA2 (PubMed:21084279). Interacts with NPM1; this interaction enhances ROCK2 activity (PubMed:17015463). Interacts with SORL1 (PubMed:21147781). Interacts with PJVK (By similarity).TISSUE SPECIFICITY Expressed in the brain (at protein level).DOMAIN An interaction between Thr-414 and Asp-48 is essential for kinase activity and dimerization.PTM Phosphorylation at Tyr-722 reduces its binding to RHOA and is crucial for focal adhesion dynamics. Dephosphorylation by PTPN11 stimulates its RHOA binding activity.PTM Cleaved by granzyme B during apoptosis. This leads to constitutive activation of the kinase and membrane blebbing.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. UniProt O75116 1 EQUAL 1388 EQUAL Reactome Database ID Release 83 419058 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419058 Reactome R-HSA-419058 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419058.1 Reactome Database ID Release 83 419057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=419057 Reactome R-HSA-419057 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-419057.1 RHOA:GTP:ROCK1,ROCK2 Reactome DB_ID: 3928564 1 1 Reactome Database ID Release 83 3928564 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3928564 Reactome R-HSA-3928564 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3928564.2 Reactome Database ID Release 83 3928647 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3928647 Reactome R-HSA-3928647 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3928647.5 8617235 Pubmed 1996 The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase Ishizaki, T Maekawa, M Fujisawa, K Okawa, K Iwamatsu, A Fujita, A Watanabe, Nobumoto Saito, Y Kakizuka, A Morii, N Narumiya, S EMBO J 15:1885-93 21445309 Pubmed 2011 Crystal structure of a coiled-coil domain from human ROCK I Tu, Daqi Li, Y Song, Hyun Kyu Toms, Angela V Gould, Christopher J Ficarro, Scott B Marto, Jarrod A Goode, Bruce L Eck, Michael J PLoS ONE 6:e18080 11082274 Pubmed 2000 Regulation and functions of Rho-associated kinase Amano, M Fukata, Y Kaibuchi, K Exp. Cell Res. 261:44-51 21242007 Pubmed 2011 Rho-associated coiled-coil-forming kinases (ROCKs): potential targets for the treatment of atherosclerosis and vascular disease Zhou, Qian Gensch, Christoph Liao, James K Trends Pharmacol. Sci. 32:167-73 ACTIVATION Reactome Database ID Release 83 5218633 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218633 Reactome R-HSA-5218633 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218633.2 LEFT-TO-RIGHT ROCK1,ROCK2 are activated RHOA propagates downstream signals by binding to effector proteins such as Rho-associated, coiled-coil containing protein kinases (ROCKs). ROCKs consist of an amino-terminal kinase domain, followed by a Rho-binding domain (RBD) and a carboxy terminal cysteine-rich domain (CRD) located within the pleckstrin homology (PH) motif. RHOA:GTP interacts with the RBD domain and activates the phosphotransferase activity (Ishizaki et al. 1996, Amano et al. 2000). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 RHOA:GTP:Mg2+:Activated ROCK1,ROCK2 Reactome DB_ID: 5228987 Converted from EntitySet in Reactome Activated ROCK1,ROCK2 Reactome DB_ID: 4687776 Rock1 Activated ROCK1 p160 ROCK Reactome DB_ID: 4687777 2 EQUAL 1354 EQUAL Reactome Database ID Release 83 4687777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4687777 Reactome R-HSA-4687777 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4687777.1 ROCK2_HUMAN Activated ROCK2 Rho-associated protein kinase 2 Reactome DB_ID: 4687775 1 EQUAL 1388 EQUAL Reactome Database ID Release 83 4687775 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4687775 Reactome R-HSA-4687775 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4687775.1 Reactome Database ID Release 83 4687776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4687776 Reactome R-HSA-4687776 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4687776.1 1 RHOA:GTP:Mg2+ Reactome DB_ID: 3858473 RHOA RhoA Transforming protein RhoA RHOA_HUMAN Reactome DB_ID: 194866 1 EQUAL 190 EQUAL Reactome Database ID Release 83 194866 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194866 Reactome R-HSA-194866 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194866.1 1 1 Mg2+ Magnesium magnesium(2+) Mg++ Reactome DB_ID: 29926 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI CHEBI:18420 Reactome Database ID Release 83 29926 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29926 Reactome R-ALL-29926 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29926.5 COMPOUND C00305 1 Reactome Database ID Release 83 3858473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3858473 Reactome R-HSA-3858473 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3858473.1 1 Reactome Database ID Release 83 5228987 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5228987 Reactome R-HSA-5228987 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5228987.1 Reactome Database ID Release 83 5228992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5228992 Reactome R-HSA-5228992 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5228992.1 LEFT-TO-RIGHT 2.7.11.1 Active ROCK1,ROCK2 phosphorylates p-5Y-PTK2 on S732 Activated ROCK directly phosphorylates FAK1 on S732. This phosphorylation induces a conformational change that is necessary to trigger the phosphorylation of FAK on Y407 (Le Bouef et al. 2006). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA:p-6Y-VEGFR2:pS-SHB:p-5Y,S732-PTK2:SRC-1:HSP90AA1 Reactome DB_ID: 5218775 VEGFA:p-6Y-VEGFR2:pS-SHB:p-5Y,S732-PTK2 Reactome DB_ID: 5218771 1 p-5Y,S732-PTK2 p-5Y,S732-FAK1 p(Y397,576,577,861,925),S732-FAK1 Reactome DB_ID: 5229006 732 EQUAL 2 EQUAL 1052 EQUAL Reactome Database ID Release 83 5229006 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5229006 Reactome R-HSA-5229006 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5229006.2 1 Reactome Database ID Release 83 5218771 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218771 Reactome R-HSA-5218771 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218771.2 1 1 1 Reactome Database ID Release 83 5218775 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218775 Reactome R-HSA-5218775 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218775.2 ACTIVATION GENE ONTOLOGY GO:0004674 Reactome Database ID Release 83 4093326 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4093326 Reactome Database ID Release 83 5218826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218826 Reactome R-HSA-5218826 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218826.3 LEFT-TO-RIGHT PTK2beta binds alphaVbeta3 Proline tyrosine kinase 2-beta (PTK2B), also known as cell adhesion kinase-beta or related adhesion focal tyrosine kinase, is a nonreceptor protein-tyrosine kinase closely related to focal adhesion kinase (FAK1) that couples receptors, including integrins, with a variety of downstream effectors such as small G proteins belonging to the Ras and Rho families, mitogen-activated protein kinases, protein kinase C, and inositol phosphate metabolism (Avraham et al. 2000). PYK2B has been shown to play a critical role in the adhesion and migration of many cell types. PYK2B has been shown to localise to integrin and has been demonstrated to associate directly with integrin beta3 cytoplasmic tail (Butler & Blystone 2005, Duong & Rodan 2000, Le Boeuf et al. 2006). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 PTK2B Protein tyrosine kinase 2 beta (PYK2) Focal adhesion kinase 2 (FADK2) Reactome DB_ID: 390932 UniProt:Q14289 PTK2B PTK2B FAK2 PYK2 RAFTK FUNCTION 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.ACTIVITY REGULATION Activated in response to stimuli that lead to increased intracellular Ca(2+) levels; this activation is indirect and may be mediated by calcium-mediated production of reactive oxygen species (ROS). Activated by autophosphorylation at Tyr-402; this creates a binding site for SRC family kinases and leads to phosphorylation at additional tyrosine residues. Phosphorylation at Tyr-402, Tyr-579 and Tyr-580 is required for optimal kinase activity. Inhibited by PF-562,271, BIRB796, PF-4618433 and by PF-431396, PF-2318841 and their derivatives. Inhibited by sulfoximine-substituted trifluoromethylpyrimidines. Inhibited by 4-amino and 5-aryl substituted pyridinone compounds.SUBUNIT Homodimer, or homooligomer. Interacts with SIRPA and SH2D3C. Interacts with ARHGAP10. Interacts with DLG4 (By similarity). Interacts with KCNA2 (By similarity). Interacts with NPHP1, ASAP1, ASAP2, ARHGAP26, SKAP2 and TGFB1I1. The Tyr-402 phosphorylated form interacts with SRC (via SH2 domain) and SRC family members. Forms a signaling complex with EPHA1, LCK and phosphatidylinositol 3-kinase; upon activation by EFNA1. Interacts with GRB2 (via SH2 domain). Interacts with P53/TP53 and MDM2. Interacts with MYLK. Interacts with BCAR1. Interacts with PDPK1. Interacts (hypophosphorylated) with PXN. Interacts with RB1CC1. Interacts with RHOU. Interacts with VAV1. Interacts with LPXN and PTPN12.TISSUE SPECIFICITY Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes.PTM Phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration; this activation is indirect and may be mediated by production of reactive oxygen species (ROS). Tyr-402 is the major autophosphorylation site, but other kinases can also phosphorylate Tyr-402. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-402 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-579; Tyr-580 and Tyr-881. Phosphorylation at Tyr-881 is important for interaction with GRB2. Phosphorylated on tyrosine residues upon activation of FGR and PKC. Recruitment by NPHP1 to cell matrix adhesions initiates Tyr-402 phosphorylation. In monocytes, adherence to substrata is required for tyrosine phosphorylation and kinase activation. Angiotensin II, thapsigargin and L-alpha-lysophosphatidic acid (LPA) also induce autophosphorylation and increase kinase activity. Phosphorylation by MYLK promotes ITGB2 activation and is thus essential to trigger neutrophil transmigration during lung injury. Dephosphorylated by PTPN12.DISEASE Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.MISCELLANEOUS Promotes bone resorption, and thus PTK2B/PYK2 inhibitors might be used to treat osteoporosis.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily. UniProt Q14289 1 EQUAL 1009 EQUAL Reactome Database ID Release 83 390932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390932 Reactome R-HSA-390932 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390932.1 VEGFA:p-6Y-VEGFR2:Integrin alphaVbeta3:PTK2B Reactome DB_ID: 5218787 1 1 Reactome Database ID Release 83 5218787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218787 Reactome R-HSA-5218787 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218787.1 Reactome Database ID Release 83 5218836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218836 Reactome R-HSA-5218836 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218836.2 15695828 Pubmed 2005 Tyrosine phosphorylation of beta3 integrin provides a binding site for Pyk2 Butler, Boyd Blystone, Scott D J. Biol. Chem. 280:14556-62 10704819 Pubmed 2000 RAFTK/Pyk2-mediated cellular signalling Avraham, H Park, S Y Schinkmann, K Avraham, S Cell. Signal. 12:123-33 11056520 Pubmed 2000 PYK2 is an adhesion kinase in macrophages, localized in podosomes and activated by beta(2)-integrin ligation Duong, L T Rodan, G A Cell Motil. Cytoskeleton 47:174-88 LEFT-TO-RIGHT 2.7.10.2 SRC-1 phosphorylates PTK2-beta Proline tyrosine kinase 2-beta (PTK2B/PYK2) is rapidly tyrosine phosphorylated on Y402 through Src-kinases in response to ligation of integrin beta3. Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA:p-6Y-VEGFR2:Integrin alphaVbeta3:p-Y402-PTK2B Reactome DB_ID: 5218778 1 PTK2B Protein tyrosine kinase 2 beta (PYK2) Focal adhesion kinase 2 (FADK2) Reactome DB_ID: 5218721 402 EQUAL 1 EQUAL 1009 EQUAL Reactome Database ID Release 83 5218721 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218721 Reactome R-HSA-5218721 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218721.1 1 Reactome Database ID Release 83 5218778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218778 Reactome R-HSA-5218778 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218778.1 ACTIVATION activeUnit: #Protein20 Reactome Database ID Release 83 5218830 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218830 Reactome R-HSA-5218830 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218830.3 LEFT-TO-RIGHT 2.7.10.2 p-Y402-PTK2B phosphorylates p-5Y,S732-PTK2 on Y407 Phosphorylation of S732 in FAK1 changes its conformation making Y407 accessible to Proline tyrosine kinase 2-beta (PTK2B). pY402-PTK2B then triggers the phosphorylation of FAK1 on Y407 (Le Boeuf et al. 2006). Phosphorylation of Y407 is required to recruit paxillin and vinculin to FAK1 and to ensure formation of focal adhesions and cell migration (Le Boeuf et al. 2004). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA:p-6Y-VEGFR2:p-SHB:p-6Y,S732-PTK2:SRC-1:HSP90AA1 Reactome DB_ID: 5218757 VEGFA:p-6Y-VEGFR2:p-SHB:p-6Y,S732-PTK2 Reactome DB_ID: 5218760 1 p-6Y,S732-PTK2 p-6Y,S732-FAK1 p(Y397,407,576,577,861,925),S732-FAK1 Reactome DB_ID: 5218694 407 EQUAL 2 EQUAL 1052 EQUAL Reactome Database ID Release 83 5218694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218694 Reactome R-HSA-5218694 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218694.2 1 Reactome Database ID Release 83 5218760 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218760 Reactome R-HSA-5218760 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218760.2 1 1 1 Reactome Database ID Release 83 5218757 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218757 Reactome R-HSA-5218757 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218757.2 ACTIVATION Reactome Database ID Release 83 5218843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218843 Reactome Database ID Release 83 5218851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218851 Reactome R-HSA-5218851 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218851.2 LEFT-TO-RIGHT PXN binds p-6Y,S732-PTK2 Paxillin (PXN) is a multidomain scaffolding protein localized primarily in focal adhesions. It binds with focal adhesion kinase (FAK1, also known as PTK2) and is recruited to the focal adhesions. VEGF induced a quick and marked increase in the recruitment of both paxillin and vinculin to FAK (Abedi & Zachary 1997). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 PXN Paxillin Reactome DB_ID: 210014 UniProt:P49023 PXN PXN FUNCTION Cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (focal adhesion).SUBUNIT Interacts in vitro with VCL/vinculin as well as to the SH3 domain of SRC and, when tyrosine phosphorylated, to the SH2 domain of CRK (PubMed:7534286). Interacts with GIT1 (PubMed:10938112). Interacts with NUDT16L1/SDOS (By similarity). Interacts with PTK2/FAK1 (PubMed:14527389). Interacts with PTK2B/PYK2 (PubMed:19358827). Interacts with ASAP2 (PubMed:10749932). Interacts with unphosphorylated ITGA4 (PubMed:10604475). Interacts with RNF5 (PubMed:12861019). Interacts with PDCD10 (PubMed:20489202). Interacts with NEK3, the interaction is prolactin-dependent (PubMed:17297458). Interacts with PTK6 (PubMed:15572663). Interacts with TGFB1I1 (By similarity). Interacts with SORBS1 (PubMed:17462669). Interacts with PARVB (PubMed:22869380). Interacts (via LD motif 4) with PARVA/PARVIN (PubMed:15817463, PubMed:18508764, PubMed:18940607). Interacts (via LD motif 4) with ILK (PubMed:15817463, PubMed:18508764, PubMed:18940607). Interacts (via cytoplasmic domain) with CEACAM1; the interaction is phosphotyrosyl-dependent (PubMed:11035932). Interacts with LIMA1; this complex stabilizes actin dynamics (PubMed:24694988). Interacts with CD36 (via C-terminus) (PubMed:20037584).PTM Phosphorylated by MAPK1/ERK2 (By similarity). Phosphorylated on tyrosine residues during integrin-mediated cell adhesion, embryonic development, fibroblast transformation and following stimulation of cells by mitogens. Phosphorylation at Ser-244 by CDK5 reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Phosphorylation at Tyr-31 and Tyr-118 by PTK6 promote the activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. Phosphorylation at Ser-250 by SLK is required for PXN redistribution and cell motility (PubMed:23128389).SIMILARITY Belongs to the paxillin family. UniProt P49023 1 EQUAL 591 EQUAL Reactome Database ID Release 83 210014 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210014 Reactome R-HSA-210014 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210014.1 VEGFA:p-6Y-VEGFR2:p-SHB:p-7Y-PTK2:SRC-1:HSP90:PXN Reactome DB_ID: 5218781 1 1 Reactome Database ID Release 83 5218781 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218781 Reactome R-HSA-5218781 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218781.2 Reactome Database ID Release 83 5218838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218838 Reactome R-HSA-5218838 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218838.2 LEFT-TO-RIGHT 2.7.10.2 PTK2 and SRC-1 phosphorylate PXN on Y31 and Y118 Upon stimulation FAK1 (also known as PTK2), in association with Src family kinases (SFKs) phosphorylates paxillin (PXN) at two main sites- tyrosine 31 and tyrosine 118. These phosphorylated sites provides the functional SH2-binding sites for members of the Crk family of SH2-SH3 adaptor proteins (Bellis et al. 1995, Shaller & Schaefer 2001). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 2 2 VEGFA:p-6Y-VEGFR2:p-SHB:p-7Y-PTK2:SRC-1:HSP90:p-Y31,Y118-PXN Reactome DB_ID: 5218756 1 p-Y31,Y118-PXN p-Y31,Y118-Paxillin Reactome DB_ID: 5218693 31 EQUAL 118 EQUAL 1 EQUAL 591 EQUAL Reactome Database ID Release 83 5218693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218693 Reactome R-HSA-5218693 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218693.2 1 Reactome Database ID Release 83 5218756 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218756 Reactome R-HSA-5218756 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218756.2 ACTIVATION Reactome Database ID Release 83 5218810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218810 Reactome Database ID Release 83 5218809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218809 Reactome R-HSA-5218809 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218809.2 7615549 Pubmed 1995 Characterization of tyrosine phosphorylation of paxillin in vitro by focal adhesion kinase Bellis, S L Miller, J T Turner, C E J. Biol. Chem. 270:17437-41 11695992 Pubmed 2001 Multiple stimuli induce tyrosine phosphorylation of the Crk-binding sites of paxillin Schaller, M D Schaefer, E M Biochem. J. 360:57-66 LEFT-TO-RIGHT BCAR1 binds p-7Y-PTK2 P130CAS (Crk-associated substrate/BCAR1) is an adaptor protein which upon phosphorylation recruits additional signaling proteins that link the scaffold to the actin cytoskeleton of the cell (Klemke at al. 1998). The C-terminal proline-rich region of Focal adhesion kinase (FAK1) spanning amino acids 712-718 binds the SH3 domain-containing region of p130CAS (Polte & Hanks 1995). P130CAS also interacts with Src-family kinases (SFKs) via its C-terminal Src-binding domain (SBD). Though FAK1 has no tyrosine kinase activity towards p130CAS, it contributes to p130CAS phosphorylation by interacting with SFKs (Ruest et al. 2001). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 BCAR1 Breast cancer anti-estrogen resistance protein 1 p130CAS CRK-associated substrate Cas scaffolding protein family member 1 CASS1 CRKAS Reactome DB_ID: 201625 UniProt:P56945 BCAR1 BCAR1 CAS CASS1 CRKAS FUNCTION Docking protein which plays a central coordinating role for tyrosine kinase-based signaling related to cell adhesion (PubMed:12832404, PubMed:12432078). Implicated in induction of cell migration and cell branching (PubMed:12432078, PubMed:12832404, PubMed:17038317). Involved in the BCAR3-mediated inhibition of TGFB signaling (By similarity).SUBUNIT Forms complexes in vivo with PTK2/FAK1, adapter protein CRKL and LYN kinase (PubMed:9020138). Heterodimerizes with NEDD9 (PubMed:10502414). Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (PubMed:12432078). Within the complex, interacts with SH2D3C (via C-terminus), and CRK (PubMed:12432078, PubMed:17174122). Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on intergrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Interacts with BCAR3 (via Ras-GEF domain); the interaction regulates adhesion-dependent serine phosphorylation (PubMed:22081014). Interacts with SMAD2 and SMAD3 (By similarity). Interacts with NPHP1 (By similarity). Interacts with PTK2B/PYK2 (PubMed:9020138, PubMed:19086031). Interacts (via C-terminus) with SH2D3C/CHAT isoform 2 (via C-terminus) (PubMed:17174122, PubMed:22081014). Interacts with activated CSPG4. Interacts with BMX, INPPL1/SHIP2 and PEAK1. Part of a collagen-stimulated complex involved in cell migration made of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with TNK2 via SH3 domains.TISSUE SPECIFICITY Expressed in B-cells (at protein level) (PubMed:9020138). Widely expressed with an abundant expression in the testis (PubMed:10639512). Low level of expression seen in the liver, thymus, and peripheral blood leukocytes (PubMed:10639512).DOMAIN Contains a central domain (substrate domain) containing multiple potential SH2-binding sites and a C-terminal domain containing a divergent helix-loop-helix (HLH) motif. The SH2-binding sites putatively bind CRK, NCK and ABL1 SH2 domains. The HLH motif is absolutely required for the induction of pseudohyphal growth in yeast and mediates heterodimerization with NEDD9 (By similarity).DOMAIN A serine-rich region promotes activation of the serum response element (SRE).DOMAIN The SH3 domain is necessary for the localization of the protein to focal adhesions and interacts with one proline-rich region of PTK2/FAK11.PTM PTK2/FAK1 activation mediates phosphorylation at the YDYVHL motif; phosphorylation is most likely catalyzed by SRC family members. SRC-family kinases are recruited to the phosphorylated sites and can phosphorylate other tyrosine residues. Tyrosine phosphorylation is triggered by integrin-mediated adhesion of cells to the extracellular matrix.PTM Dephosphorylated by PTPN14 at Tyr-128.PTM Phosphorylated by SRC kinase in a EDN1- and PTK2B-mediated manner; phosphorylation strengthens its interaction with BCAR3 as part of the PTK2B/BCAR1/BCAR3/RAP1 signaling pathway.SIMILARITY Belongs to the CAS family. UniProt P56945 1 EQUAL 870 EQUAL Reactome Database ID Release 83 201625 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201625 Reactome R-HSA-201625 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201625.2 VEGFA:p-6Y-VEGFR2:p-SHB:p-6Y,S732-PTK2:SRC-1:HSP90AA1:BCAR1 Reactome DB_ID: 5218790 1 1 Reactome Database ID Release 83 5218790 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218790 Reactome R-HSA-5218790 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218790.2 Reactome Database ID Release 83 5218855 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218855 Reactome R-HSA-5218855 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218855.2 9472046 Pubmed 1998 CAS/Crk coupling serves as a "molecular switch" for induction of cell migration Klemke, R L Leng, J Molander, R Brooks, P C Vuori, K Cheresh, D A J. Cell Biol. 140:961-72 LEFT-TO-RIGHT 2.7.10.2 PTK2/SRC-1 phosphorylates BCAR1 P130CAS (CRK-associated substrate/BCAR1) contains multiple protein-protein interaction domains including an N-terminal SH3 domain, an interior substrate domain (SD), a Src-binding domain (SBD) near the C-terminus and a conserved C-terminal Cas-family homology (CCH) domain. The SH3 and CCH domains mediate localization to focal adhesions (FAs) while SD and SBD are involved in initiating signaling events (Meenderink et al. 2010, Shin et al. 2004). The BCAR1 SD undergoes tyrosine phosphorylation and mediates signals by recruiting downstream effectors. The SD is characterised by fifteen YxxP motifs, of which ten can be efficiently phosphorylated by Src family kinases (SFKs) (Shin et al. 2004). PTK2/FAK kinase phosphorylates the nearby SBD tyrosines 664 and 666 (mouse 668/670). These SBD tyrosines provide the additional binding sites for Src-SH2 domains, stabilizing the SRC-BCAR1 association (Ruest et al. 2001). Note: Phosphorylated tyrosine numbering in human BCAR1 is based on similarity with the mouse p130Cas. Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 12 12 VEGFA:p-6Y-VEGFR2:p-SHB:p-7Y-PTK2:SRC-1:HSP90:p-12Y-BCAR1 Reactome DB_ID: 5218762 1 p-Y12-BCAR1 p-Y12-P130CAS Reactome DB_ID: 5218739 234 EQUAL 249 EQUAL 267 EQUAL 287 EQUAL 306 EQUAL 327 EQUAL 362 EQUAL 372 EQUAL 387 EQUAL 410 EQUAL 664 EQUAL 666 EQUAL 1 EQUAL 870 EQUAL Reactome Database ID Release 83 5218739 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218739 Reactome R-HSA-5218739 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218739.2 1 Reactome Database ID Release 83 5218762 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218762 Reactome R-HSA-5218762 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218762.2 ACTIVATION Reactome Database ID Release 83 5218816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218816 Reactome Database ID Release 83 5218828 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218828 Reactome R-HSA-5218828 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218828.3 15247284 Pubmed 2004 Subsets of the major tyrosine phosphorylation sites in Crk-associated substrate (CAS) are sufficient to promote cell migration Shin, Nah-Young Dise, Rebecca S Schneider-Mergener, Jens Ritchie, Marylyn D Kilkenny, Dawn M Hanks, Steven K J. Biol. Chem. 279:38331-7 20976150 Pubmed 2010 P130Cas Src-binding and substrate domains have distinct roles in sustaining focal adhesion disassembly and promoting cell migration Meenderink, Leslie M Ryzhova, Larisa M Donato, Dominique M Gochberg, Daniel F Kaverina, Irina Hanks, Steven K PLoS ONE 5:e13412 11604500 Pubmed 2001 Mechanisms of CAS substrate domain tyrosine phosphorylation by FAK and Src Ruest, P J Shin, N Y Polte, T R Zhang, X Hanks, SK Mol. Cell. Biol. 21:7641-52 LEFT-TO-RIGHT CRK binds BCAR1 and or PXN CRK (CT10 Regulator of Kinase) is composed of one SH2 and one or two SH3 domains. This adaptor protein binds with phosphorylated tyrosine motifs found in proteins involved in cell spreading, actin reorganisation, and cell migration. Paxillin (PAX) and p130CAS are the two major focal adhesion components that binds with CRK to form multiprotein signaling complexes and regulate cell migration (Klemke et al. 1998, Valles et al. 2004, Lamorte et al. 2003). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 Converted from EntitySet in Reactome VEGFA:p-6Y-VEGFR2:p-SHB:p-7Y-PTK2:SRC-1:HSP90:p-12Y-BCAR1,VEGFA:p-6Y-VEGFR2:p-SHB:p-7Y-PTK2:SRC-1:HSP90:p-Y31,Y118-PXN Reactome DB_ID: 5218759 Reactome Database ID Release 83 5218759 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218759 Reactome R-HSA-5218759 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218759.3 CRK Adapter molecule crk CRK_HUMAN Reactome DB_ID: 2980677 UniProt:P46108 CRK CRK FUNCTION Involved in cell branching and adhesion mediated by BCAR1-CRK-RAPGEF1 signaling and activation of RAP1.SUBUNIT Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (PubMed:12432078). Within the complex, interacts with SH2D3C (via C-terminus), and BCAR1/CAS (PubMed:12432078). Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases (PubMed:19381274). Interacts with ABL1, C3G, DOCK3, DOCK5, MAP4K1, MAPK8 and SOS via its first SH3 domain. Interacts (via SH2 domain) with BCAR1, CBL, CBLB, PXN, IRS4 and GAB1 upon stimulus-induced tyrosine phosphorylation. Interacts (via SH2 domain) with several tyrosine-phosphorylated growth factor receptors such as EGFR and INSR. Interacts with FLT1 (tyrosine-phosphorylated). Interacts with DOCK1 and DOCK4. Interacts with SHB. Interacts with PEAK1. Interacts with FASLG. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and p130cas/BCAR1. Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1. Interacts with CBLC.DOMAIN The C-terminal SH3 domain function as a negative modulator for transformation and the N-terminal SH3 domain appears to function as a positive regulator for transformation.DOMAIN The SH2 domain mediates interaction with tyrosine phosphorylated proteins. Mediates interaction with SHB.PTM Phosphorylated on Tyr-221 upon cell adhesion. Results in the negative regulation of the association with SH2- and SH3-binding partners, possibly by the formation of an intramolecular interaction of phosphorylated Tyr-221 with the SH2 domain. This leads finally to the down-regulation of the Crk signaling pathway (PubMed:17515907). Isoform Crk-II: Phosphorylated by KIT (By similarity).PTM Proline isomerization at Pro-237 by PPIA acts as a switch between two conformations: an autoinhibitory conformation in the cis form, where the tandem SH3 domains interact intramolecularly, and an activated conformation in the trans form.SIMILARITY Belongs to the CRK family. UniProt P46108 1 EQUAL 304 EQUAL Reactome Database ID Release 83 2980677 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2980677 Reactome R-HSA-2980677 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2980677.1 VEGFA:p-6Y-VEGFR2:p-SHB:p-7Y-PTK2:SRC-1:HSP90:p-12Y-BCAR1/p-Y31,Y118-PAX:CRK Reactome DB_ID: 5218765 1 1 Reactome Database ID Release 83 5218765 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218765 Reactome R-HSA-5218765 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218765.2 Reactome Database ID Release 83 5218822 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218822 Reactome R-HSA-5218822 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218822.2 12857867 Pubmed 2003 Crk associates with a multimolecular Paxillin/GIT2/beta-PIX complex and promotes Rac-dependent relocalization of Paxillin to focal contacts Lamorte, Louie Rodrigues, Sonia Sangwan, Veena Turner, Christopher E Park, Morag Mol. Biol. Cell 14:2818-31 15308668 Pubmed 2004 Activation of Rac1 by paxillin-Crk-DOCK180 signaling complex is antagonized by Rap1 in migrating NBT-II cells Vallés, Ana M Beuvin, Maud Boyer, Brigitte J. Biol. Chem. 279:44490-6 LEFT-TO-RIGHT DOCK180:ELMO binds CRK The SH3 domain of CRK interacts constitutively with proline rich motifs present in Dedicator of cytokinesis (DOCK180), an exchange factor for RAC1. Unlike many GEFs, DOCK180 does not contain a conserved Dbl homology (DH) domain. Instead, it has a DHR2 or DOCKER domain capable of loading RAC1 with GTP (Brugnera et al 2002). Binding of DOCK180 to RAC1 alone is insufficient for GTP loading, a DOCK180-ELMO interaction is required. Engulfment and cell motility protein 1 (ELMO1) or ELMO2 form a complex with DOCK180 which functions as a bipartite GEF to optimally activate RAC1 (Gumienny et al 2001, Brugnera et al 2002, Birge et al. 2009). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 DOCK180:ELMO1,ELMO2 Reactome DB_ID: 5218785 DOCK1 DOCK180 Reactome DB_ID: 372654 UniProt:Q14185 DOCK1 DOCK1 FUNCTION Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Along with DOCK1, mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on type IV collagen (PubMed:19004829). Functions as a guanine nucleotide exchange factor (GEF), which activates Rac Rho small GTPases by exchanging bound GDP for free GTP. Its GEF activity may be enhanced by ELMO1 (PubMed:8657152).SUBUNIT Interacts with the SH3 domains of CRK and NCK2 via multiple sites (PubMed:8657152, PubMed:8662907, PubMed:11240126). Interacts with nucleotide-free RAC1 via its DOCKER domain (PubMed:9808620, PubMed:12134158). Interacts with ELMO1, ELMO2 and probably ELMO3 via its SH3 domain (PubMed:12134158). Interacts with ADGRB1. Identified in a complex with AUTS2 and ELMO2 (By similarity).TISSUE SPECIFICITY Highly expressed in placenta, lung, kidney, pancreas and ovary. Expressed at intermediate level in thymus, testes and colon.DOMAIN The DOCKER domain is necessary and sufficient for the GEF activity.SIMILARITY Belongs to the DOCK family. UniProt Q14185 1 EQUAL 1865 EQUAL Reactome Database ID Release 83 372654 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=372654 Reactome R-HSA-372654 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-372654.1 1 Converted from EntitySet in Reactome ELMO1,ELMO2 Reactome DB_ID: 372640 ELMO1 Engulfment and cell motility protein 1 ELM1_HUMAN Reactome DB_ID: 200932 UniProt:Q92556 ELMO1 ELMO1 KIAA0281 FUNCTION Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Acts in association with DOCK1 and CRK. Was initially proposed to be required in complex with DOCK1 to activate Rac Rho small GTPases. May enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1.SUBUNIT Interacts with ADGRB1 (By similarity). Interacts directly with the SH3-domain of DOCK1 via its SH3-binding site. Part of a complex with DOCK1 and RAC1. Part of a complex with DOCK1 and CRK isoform CRK-II. Interacts with PLEKHG6. Interacts with HCK (via SH3 domain). Interacts with ADGRB3 (PubMed:24567399).TISSUE SPECIFICITY Widely expressed, with a higher expression in the spleen and placenta.PTM Phosphorylated by HCK. UniProt Q92556 1 EQUAL 727 EQUAL Reactome Database ID Release 83 200932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200932 Reactome R-HSA-200932 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200932.1 ELMO2 Engulfment and cell motility protein 2 Reactome DB_ID: 372642 UniProt:Q96JJ3 ELMO2 ELMO2 CED12A KIAA1834 FUNCTION Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Acts in association with DOCK1 and CRK. Was initially proposed to be required in complex with DOCK1 to activate Rac Rho small GTPases. May enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1.SUBUNIT Interacts with the SH3-domain of DOCK1 via its SH3-binding site. Probably part of a complex with DOCK1 and RAC1. Probably part of a complex with DOCK1 and CRK isoform CRK-II. Interacts with ARHGEF16, DOCK4 and EPHA2; mediates activation of RAC1 by EPHA2 (PubMed:20679435). Interacts with ADGRB3 (PubMed:24567399). Interacts with AUTS2; the interaction is direct (By similarity).TISSUE SPECIFICITY Widely expressed, with a higher expression in skeletal muscle, kidney and placenta. UniProt Q96JJ3 1 EQUAL 720 EQUAL Reactome Database ID Release 83 372642 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=372642 Reactome R-HSA-372642 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-372642.1 Reactome Database ID Release 83 372640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=372640 Reactome R-HSA-372640 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-372640.1 1 Reactome Database ID Release 83 5218785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218785 Reactome R-HSA-5218785 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218785.1 CRK:DOCK180:ELMO1,ELMO2:VEGFA:p-6Y-VEGFR2:p-SHB:p-7Y-PTK2:SRC-1:HSP90:p-12Y-BCAR1,VEGFA:p-6Y-VEGFR2:p-SHB:p-7Y-PTK2:SRC-1:HSP90:p-Y31,Y118-PXN Reactome DB_ID: 5218776 1 CRK:DOCK180:ELMO1,ELMO2 Reactome DB_ID: 2029141 1 1 1 Reactome Database ID Release 83 2029141 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029141 Reactome R-HSA-2029141 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029141.1 1 Reactome Database ID Release 83 5218776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218776 Reactome R-HSA-5218776 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218776.2 Reactome Database ID Release 83 5218811 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218811 Reactome R-HSA-5218811 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218811.1 19426560 Pubmed 2009 Crk and CrkL adaptor proteins: networks for physiological and pathological signaling Birge, Raymond B Kalodimos, Charalampos Inagaki, F Tanaka, Shinya Cell Commun. Signal 7:13 12134158 Pubmed 2002 Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex Brugnera, E Haney, L Grimsley, C Lu, M Walk, SF Tosello-Trampont, AC Macara, IG Madhani, H Fink, GR Ravichandran, KS Nat Cell Biol 4:574-82 11595183 Pubmed 2001 CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration Gumienny, TL Brugnera, E Tosello-Trampont, AC Kinchen, JM Haney, LB Nishiwaki, K Walk, SF Nemergut, ME Macara, IG Francis, R Schedl, T Qin, Y Van Aelst, L Hengartner, MO Ravichandran, KS Cell 107:27-41 LEFT-TO-RIGHT DOCK180:ELMO exchanges GTP for GDP, activating RAC1 RAC1 is activated from inactive GDP-bound state to active GTP-bound form by the GEF activity of DOCK180:ELMO complex. RAC1 signaling facilitates VEGF-stimulated angiogenesis by regulating endothelial cell migration and vascular permeability. RAC1 promotes migration by stimulating actin reorganisation to form membrane ruffles and lamellipodia. RAC1 is also a critical component of endothelial NADPH oxidase promoting reactive oxygen species (ROS) prodcution. Specifically, VEGF acts through RAC1 to stimulate lamellipodia formation at the leading edge of polarized cells for directional migration, or chemotaxis. RAC1 induces vascular permeability in part by disrupting endothelial cell-cell junctions (Soga et al. 2001a, Soga et al. 2001b, Claesson-Welsh & Welsh, 2013). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 RAC1:GDP Reactome DB_ID: 5674631 GDP Guanosine 5'-diphosphate Guanosine diphosphate GDP(3-) Reactome DB_ID: 29420 GDP(3-) [ChEBI:58189] GDP(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate(3-) GDP guanosine 5'-diphosphate trianion guanosine 5'-diphosphate GDP trianion ChEBI CHEBI:58189 Reactome Database ID Release 83 29420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29420 Reactome R-ALL-29420 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29420.3 COMPOUND C00035 1 RAC1 Reactome DB_ID: 351141 UniProt:P63000 RAC1 RAC1 TC25 MIG5 FUNCTION Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles (PubMed:1643658, PubMed:28886345). Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity (PubMed:9121475). In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts (PubMed:1643658). In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In neurons, is involved in dendritic spine formation and synaptic plasticity (By similarity). In hippocampal neurons, involved in spine morphogenesis and synapse formation, through local activation at synapses by guanine nucleotide exchange factors (GEFs), such as ARHGEF6/ARHGEF7/PIX (PubMed:12695502). In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in PAK1 activation and eventually F-actin stabilization (By similarity).ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. GTP hydrolysis is stimulated by ARHGAP30.SUBUNIT Interacts with NISCH. Interacts with PIP5K1A. Interacts with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Interacts with PARD6A, PARD6B and PARD6G in a GTP-dependent manner. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with PLXNB1. Part of a complex with MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2. Interacts with NOXA1. Interacts with ARHGEF2. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with ITGB4. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains) (PubMed:18499456). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation (PubMed:20875796). Interacts with PAK2 (PubMed:20696164). Interacts (GTP-bound form) with SH3RF1 and SH3RF3 (PubMed:20696164). Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2 (By similarity). Interacts (GTP-bound form preferentially) with CYRIB (PubMed:31285585, PubMed:30250061). Interacts with DOCK4 (via DOCKER domain); functions as a guanine nucleotide exchange factor (GEF) for RAC1 (PubMed:16464467). Interacts with GARRE1 (PubMed:31871319). Interacts with RAP1GDS1 (PubMed:20709748, PubMed:12551911).TISSUE SPECIFICITY Isoform B is predominantly identified in skin and epithelial tissues from the intestinal tract. Its expression is elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues.DOMAIN The effector region mediates interaction with DEF6.PTM GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.PTM (Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM (Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rac and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium, and by P.sordellii toxin TcsL in the vascular endothelium (PubMed:7777059, PubMed:7775453, PubMed:8626575, PubMed:19744486, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-35 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).PTM (Microbial infection) Palmitoylated by the N-epsilon-fatty acyltransferase F2 chain of V.cholerae toxin RtxA (PubMed:29074776). Palmitoylation inhibits activation by guanine nucleotide exchange factors (GEFs), preventing Rho GTPase signaling (PubMed:29074776).SIMILARITY Belongs to the small GTPase superfamily. Rho family.CAUTION The interaction between DSCAM, PAK1 and RAC1 has been described. This article has been withdrawn by the authors. UniProt P63000 1 EQUAL 189 EQUAL Reactome Database ID Release 83 351141 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351141 Reactome R-HSA-351141 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351141.1 1 Reactome Database ID Release 83 5674631 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5674631 Reactome R-HSA-5674631 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5674631.1 RAC1:GTP Reactome DB_ID: 442641 1 1 Reactome Database ID Release 83 442641 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442641 Reactome R-HSA-442641 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442641.1 ACTIVATION activeUnit: #Complex49 GENE ONTOLOGY GO:0005085 Reactome Database ID Release 83 5218831 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218831 Reactome Database ID Release 83 5218839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218839 Reactome R-HSA-5218839 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218839.3 11525641 Pubmed 2001 Rho family GTPases regulate VEGF-stimulated endothelial cell motility Soga, N Namba, N McAllister, S Cornelius, L Teitelbaum, S L Dowdy, S F Kawamura, J Hruska, K A Exp. Cell Res. 269:73-87 11775025 Pubmed 2001 Rac regulates vascular endothelial growth factor stimulated motility Soga, N Connolly, J O Chellaiah, M Kawamura, J Hruska, K A Cell Commun. Adhes. 8:1-13 LEFT-TO-RIGHT RAC1:GTP and PIP3 bind WAVE Regulatory Complex (WRC) WASP family verprolin-homologous proteins (WAVEs) function downstream of RAC1 and are involved in activation of the ARP2/3 complex. The resulting actin polymerization mediates the projection of the plasma membrane in lamellipodia and membrane ruffles. WAVEs exist as a pentameric hetero-complex called WAVE Regulatory Complex (WRC). The WRC consists of a WAVE family protein (WASF1, WASF2 or WASF3 - commonly known as WAVE1, WAVE2 or WAVE3), ABI (Abelson-interacting protein), NCKAP1 (NAP1, p125NAP1), CYFIP1 (SRA1) or the closely related CYFIP2 (PIR121), and BRK1 (HSPC300, BRICK). Of the three structurally conserved WAVEs in mammals, the importance of WAVE2 in activation of the ARP2/3 complex and the consequent formation of branched actin filaments is best established. WAVEs in the WRC are intrinsically inactive and are stimulated by RAC1 GTPase and phosphatidylinositols (PIP3). The C-terminal VCA domain of WAVE2 (and likely WAVE1 and WAVE3) which can bind both the ARP2/3 complex and actin monomers (G-actin) is masked in the inactive state. After PIP3 binds to the polybasic region of WAVE2 (and likely WAVE1 and WAVE3) and RAC1:GTP binds to the CYFIP1 (or CYFIP2) subunit of the WRC, allosteric changes most likely occur which allow WAVEs to interact with the ARP2/3 complex. The interactions between WAVEs and RAC1 are indirect. BAIAP2/IRSp53, an insulin receptor substrate, acts as a linker, binding both activated RAC1 and the proline-rich region of WAVE2 (and likely WAVE1 and WAVE3) and forming a trimolecular complex. CYFIP1 (or CYFIP2) in the WAVE regulatory complex binds directly to RAC1:GTP and links it to WAVE2 (and likely WAVE1 and WAVE3) (Derivery et al. 2009, Yamazaki et al. 2006, Takenawa & Suetsugu 2007, Chen et al. 2010, Pollard 2007, Lebensohn & Kirschner 2009). Authored: Jupe, S, 2009-09-02 Reviewed: Rosales, C, 2012-05-14 Reviewed: Rivero Crespo, Francisco, 2014-12-26 Edited: Garapati, P V, 2012-01-04 Edited: Orlic-Milacic, Marija, 2015-02-02 BAIAP2 IRSp53/58 Brain-specific angiogenesis inhibitor 1-associated protein 2 BAIP2_HUMAN Reactome DB_ID: 442574 UniProt:Q9UQB8 BAIAP2 BAIAP2 FUNCTION Adapter protein that links membrane-bound small G-proteins to cytoplasmic effector proteins. Necessary for CDC42-mediated reorganization of the actin cytoskeleton and for RAC1-mediated membrane ruffling. Involved in the regulation of the actin cytoskeleton by WASF family members and the Arp2/3 complex. Plays a role in neurite growth. Acts syngeristically with ENAH to promote filipodia formation. Plays a role in the reorganization of the actin cytoskeleton in response to bacterial infection. Participates in actin bundling when associated with EPS8, promoting filopodial protrusions.SUBUNIT Homodimer. Interacts with CDC42 and RAC1 that have been activated by GTP binding. Interacts with ATN1, ADGRB1, EPS8, SHANK1, SHANK2, SHANK3, WASF1 and WASF2. Interacts with ENAH after recruitment of CDC42. Interacts with TIAM1 and DIAPH1 (By similarity). Interacts (via SH3 domain) with E.coli effector protein EspF(U) (via PXXP motifs). Interacts with E.coli intimin receptor Tir.TISSUE SPECIFICITY Isoform 1 and isoform 4 are expressed almost exclusively in brain. Isoform 4 is barely detectable in placenta, prostate and testis. A short isoform is ubiquitous, with the highest expression in liver, prostate, testis and placenta.DOMAIN The IMD domain forms a coiled coil. The isolated domain can induce actin bundling and filopodia formation. In the absence of G-proteins intramolecular interaction between the IMD and the SH3 domain gives rise to an auto-inhibited state of the protein. Interaction of the IMD with RAC1 or CDC42 leads to activation.DOMAIN The SH3 domain interacts with ATN1, ADGRB1, WASF1, WASF2, SHANK1, DIAPH1 and ENAH.PTM Phosphorylated on tyrosine residues by INSR in response to insulin treatment.CAUTION It is uncertain whether Met-1 or Met-59 is the initiator. UniProt Q9UQB8 1 EQUAL 552 EQUAL Reactome Database ID Release 83 442574 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442574 Reactome R-HSA-442574 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442574.1 PIP3 PI(3,4,5)P3 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate Phosphatidylinositol-3,4,5-trisphosphate Reactome DB_ID: 179838 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) [ChEBI:57836] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) 2,3-bis(alkanoyloxy)propyl (1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonatooxy)cyclohexyl phosphate a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) ChEBI CHEBI:57836 Reactome Database ID Release 83 179838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179838 Reactome R-ALL-179838 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179838.4 COMPOUND C05981 WRC WAVE Regulatory Complex WAVE complex Reactome DB_ID: 2029154 Converted from EntitySet in Reactome WAVEs Reactome DB_ID: 2029114 WASF2 Wave2 Reactome DB_ID: 200972 UniProt:Q9Y6W5 WASF2 WASF2 WAVE2 FUNCTION Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Promotes formation of actin filaments. Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex.SUBUNIT Binds actin and the Arp2/3 complex. Interacts with BAIAP2. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 (NCKAP1l/HEM1 in hematopoietic cells) and WASF2/WAVE2 (PubMed:16417406). Directly interacts with BRK1. Interacts with FNBP1L (via the SH3 domain) (PubMed:19798448).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL135.TISSUE SPECIFICITY Expressed in all tissues with strongest expression in placenta, lung, and peripheral blood leukocytes, but not in skeletal muscle.DOMAIN Binds and activates the Arp2/3 complex via the C-terminal domain. Interacts with actin via the WH2 domain.SIMILARITY Belongs to the SCAR/WAVE family. UniProt Q9Y6W5 1 EQUAL 498 EQUAL Reactome Database ID Release 83 200972 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200972 Reactome R-HSA-200972 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200972.1 WASF1 Wave1 Reactome DB_ID: 200965 UniProt:Q92558 WASF1 WASF1 KIAA0269 SCAR1 WAVE1 FUNCTION Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Promotes formation of actin filaments. Part of the WAVE complex that regulates lamellipodia formation (PubMed:29961568). The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex (By similarity). As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity). Also involved in the regulation of mitochondrial dynamics (PubMed:29961568).SUBUNIT Component of the WAVE1 complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1. The complex can also be activated by NCK1. Binds actin and the Arp2/3 complex. Interacts with BAIAP2. Interacts with SHANK3; the interaction mediates the association of SHANK3 with the WAVE1 complex. Interacts with ABI1 (via N-terminus). Interacts with SORBS2; this interaction greatly enhances phosphorylation by ABL1 and dephosphorylation by PTPN12 and might mediate partial to focal adhesion sites.TISSUE SPECIFICITY Highly expressed in brain. Lowly expressed in testis, ovary, colon, kidney, pancreas, thymus, small intestine and peripheral blood.DOMAIN Binds the Arp2/3 complex through the C-terminal region and actin through verprolin homology (VPH) domain.PTM Phosphorylated on tyrosine residues by ABL1 and dephosphorylated by PTPN12.SIMILARITY Belongs to the SCAR/WAVE family. UniProt Q92558 1 EQUAL 559 EQUAL Reactome Database ID Release 83 200965 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200965 Reactome R-HSA-200965 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200965.1 WASF3 Wave3 Reactome DB_ID: 200975 UniProt:Q9UPY6 WASF3 WASF3 KIAA0900 SCAR3 WAVE3 FUNCTION Downstream effector molecules involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape.SUBUNIT Binds actin and the Arp2/3 complex.TISSUE SPECIFICITY Expressed in ovary and brain.DOMAIN Binds the Arp2/3 complex through the C-terminal region and actin through verprolin homology (VPH) domain.PTM Phosphorylation by ABL1 promotes lamellipodia formation and cell migration.SIMILARITY Belongs to the SCAR/WAVE family. UniProt Q9UPY6 1 EQUAL 502 EQUAL Reactome Database ID Release 83 200975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200975 Reactome R-HSA-200975 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200975.1 Reactome Database ID Release 83 2029114 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029114 Reactome R-HSA-2029114 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029114.1 1 HEM1 NCKAP1L Nck-associated protein 1-like NCKPL_HUMAN Reactome DB_ID: 5694031 UniProt:P55160 NCKAP1L NCKAP1L HEM1 FUNCTION Essential hematopoietic-specific regulator of the actin cytoskeleton (Probable). Controls lymphocyte development, activation, proliferation and homeostasis, erythrocyte membrane stability, as well as phagocytosis and migration by neutrophils and macrophages (PubMed:16417406, PubMed:17696648). Component of the WAVE2 complex which signals downstream of RAC to stimulate F-actin polymerization. Required for stabilization and/or translation of the WAVE2 complex proteins in hematopoietic cells (By similarity). Within the WAVE2 complex, enables the cortical actin network to restrain excessive degranulation and granule release by T-cells (PubMed:32647003). Required for efficient T-lymphocyte and neutrophil migration (PubMed:32647003). Exhibits complex cycles of activation and inhibition to generate waves of propagating the assembly with actin (PubMed:16417406). Also involved in mechanisms WAVE-independent to regulate myosin and actin polymerization during neutrophil chemotaxis (PubMed:17696648). In T-cells, required for proper mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, cell proliferation and cytokine secretion, including that of IL2 and TNF (PubMed:32647003).SUBUNIT In hematopoietic cells, component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1L/HEM1 and WASF2/WAVE2 (PubMed:16417406, PubMed:32647003). Interacts with ARHGAP4, PIK3C3/VPS34 and PPP1R12A/MYPT1 (PubMed:16417406). Interacts with mammalian target of rapamycin complex 2 (mTORC2) components, including MTOR and RICTOR (PubMed:32647003).TISSUE SPECIFICITY Expressed only in cells of hematopoietic origin (PubMed:7643388, PubMed:1932118). Expressed in neutrophils (at protein level) (PubMed:16417406). Expressed in T-cells (at protein level) (PubMed:32647003).SIMILARITY Belongs to the HEM-1/HEM-2 family. UniProt P55160 1 EQUAL 1127 EQUAL Reactome Database ID Release 83 5694031 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5694031 Reactome R-HSA-5694031 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5694031.1 1 NAP1 NCKAP1 p125NAP1 Reactome DB_ID: 200979 UniProt:Q9Y2A7 NCKAP1 NCKAP1 HEM2 KIAA0587 NAP1 FUNCTION Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes.SUBUNIT Component of the WAVE1 complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 and WASF2/WAVE2. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1. The complex can also be activated by NCK1. Associates preferentially with the first SH3 domain of NCK. Interacts with NYAP1, NYAP2 and MYO16 (By similarity).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL135.TISSUE SPECIFICITY Expressed in all tissues examined except peripheral blood leukocytes, with highest expression in brain, heart, and skeletal muscle. Expressed in cells of various brain regions including Purkinje cells and dentate nucleus of the cerebellum, CA4 region and dentate gyrus of the hippocampus, and in frontal gray and white matter (PubMed:28940097).SIMILARITY Belongs to the HEM-1/HEM-2 family. UniProt Q9Y2A7 1 EQUAL 1128 EQUAL Reactome Database ID Release 83 200979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200979 Reactome R-HSA-200979 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200979.1 1 BRK1 HSPC300 Protein BRICK1 BRK1_HUMAN Reactome DB_ID: 1671645 UniProt:Q8WUW1 BRK1 BRK1 C3orf10 HSPC300 MDS027 FUNCTION Involved in regulation of actin and microtubule organization. Part of a WAVE complex that activates the Arp2/3 complex. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity).SUBUNIT Homotrimer when in free form. Directly interacts with WASF2. Component of the WAVE1 complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1.SIMILARITY Belongs to the BRK1 family. UniProt Q8WUW1 2 EQUAL 75 EQUAL Reactome Database ID Release 83 1671645 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1671645 Reactome R-HSA-1671645 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1671645.1 1 Converted from EntitySet in Reactome CYFIP1,CYFIP2 Reactome DB_ID: 5672576 SRA1 CYFIP1 Cytoplasmic FMR1-interacting protein 1 SRA-1 Reactome DB_ID: 5672575 UniProt:Q7L576 CYFIP1 CYFIP1 KIAA0068 FUNCTION Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit is an adapter between EIF4E and FMR1. Promotes the translation repression activity of FMR1 in brain probably by mediating its association with EIF4E and mRNA (By similarity). Regulates formation of membrane ruffles and lamellipodia. Plays a role in axon outgrowth. Binds to F-actin but not to RNA. Part of the WAVE complex that regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. Regulator of epithelial morphogenesis. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity). May act as an invasion suppressor in cancers.SUBUNIT Component of the WAVE1 complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1. Component of the CYFIP1-EIF4E-FMR1 complex which is composed of CYFIP, EIF4E and FMR1. Interacts with FMR1 but does not bind to related proteins FXR1 or FXR2. Interaction with EIF4E stimulates FMR1 binding. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 (NCKAP1l/HEM1 in hematopoietic cells) and WASF2/WAVE2 (PubMed:16417406). Interacts with the active GTP-bound form of RAC1. Interacts through its C-terminus with the C-terminus of DPYSL2/CRMP2 which is necessary for DPYSL2-induced axon outgrowth. Interacts with NYAP1, NYAP2 and MYO16. Interacts with TMEM108 (via N-terminus); the interaction associates TMEM108 with the WAVE1 complex (By similarity).MISCELLANEOUS Breakpoint hotspot for the Prader-Willi/Angelman syndromes and may be implicated in autism. Commonly altered in tumors.SIMILARITY Belongs to the CYFIP family. UniProt Q7L576 1 EQUAL 1253 EQUAL Reactome Database ID Release 83 5672575 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5672575 Reactome R-HSA-5672575 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5672575.1 CYFIP2 Cytoplasmic FMR1-interacting protein 2 CYFP2_HUMAN PIR121 Reactome DB_ID: 1671642 UniProt:Q96F07 CYFIP2 CYFIP2 KIAA1168 PIR121 FUNCTION Involved in T-cell adhesion and p53/TP53-dependent induction of apoptosis. Does not bind RNA. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity).SUBUNIT Component of the WAVE1 complex composed of ABI2, CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Interacts with FMR1, FXR1 and FXR2 (By similarity). Interacts with FMR1 isoform 6; the interaction occurs in a RNA-dependent manner (PubMed:24658146). Interacts with RAC1 (activated form) which causes the complex to dissociate, releasing activated WASF1 (PubMed:15048733). The complex can also be activated by NCK1 (PubMed:15048733). Interacts with SHANK3; the interaction mediates the association of SHANK3 with the WAVE1 complex (By similarity). Interacts with TMEM108 (via N-terminus); the interaction associates TMEM108 with the WAVE1 complex (By similarity).TISSUE SPECIFICITY Expressed in T-cells. Increased expression is observed in CD4(+) T-lymphocytes from patients with multiple sclerosis (at protein level).INDUCTION By p53/TP53.SIMILARITY Belongs to the CYFIP family. UniProt Q96F07 1 EQUAL 1278 EQUAL Reactome Database ID Release 83 1671642 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1671642 Reactome R-HSA-1671642 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1671642.1 Reactome Database ID Release 83 5672576 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5672576 Reactome R-HSA-5672576 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5672576.1 1 Converted from EntitySet in Reactome ABI Reactome DB_ID: 1671649 ABI1 Abl interactor 1 ABI1_HUMAN Reactome DB_ID: 1671643 UniProt:Q8IZP0 ABI1 ABI1 SSH3BP1 FUNCTION May act in negative regulation of cell growth and transformation by interacting with nonreceptor tyrosine kinases ABL1 and/or ABL2. May play a role in regulation of EGF-induced Erk pathway activation. Involved in cytoskeletal reorganization and EGFR signaling. Together with EPS8 participates in transduction of signals from Ras to Rac. In vitro, a trimeric complex of ABI1, EPS8 and SOS1 exhibits Rac specific guanine nucleotide exchange factor (GEF) activity and ABI1 seems to act as an adapter in the complex. Regulates ABL1/c-Abl-mediated phosphorylation of ENAH. Recruits WASF1 to lamellipodia and there seems to regulate WASF1 protein level. In brain, seems to regulate the dendritic outgrowth and branching as well as to determine the shape and number of synaptic contacts of developing neurons.SUBUNIT Interacts with ABL1, ENAH, STX1A, SNAP25, VAMP2, EPS8, and through its N-terminus with WASF1. Part of a complex consisting of ABI1, STX1A and SNAP25. Part of a complex consisting of ABI1, EPS8 and SOS1 (By similarity). Interacts with SOS1, SOS2, GRB2, SPTA1 and the first SH3 domain of NCK1. Isoform 6 does not interact with NCK1. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 (NCKAP1l/HEM1 in hematopoietic cells) and WASF2/WAVE2 (PubMed:16417406). Interacts (via SH3 domain) with SHANK2 and SHANK3, but not SHANK1; the interaction is direct. Interacts with the heterodimer MYC:MAX; the interaction may enhance MYC:MAX transcriptional activity. Interacts with FNBP1L (via the SH3 domain), WASF2, and CDC42, but only in the presence of FNBP1L (PubMed:19798448).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL135.TISSUE SPECIFICITY Widely expressed, with highest expression in brain.DOMAIN The t-SNARE coiled-coil homology domain is necessary and sufficient for interaction with STX1A.PTM Phosphorylated on tyrosine residues after serum stimulation or induction by v-Abl. Seems to be phosphorylated at Tyr-53 by ABL1, required for nuclear but not for synaptic localization.DISEASE A chromosomal aberration involving ABI1 is a cause of acute leukemias. Translocation t(10;11)(p11.2;q23) with KMT2A/MLL1. ABI1 isoform 2 was found to be present in acute leukemia KMT2A/MLL1-ABI1 fusion transcript.SIMILARITY Belongs to the ABI family. UniProt Q8IZP0 2 EQUAL 508 EQUAL Reactome Database ID Release 83 1671643 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1671643 Reactome R-HSA-1671643 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1671643.1 ABI2 Abl interactor 2 ABI2_HUMAN Reactome DB_ID: 1671647 UniProt:Q9NYB9 ABI2 ABI2 ARGBPIA FUNCTION Regulator of actin cytoskeleton dynamics underlying cell motility and adhesion. Functions as a component of the WAVE complex, which activates actin nucleating machinery Arp2/3 to drive lamellipodia formation (PubMed:21107423). Acts as regulator and substrate of nonreceptor tyrosine kinases ABL1 and ABL2 involved in processes linked to cell growth and differentiation. Positively regulates ABL1-mediated phosphorylation of ENAH, which is required for proper polymerization of nucleated actin filaments at the leading edge (PubMed:7590236, PubMed:8649853, PubMed:10498863). Contributes to the regulation of actin assembly at the tips of neuron projections. In particular, controls dendritic spine morphogenesis and may promote dendritic spine specification toward large mushroom-type spines known as repositories of memory in the brain (By similarity). In hippocampal neurons, may mediate actin-dependent BDNF-NTRK2 early endocytic trafficking that triggers dendrite outgrowth (By similarity). Participates in ocular lens morphogenesis, likely by regulating lamellipodia-driven adherens junction formation at the epithelial cell-secondary lens fiber interface (By similarity). Also required for nascent adherens junction assembly in epithelial cells (PubMed:15572692).SUBUNIT Component of the WAVE complex composed of ABI2, CYFIP1 or CYFIP2, BRK1, NCKAP1 and WASF1/WAVE1. Within the complex, a heterodimer containing NCKAP1 and CYFIP1 interacts with a heterotrimer formed by WAVE1, ABI2 and BRK1. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1 (PubMed:21107423). Interacts (via SH3 domain) with ABL1 and ABL2 (PubMed:7590236, PubMed:8649853).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL135.TISSUE SPECIFICITY Widely expressed. Abundant in testes, ovary, thymus, and colon, with lower but detectable levels in prostate, peripheral blood leukocytes, and spleen.DOMAIN The SH3 domain is critical for binding to ABL1 and ABL2.PTM Phosphorylated by ABL1.SIMILARITY Belongs to the ABI family. UniProt Q9NYB9 1 EQUAL 513 EQUAL Reactome Database ID Release 83 1671647 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1671647 Reactome R-HSA-1671647 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1671647.1 Reactome Database ID Release 83 1671649 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1671649 Reactome R-HSA-1671649 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1671649.1 1 Reactome Database ID Release 83 2029154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029154 Reactome R-HSA-2029154 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029154.1 WRC:IRSp53/58:RAC1:GTP:PIP3 Reactome DB_ID: 2029147 1 1 1 1 Reactome Database ID Release 83 2029147 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029147 Reactome R-HSA-2029147 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029147.2 Reactome Database ID Release 83 2029465 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029465 Reactome R-HSA-2029465 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029465.4 21107423 Pubmed 2010 Structure and control of the actin regulatory WAVE complex Chen, Z Borek, D Padrick, SB Gomez, TS Metlagel, Z Ismail, AM Umetani, J Billadeau, DD Otwinowski, Z Rosen, MK Nature 468:533-8 17164293 Pubmed 2007 Rac-WAVE-mediated actin reorganization is required for organization and maintenance of cell-cell adhesion Yamazaki, D Oikawa, T Takenawa, T J Cell Sci 120:86-100 9843499 Pubmed 1998 WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac Miki, H Suetsugu, S Takenawa, T EMBO J 17:6932-41 19917258 Pubmed 2009 Activation of the WAVE complex by coincident signals controls actin assembly Lebensohn, AM Kirschner, Marc W Mol Cell 36:512-24 16702231 Pubmed 2006 Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac Suetsugu, S Kurisu, S Oikawa, T Yamazaki, D Oda, A Takenawa, T J Cell Biol 173:571-85 17183359 Pubmed 2007 The WASP-WAVE protein network: connecting the membrane to the cytoskeleton Takenawa, T Suetsugu, S Nat Rev Mol Cell Biol 8:37-48 17477841 Pubmed 2007 Regulation of actin filament assembly by Arp2/3 complex and formins Pollard, TD Annu Rev Biophys Biomol Struct 36:451-77 19206172 Pubmed 2009 The Wave complex is intrinsically inactive Derivery, E Lombard, B Loew, D Gautreau, A Cell Motil Cytoskeleton 66:777-90 LEFT-TO-RIGHT p-6Y-VEGFR2 binds SHC-transforming protein 2 Phosphorylated tyrosine Y1175 of VEGFR2 provides the binding site for the adaptor protein SHC-transforming protein 2 (SHC2) also referred as Shc-like protein (SCK). SCK is plausibly involved in coupling VEGFR2 to ERK (Warner et al. 2000, Ratcliffe et al. 2002). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 SHC2 SHC transforming protein 2 Reactome DB_ID: 167050 UniProt:P98077 SHC2 SHC2 SCK SHCB FUNCTION Signaling adapter that couples activated growth factor receptors to signaling pathway in neurons. Involved in the signal transduction pathways of neurotrophin-activated Trk receptors in cortical neurons (By similarity).SUBUNIT Interacts with the Trk receptors in a phosphotyrosine-dependent manner and MEGF12. Once activated, binds to GRB2.TISSUE SPECIFICITY Expressed in brain. Expressed at high level in the hypothalamus and at low level in the caudate nucleus.DOMAIN The PID domain mediates binding to the TrkA receptor.PTM Phosphorylated on tyrosines by the Trk receptors.MISCELLANEOUS PubMed:15057824 has shown that SHC2 is poorly phosphorylated by the Trk receptors, in opposite to PubMed:12006576. UniProt P98077 1 EQUAL 582 EQUAL Reactome Database ID Release 83 167050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167050 Reactome R-HSA-167050 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-167050.1 VEGFA:p-6Y-VEGFR2:SHC2 Reactome DB_ID: 4420171 1 1 Reactome Database ID Release 83 4420171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420171 Reactome R-HSA-4420171 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420171.1 Reactome Database ID Release 83 4420107 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420107 Reactome R-HSA-4420107 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420107.1 12214271 Pubmed 2002 Sck is expressed in endothelial cells and participates in vascular endothelial growth factor-induced signaling Ratcliffe, Kirsty E Tao, Qi Yavuz, Burju Stoletov, Konstantin V Spring, Simone C Terman, Bruce I Oncogene 21:6307-16 10749680 Pubmed 2000 The Shc-related adaptor protein, Sck, forms a complex with the vascular-endothelial-growth-factor receptor KDR in transfected cells Warner, A J Lopez-Dee, J Knight, E L Feramisco, J R Prigent, S A Biochem. J. 347:501-9 LEFT-TO-RIGHT p-6Y-VEGFR2 binds SH2D2A Two-hybrid mapping showed that tyrosine 951 (Y951) serves as the binding site for T-cell specific adapter molecule (TSAD/ SH2 domain-containing protein 2A (SH2D2A)), also referred as VEGF-receptor-associated protein (VRAP) (Wu et al. 2000). SH2D2A mediates vasular permeability downstream of VEGFR2 by forming a complex with c-SRC (Sun et al. 2012). Site-directed mutation of Y951 to phenylalanine (Y951F) in the VEGFR2, or siRNA mediated silencing of SH2D2A expression, prevented VEGFA mediated cytoskeletal reorganisation and migration but not mitogenicity (Matsumoto et al. 2005). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 TSAD SH2D2A T-cell specific adapter molecule VRAP SH2 domain-containing protein 2A VEGFR associated protein Reactome DB_ID: 4420125 UniProt:Q9NP31 SH2D2A SH2D2A SCAP TSAD VRAP FUNCTION Could be a T-cell-specific adapter protein involved in the control of T-cell activation. May play a role in the CD4-p56-LCK-dependent signal transduction pathway. Could also play an important role in normal and pathological angiogenesis. Could be an adapter protein that facilitates and regulates interaction of KDR with effector proteins important to endothelial cell survival and proliferation.SUBUNIT Interacts with KDR. Interacts with TXK and ITK (By similarity).TISSUE SPECIFICITY Expression limited to tissues of the immune system and, in particular, activated T-cells. Expressed in peripheral blood leukocytes, thymus and spleen. Much lower expression or undetectable, in brain, placenta, skeletal muscle, prostate, testis, ovary, small intestine, and colon. Expressed at low levels in unstimulated T-cells, but not expressed in normal resting or activated B-cells. According to PubMed:10692392, expression is not restricted to activated T-cells, but strongly expressed in blood cell lineages, the endothelium and other cell and tissue types, such as heart, lung, and liver.INDUCTION Rapidly induced after activation of T-cells. However, the gene continues to be expressed in long-term cultures of activated T-cells.PTM Phosphorylated on tyrosine residues. UniProt Q9NP31 1 EQUAL 389 EQUAL Reactome Database ID Release 83 4420125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420125 Reactome R-HSA-4420125 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420125.2 VEGFA dimer:p-6Y-VEGFR2 dimer:SH2D2A Reactome DB_ID: 4420137 1 1 Reactome Database ID Release 83 4420137 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420137 Reactome R-HSA-4420137 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420137.1 Reactome Database ID Release 83 4420143 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420143 Reactome R-HSA-4420143 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420143.2 10692392 Pubmed 2000 VRAP is an adaptor protein that binds KDR, a receptor for vascular endothelial cell growth factor Wu, LW Mayo, L D Dunbar, J D Kessler, K M Ozes, O N Warren, R S Donner, D B J. Biol. Chem. 275:6059-62 22689825 Pubmed 2012 VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd Sun, Zuyue Li, Xiujuan Massena, Sara Kutschera, Simone Padhan, Narendra Gualandi, Laura Sundvold-Gjerstad, Vibeke Gustafsson, Karin Choy, Wing Wen Zang, Guangxiang Quach, My Jansson, Leif Phillipson, Mia Abid, Md Ruhul Spurkland, Anne Claesson-Welsh, Lena J. Exp. Med. 209:1363-77 LEFT-TO-RIGHT SRC1-1 binds SH2D2A and is recruited to VEGFR2 SH2D2A (also known as TSAD) bound to VEGFR2 forms a complex with Src to regulate stress fiber formation and endothelial cell (EC) migration. This contributes to EC migration during pathological angiogenesis and thus the recruitment of SH2D2A is associated with cancer angiogenesis (Matsumoto et al. 2005). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA dimer:p-6Y-VEGFR2 dimer:SH2D2A:SRC-1 Reactome DB_ID: 4420169 1 1 Reactome Database ID Release 83 4420169 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420169 Reactome R-HSA-4420169 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420169.1 Reactome Database ID Release 83 4420140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420140 Reactome R-HSA-4420140 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420140.2 LEFT-TO-RIGHT 2.7.10.2 Phosphorylation of SRC-1 SRC is activated in vivo and in vitro in a VEGF/SH2D2A-dependent manner. VEGF induces phosphorylation of the activating Y418 residue, located on the c-SRC kinase activation loop, but also decreases phosphorylation of the negative regulatory Y527 (Sun et al. 2012). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA:p-6Y-VEGFR2:SH2D2A:p-Y418-SRC-1 Reactome DB_ID: 5218788 1 1 Reactome Database ID Release 83 5218788 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218788 Reactome R-HSA-5218788 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218788.2 ACTIVATION Reactome Database ID Release 83 5218915 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218915 Reactome Database ID Release 83 4420206 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4420206 Reactome R-HSA-4420206 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4420206.2 LEFT-TO-RIGHT AXL binds SRC-1 AXL/UFO (Tyrosine-protein kinase receptor UFO) is a member of the TAM (Tyro3/Axl/Mer) family of receptor tyrosine kinases (RTKs). AXL has been implicated in angiogenesis because of its ability to promote angiogenically related cellular responses in endothelial cells (Holland et al, 2005). AXL is required for VEGFA-dependent activation of PI3K. Activated Src family kinases recruit AXL via its juxtamembrane domain and thereby trigger ligand-independent autophosphorylation of AXL that promotes association with PI3K and activation (Ruan & Kazlauskas 2012). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 AXL Tyrosine-protein kinase receptor UFO precursor UFO_HUMAN Reactome DB_ID: 197705 UniProt:P30530 AXL AXL UFO FUNCTION 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.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.FUNCTION (Microbial infection) Acts as a receptor for Ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope.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).ACTIVITY REGULATION Activated by GAS6-binding and subsequent autophosphorylation.SUBUNIT Heterodimer and heterotetramer with ligand GAS6. Interacts with CBL, GRB2, LCK, NCK2, PIK3R1, PIK3R2, PIK3R3, PLCG1, SOCS1 and TNS2. Part of a complex including AXL, TNK2 and GRB2, in which GRB2 promotes AXL recruitment by TNK2.TISSUE SPECIFICITY Highly expressed in metastatic colon tumors. Expressed in primary colon tumors. Weakly expressed in normal colon tissue.PTM Monoubiquitinated upon GAS6-binding. A very small proportion of the receptor could be subjected to polyubiquitination in a very transient fashion.PTM Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity.DISEASE AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. AXL/UFO subfamily. UniProt P30530 26 EQUAL 894 EQUAL Reactome Database ID Release 83 197705 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197705 Reactome R-HSA-197705 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-197705.1 VEGFA:p-6Y-VEGFR2:SH2D2A:p-Y418-SRC-1:AXL Reactome DB_ID: 5357442 1 1 Reactome Database ID Release 83 5357442 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357442 Reactome R-HSA-5357442 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357442.2 Reactome Database ID Release 83 5357432 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357432 Reactome R-HSA-5357432 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357432.1 22327215 Pubmed 2012 Axl is essential for VEGF-A-dependent activation of PI3K/Akt Ruan, Guo-Xiang Kazlauskas, Andrius EMBO J. 31:1692-703 LEFT-TO-RIGHT 2.7.10.2 AXL autophosphorylates on Y772 and Y814 VEGFA-dependent activation of VEGFR2 causes autophosphorylation and activation of the Axl receptor tyrosine kinase via Src-1:SH2D2A-dependent reaction. Phosphorylation of Axl tyrosine residues 772 and 814 (773 and 815 in mouse) is required for VEGFA-dependent binding of the p85-subunit of PI3K and activation of PI3K (Ruan & Kazlauskas, 2012). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 2 VEGFA:p-6Y-VEGFR2:SH2D2A:p-Y418-SRC-1:p-Y772,Y814-AXL Reactome DB_ID: 5357462 1 p-Y772,Y814-AXL Reactome DB_ID: 5357460 772 EQUAL 814 EQUAL 26 EQUAL 894 EQUAL Reactome Database ID Release 83 5357460 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357460 Reactome R-HSA-5357460 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357460.1 1 Reactome Database ID Release 83 5357462 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357462 Reactome R-HSA-5357462 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357462.2 2 ACTIVATION activeUnit: #Protein66 Reactome Database ID Release 83 5357465 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357465 Reactome Database ID Release 83 5357429 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357429 Reactome R-HSA-5357429 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357429.2 LEFT-TO-RIGHT p-AXL binds PI3K Axl with its two phopshorylated YxxM motifs associates with the p85 subunit of PI3K and mediates VEGFA mediated activation of PI3K/AKT pathway (Ruan & Kazlauskas, 2012). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 PI3K Reactome DB_ID: 74693 Converted from EntitySet in Reactome PI3K-catalytic subunit Reactome DB_ID: 74689 PIK3CA PI3K-p110 PI3-kinase p110 subunit alpha Phosphatidylinositol 3-kinase catalytic subunit, alpha isoform (EC 2.7.1.137) (PI3-kinase p110 subunit alpha) (PtdIns-3-kinase p110) (PI3K) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, alpha isoform PtdIns- 3-kinase p110 Reactome DB_ID: 74787 UniProt:P42336 PIK3CA PIK3CA FUNCTION Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396, PubMed:28676499). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. In addition to its lipid kinase activity, it displays a serine-protein kinase activity that results in the autophosphorylation of the p85alpha regulatory subunit as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others (PubMed:23936502, PubMed:28676499). Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity).PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3) (PubMed:26593112). Interacts with IRS1 in nuclear extracts (By similarity). Interacts with RUFY3 (By similarity). Interacts with RASD2 (By similarity). Interacts with APPL1. Interacts with HRAS and KRAS (By similarity). Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2 (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467).DOMAIN The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane. The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1.DISEASE PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis.MISCELLANEOUS The avian sarcoma virus 16 genome encodes an oncogene derived from PIK3CA.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt P42336 1 EQUAL 1068 EQUAL Reactome Database ID Release 83 74787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74787 Reactome R-HSA-74787 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74787.1 PIK3CB PI3-kinase p110 catalytic subunit beta Phosphatidylinositol 3-kinase catalytic subunit, beta isoform (EC 2.7.1.137) (PI3-kinase p110 subunit beta) (PtdIns-3-kinase p110) (PI3K) (PI3Kbeta) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, beta isoform Reactome DB_ID: 74788 UniProt:P42338 PIK3CB PIK3CB PIK3C1 FUNCTION Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors. Has also a protein kinase activity showing autophosphorylation (PubMed:12502714).PATHWAY Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.SUBUNIT Heterodimer of a catalytic subunit PIK3CB and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interaction with PIK3R2 is required for nuclear localization and nuclear export. Part of a complex with PIK3R1 and PTEN. Binding to PTEN may antagonize the lipid kinase activity under normal growth conditions. Part of a complex involved in autophagosome formation composed of PIK3C3 and PIK3R4 (By similarity). Interacts with BECN1, ATG14 and RAB5A (By similarity).TISSUE SPECIFICITY Expressed ubiquitously.DOMAIN The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1; the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1; and the PI3K/PI4K kinase domain with the cSH2 (C-terminal SH2) region of PIK3R1. The inhibitory interaction between the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1 is weak. The nuclear localization signal (NLS) is required for its function in cell survival.PTM Autophosphorylation at Ser-1070 negatively regulates the phosphatidylinositol-4,5-bisphosphate 3-kinase activity.SIMILARITY Belongs to the PI3/PI4-kinase family. UniProt P42338 1 EQUAL 1070 EQUAL Reactome Database ID Release 83 74788 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74788 Reactome R-HSA-74788 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74788.1 Reactome Database ID Release 83 74689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74689 Reactome R-HSA-74689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74689.1 1 Converted from EntitySet in Reactome PI3K-regulatory subunit Reactome DB_ID: 74688 PIK3R1 PI3K p85 alpha Phosphatidylinositol 3-kinase regulatory alpha subunit PI3-kinase p85-alpha subunit PtdIns-3-kinase p85-alpha Reactome DB_ID: 74789 UniProt:P27986 PIK3R1 PIK3R1 GRB1 FUNCTION Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling (PubMed:17626883, PubMed:19805105, PubMed:7518429). Modulates the cellular response to ER stress by promoting nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (PubMed:20348923).SUBUNIT Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts (via SH2 domains) with CCDC88A/GIV (tyrosine-phosphorylated form); the interaction enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (PubMed:21954290). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with PIK3R2; the interaction is dissociated in an insulin-dependent manner (By similarity). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (PubMed:20348923). Interacts with FER. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with PTK2/FAK1 (By similarity). Interacts with phosphorylated TOM1L1. Interacts with phosphorylated LIME1 upon TCR and/or BCR activation. Interacts with SOCS7. Interacts with RUFY3. Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with LYN (via SH3 domain); this enhances enzyme activity (By similarity). Interacts with phosphorylated LAT, LAX1 and TRAT1 upon TCR activation. Interacts with CBLB. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with IRS1 and phosphorylated IRS4, as well as with NISCH and HCST. Interacts with FASLG, KIT and BCR. Interacts with AXL, FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with FGR and HCK. Interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts with ERBB4 (phosphorylated). Interacts with NTRK1 (phosphorylated upon ligand-binding). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with APPL1 and APPL2 (By similarity). Interacts with SRC (PubMed:28903391). Interacts with ALOX5; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (PubMed:21200133). Interacts with TYK2 (PubMed:10995743).SUBUNIT (Microbial infection) Interacts with HIV-1 Nef to activate the Nef associated p21-activated kinase (PAK). This interaction depends on the C-terminus of both proteins and leads to increased production of HIV.SUBUNIT (Microbial infection) Interacts with HCV NS5A.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 UL46; this interaction activates the PI3K/AKT pathway.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 UL46 and varicella virus ORF12; this interaction activates the PI3K/AKT pathway.TISSUE SPECIFICITY Isoform 2 is expressed in skeletal muscle and brain, and at lower levels in kidney and cardiac muscle. Isoform 2 and isoform 4 are present in skeletal muscle (at protein level).DOMAIN The SH3 domain mediates the binding to CBLB, and to HIV-1 Nef.PTM Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation.PTM Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated by CSF1R. Phosphorylated by ERBB4. Phosphorylated on tyrosine residues by TEK/TIE2. Dephosphorylated by PTPRJ. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear (By similarity). Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated by FGR.SIMILARITY Belongs to the PI3K p85 subunit family. UniProt P27986 1 EQUAL 724 EQUAL Reactome Database ID Release 83 74789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74789 Reactome R-HSA-74789 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74789.1 PIK3R2 PI3K-p85 beta Phosphatidylinositol 3-kinase regulatory beta subunit PI3-kinase p85-beta subunit PtdIns-3-kinase p85-beta Reactome DB_ID: 74791 UniProt:O00459 PIK3R2 PIK3R2 FUNCTION Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Binds to activated (phosphorylated) protein-tyrosine kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Indirectly regulates autophagy (PubMed:23604317). Promotes nuclear translocation of XBP1 isoform 2 in a ER stress- and/or insulin-dependent manner during metabolic overloading in the liver and hence plays a role in glucose tolerance improvement (By similarity).SUBUNIT Heterodimer of a regulatory subunit PIK3R2 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD) (PubMed:23604317). Interacts with AXL (PubMed:9178760). Interacts with FLT1 (tyrosine-phosphorylated) and FLT4 (tyrosine-phosphorylated) (PubMed:9600074, PubMed:15102829). Interacts with NYAP1, NYAP2 and MYO16 (By similarity). Interacts with FBXL2; PIK3R2 is a substrate of the SCF(FBXL2) complex (PubMed:23604317). Interacts with PTPN13; dephosphorylates PIK3R2 (PubMed:23604317). Interacts with XBP1 isoform 2; the interaction is direct and induces translocation of XBP1 isoform 2 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (By similarity). Interacts with PIK3R1; the interaction is dissociated in an insulin-dependent manner (By similarity). Interacts with SRC (PubMed:28903391).DOMAIN The SH2 2 domain is required for interaction with FBXL2 and PTPN13.PTM Phosphorylated in response to signaling from activated receptor-type protein kinases (PubMed:19690332, PubMed:20068231). Dephosphorylated by PTPRJ (PubMed:18348712). Dephosphorylated at Tyr-655 by PTPN13. Phosphorylation of Tyr-655 impairs while its dephosphorylation promotes interaction with FBXL2 and SCF(FBXL2)-mediated polyubiquitination (PubMed:23604317).PTM Ubiquitinated. Polyubiquitination by the SCF(FBXL2) complex probably promotes proteasomal degradation of PIK3R2.SIMILARITY Belongs to the PI3K p85 subunit family. UniProt O00459 1 EQUAL 728 EQUAL Reactome Database ID Release 83 74791 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74791 Reactome R-HSA-74791 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74791.1 Reactome Database ID Release 83 74688 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74688 Reactome R-HSA-74688 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74688.1 1 Reactome Database ID Release 83 74693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74693 Reactome R-HSA-74693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74693.1 ComplexPortal CPX-73 VEGFA:p-6Y-VEGFR2:SH2D2A:p-Y418-SRC-1:p-Y772,Y814-AXL:PI3K Reactome DB_ID: 5357453 1 1 Reactome Database ID Release 83 5357453 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357453 Reactome R-HSA-5357453 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357453.2 Reactome Database ID Release 83 5357479 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357479 Reactome R-HSA-5357479 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357479.2 LEFT-TO-RIGHT p-6Y-VEGFR2 binds PI3K Activation of VEGFR2 results in the activation of phosphatidylinositol 3-kinase (PI3K) which plays an important role in regulating endothelial proliferation, migration and survival (Jiang et al. 2000). Activation of PI3K is also essential for VEGF-stimulated nitric oxide (NO) production from endothelial cells via protein kinase B (PKB/AKT) signaling to eNOS (Nitric oxide synthase, endothelial) (Blanes et al. 2007). Upon stimulation by VEGF the p85 regulatory subunit of PI3K is recruited to phosphorylated tyrosine-801 of VEGFR2 (Dayanir et al. 2001). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VEGFA dimer:p-6Y-VEGFR2 dimer:PI3K Reactome DB_ID: 5218777 1 1 Reactome Database ID Release 83 5218777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218777 Reactome R-HSA-5218777 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218777.1 Reactome Database ID Release 83 5218852 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218852 Reactome R-HSA-5218852 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218852.2 17303569 Pubmed 2007 Phosphorylation of tyrosine 801 of vascular endothelial growth factor receptor-2 is necessary for Akt-dependent endothelial nitric-oxide synthase activation and nitric oxide release from endothelial cells Blanes, Mariela Garcia Oubaha, Malika Rautureau, Yohann Gratton, Jean-Philippe J. Biol. Chem. 282:10660-9 11278468 Pubmed 2001 Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation Dayanir, V Meyer, R D Lashkari, K Rahimi, N J. Biol. Chem. 276:17686-92 10677529 Pubmed 2000 Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells Jiang, B H Zheng, J Z Aoki, M Vogt, P K Proc. Natl. Acad. Sci. U.S.A. 97:1749-53 LEFT-TO-RIGHT 2.7.1.153 VEGFA dimer:p-6Y-VEGFR2 dimer:PI3K phosphorylates PIP2 to PIP3 PI3-kinase (PI3K) catalyzes the phosphorylation of inositol phospholipids at the 3 position to generate phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate. PIP2 and PIP3 generated serve as lipid substrates where they recruit guanine nucleotide exchange factors (GEFs) like VAV (Proto-oncogene vav) that catalyze the exchange of GDP for GTP on Rac, activating it (Han et al. 1998). VAV2 acts downstream of VEGF to activate Rac1 (Garretta et al. 2007). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 PIP2 PI(4,5)P2 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate Phosphatidylinositol-4,5-bisphosphate 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate Reactome DB_ID: 179856 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) [ChEBI:58456] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) 2,3-bis(alkanoyloxy)propyl (1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonatooxy)cyclohexyl phosphate ChEBI CHEBI:58456 Reactome Database ID Release 83 179856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179856 Reactome R-ALL-179856 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-179856.4 COMPOUND C04637 ACTIVATION activeUnit: #Complex60 Converted from EntitySet in Reactome VEGFA dimer:p-6Y-VEGFR2 dimer:PI3K/VEGFA:p-6Y-VEGFR2:SH2D2A:p-Y418-SRC-1:p-Y772,Y814-AXL:PI3K Reactome DB_ID: 5357488 Reactome Database ID Release 83 5357488 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357488 Reactome R-HSA-5357488 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357488.2 GENE ONTOLOGY GO:0046934 Reactome Database ID Release 83 5218825 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218825 Reactome Database ID Release 83 5218819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218819 Reactome R-HSA-5218819 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218819.1 12660731 Pubmed 2003 The role of PI3K in immune cells Koyasu, S Nat Immunol 4:313-9 9438848 Pubmed 1998 Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav Han, J Luby-Phelps, K Das, B Shu, X Xia, Y Mosteller, RD Krishna, UM Falck, JR White, MA Broek, D Science 279:558-60 17686471 Pubmed 2007 VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2 Garrett, Tiana A Van Buul, Jaap D Burridge, Keith Exp. Cell Res. 313:3285-97 17199126 Pubmed 2007 Leading-edge research: PtdIns(3,4,5)P3 and directed migration Franca-Koh, Jonathan Kamimura, Yoichiro Devreotes, Peter N Nat. Cell Biol. 9:15-7 LEFT-TO-RIGHT PI(3,4,5)P3 binds VAV1,2,3 Vav interacts directly with PIP2 and PIP3, with a fivefold selectivity for PIP3 over PIP2. PIP3 gives a twofold stimulation of Vav1 GEF activity while PIP2 leads to 90% inhibition. Binding probably occurs through the PH domain, known to bind phosphoinositides. Authored: Jupe, S, 2009-09-02 Reviewed: Poole, AW, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Harper, MT, 2009-11-02 Edited: Jupe, S, 2009-11-03 Converted from EntitySet in Reactome VAV1,2,3 VAV1,VAV2,VAV3 Reactome DB_ID: 430172 VAV1 Reactome DB_ID: 195066 UniProt:P15498 VAV1 VAV1 VAV FUNCTION Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.SUBUNIT Interacts with SHB (PubMed:12084069). Interacts with SH2B2, GRB2, GRB3, DOCK2, SLA, TEC and ZNF655/VIK (PubMed:12393632, PubMed:12400014, PubMed:15558030). Interacts with SIAH2; without leading to its degradation (PubMed:10207103). Associates with BLNK, PLCG1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion (PubMed:9697839). Interacts with CBLB; which inhibits tyrosine phosphorylation and down-regulates activity (PubMed:9399639). May interact with CCPG1. Interacts with CLNK. Interacts with THEMIS2 (By similarity). Interacts with NEK3 and this interaction is prolactin-dependent (PubMed:15618286). Interacts with ITK (PubMed:15661896). Interacts with PTK2B/PYK2 (By similarity). Interacts with HCK. Interacts with PTK2B/PYK2 (PubMed:19207108). Interacts (via SH2 domain) with SYK (PubMed:8986718). Interacts with ANKRD54. Interacts with CD6 (By similarity). Interacts with isoform 2 of CRACR2A (PubMed:27016526).TISSUE SPECIFICITY Widely expressed in hematopoietic cells but not in other cell types.DOMAIN The DH domain is involved in interaction with CCPG1.PTM Phosphorylated on tyrosine residues by HCK in response to IFNG and bacterial lipopolysaccharide (LPS) (By similarity). Phosphorylated by FYN.MISCELLANEOUS 'Vav' stands for the sixth letter of the Hebrew alphabet. UniProt P15498 1 EQUAL 845 EQUAL Reactome Database ID Release 83 195066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195066 Reactome R-HSA-195066 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195066.1 VAV2 Reactome DB_ID: 195012 UniProt:P52735 VAV2 VAV2 FUNCTION Guanine nucleotide exchange factor for the Rho family of Ras-related GTPases. Plays an important role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly (By similarity).SUBUNIT Interacts (via SH2 domains) with the phosphorylated form of EPHA2. Interacts with SSX2IP (By similarity). Interacts with NEK3 and PRLR and this interaction is prolactin-dependent.TISSUE SPECIFICITY Widely expressed.PTM Phosphorylated on tyrosine residues in response to FGR activation. UniProt P52735 1 EQUAL 878 EQUAL Reactome Database ID Release 83 195012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=195012 Reactome R-HSA-195012 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-195012.1 VAV3 Guanine nucleotide exchange factor VAV3 VAV3_HUMAN Reactome DB_ID: 430152 UniProt:Q9UKW4 VAV3 VAV3 FUNCTION Exchange factor for GTP-binding proteins RhoA, RhoG and, to a lesser extent, Rac1. Binds physically to the nucleotide-free states of those GTPases. Plays an important role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly (By similarity). May be important for integrin-mediated signaling, at least in some cell types. In osteoclasts, along with SYK tyrosine kinase, required for signaling through integrin alpha-v/beta-1 (ITAGV-ITGB1), a crucial event for osteoclast proper cytoskeleton organization and function. This signaling pathway involves RAC1, but not RHO, activation. Necessary for proper wound healing. In the course of wound healing, required for the phagocytotic cup formation preceding macrophage phagocytosis of apoptotic neutrophils. Responsible for integrin beta-2 (ITGB2)-mediated macrophage adhesion and, to a lesser extent, contributes to beta-3 (ITGB3)-mediated adhesion. Does not affect integrin beta-1 (ITGB1)-mediated adhesion (By similarity).SUBUNIT Interacts with the PH domain of SH2B2. Interacts (via SH2 domains) with the phosphorylated form of EPHA2. Interacts with ROS1; constitutive interaction that mediates VAV3 phosphorylation.TISSUE SPECIFICITY Isoform 1 and isoform 3 are widely expressed; both are expressed at very low levels in skeletal muscle. In keratinocytes, isoform 1 is less abundant than isoform 3. Isoform 3 is detected at very low levels, if any, in adrenal gland, bone marrow, spleen, fetal brain and spinal chord; in these tissues, isoform 1 is readily detectable.INDUCTION Down-regulated by EGF and TGF-beta.PTM Phosphorylated. Phosphorylation can be mediated by ROS1. In osteoclasts, undergoes tyrosine phosphorylation in response to CSF1 (By similarity). UniProt Q9UKW4 1 EQUAL 847 EQUAL Reactome Database ID Release 83 430152 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430152 Reactome R-HSA-430152 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430152.1 Reactome Database ID Release 83 430172 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=430172 Reactome R-HSA-430172 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-430172.1 PIP3:VAV1,2,3 Reactome DB_ID: 5340329 1 1 Reactome Database ID Release 83 5340329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5340329 Reactome R-HSA-5340329 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5340329.1 Reactome Database ID Release 83 434637 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434637 Reactome R-HSA-434637 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-434637.3 LEFT-TO-RIGHT 2.7.10.2 Src kinases phosphorylate VAV Following VEGF treatment, VAV2 phosphorylation on tyrosine 172 stimulates its GEF activity for RAC1 (Garrett et al. 2007) and thus plays an important role in linking VEGFR2 to endothelial migration. VAV exists in an auto-inhibitory state, folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the calponin homology (CH) domain to the C1 region. Activation of VAV is thought to involve three events which relieve this auto-inhibition: phosphorylation of tyrosines in the acidic domain causes them to be displaced from the DH domain; binding of a ligand to the CH domain may cause it to release the C1 domain; binding of the PI3K product PIP3 to the PH domain may alter its conformation (Aghazadeh et al. 2000). VAV is phosphorylated on a tyrosine residue (Y174 in VAV1, 172 in VAV2, 173 in VAV3) in the acidic domain. This is mediated by Src and related family tyrosine kinases (Deckert et al. 1996, Schuebel et al. 1998). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 p-VAV family:PIP3 Reactome DB_ID: 5218789 1 Converted from EntitySet in Reactome p-VAV family Reactome DB_ID: 2029115 p-Y174-VAV1 p-VAV1(Y174) Reactome DB_ID: 437946 174 EQUAL 1 EQUAL 845 EQUAL Reactome Database ID Release 83 437946 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437946 Reactome R-HSA-437946 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-437946.1 p-Y172-VAV2 p-VAV2(Y172) Reactome DB_ID: 442307 172 EQUAL 1 EQUAL 878 EQUAL Reactome Database ID Release 83 442307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442307 Reactome R-HSA-442307 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442307.1 p-Y173-VAV3 p-VAV3(Y173) Guanine nucleotide exchange factor VAV3 Reactome DB_ID: 442287 173 EQUAL 1 EQUAL 847 EQUAL Reactome Database ID Release 83 442287 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442287 Reactome R-HSA-442287 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442287.1 Reactome Database ID Release 83 2029115 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029115 Reactome R-HSA-2029115 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029115.1 1 Reactome Database ID Release 83 5218789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218789 Reactome R-HSA-5218789 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218789.1 ACTIVATION activeUnit: #Protein20 Reactome Database ID Release 83 5218820 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218820 Reactome R-HSA-5218820 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218820.2 10395673 Pubmed 1999 Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathway Song, J S Haleem-Smith, H Arudchandran, R Gomez, J Scott, P M Mill, J F Tan, T H Rivera, J J. Immunol. 163:802-10 9822605 Pubmed 1998 Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2 Schuebel, K E Movilla, N Rosa, J L Bustelo, X R EMBO J. 17:6608-21 8986718 Pubmed 1996 Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product Deckert, M Tartare-Deckert, S Couture, C Mustelin, T Altman, A Immunity 5:591-604 11007481 Pubmed 2000 Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation Aghazadeh, B Lowry, WE Huang, XY Rosen, MK Cell 102:625-33 9099726 Pubmed 1997 Tyrosine phosphorylation of the vav proto-oncogene product links FcepsilonRI to the Rac1-JNK pathway Teramoto, H Salem, P Robbins, K C Bustelo, X R Gutkind, J S J. Biol. Chem. 272:10751-5 LEFT-TO-RIGHT p-VAV family:PIP3 binds RAC1:GDP Tyrosine-phosphorylated VAVs bind RAC1:GDP as RAC1 guanine nucleotide exchange factors (GEFs), catalysing the exchange of bound GDP for GTP. RAC1 is a key regulator for actin cytoskeleton and cell migration and is also a critical component of endothelial NADPH oxidase (Wittmann et al. 2003, Tan et al. 2008, Ushio–Fukai 2007, Ushio–Fukai et al. 2002). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Jupe, Steve, 2016-12-08 p-VAV family:PIP3:RAC1:GDP Reactome DB_ID: 8951587 1 1 Reactome Database ID Release 83 8951587 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8951587 Reactome R-HSA-8951587 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8951587.2 Reactome Database ID Release 83 8951586 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8951586 Reactome R-HSA-8951586 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8951586.2 12796474 Pubmed 2003 Regulation of leading edge microtubule and actin dynamics downstream of Rac1 Wittmann, Torsten Bokoch, Gary M Waterman-Storer, Clare M J. Cell Biol. 161:845-51 12480817 Pubmed 2002 Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis Ushio-Fukai, Masuko Tang, Yan Fukai, Tohru Dikalov, Sergey I Ma, Yuxian Fujimoto, Mitsuaki Quinn, Mark T Pagano, Patrick J Johnson, Chad Alexander, R Wayne Circ. Res. 91:1160-7 17511588 Pubmed 2007 VEGF signaling through NADPH oxidase-derived ROS Ushio-Fukai, Masuko Antioxid. Redox Signal. 9:731-9 LEFT-TO-RIGHT VAV exchanges GTP for GDP on RAC1, activating it Tyrosine-phosphorylated VAVs act as guanine nucleotide exchange factors (GEFs) for RAC1, catalysing the exchange of bound GDP for GTP. RAC1 is a key regulator for actin cytoskeleton and cell migration and is also a critical component of endothelial NADPH oxidase (Wittmann et al. 2003, Tan et al. 2008, Ushio–Fukai 2007, Ushio–Fukai et al. 2002). Activated RAC1 then stimulates actin polymerisation to form lamellipodia through a number of proteins such as WASP-family veroprilin homologous protein (WAV). WAVE proteins stimulate the formation of a branched actin network by binding to the p21 subunit of the ARP2/3 nucleating complex, which is located on the sides of the pre-existing filaments. Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 p-VAV family:PIP3:RAC1:GTP Reactome DB_ID: 5218784 1 1 Reactome Database ID Release 83 5218784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218784 Reactome R-HSA-5218784 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218784.2 ACTIVATION activeUnit: #Protein82 Reactome Database ID Release 83 8951588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8951588 Converted from EntitySet in Reactome VAV family Reactome DB_ID: 442295 Reactome Database ID Release 83 442295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442295 Reactome R-HSA-442295 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442295.1 Reactome Database ID Release 83 5218850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5218850 Reactome R-HSA-5218850 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5218850.2 VEGFR2 mediated vascular permeability The free radical nitric oxide (NO), produced by endothelial NO synthase (eNOS), is an important vasoactive substance in normal vascular biology and pathophysiology. It plays an important role in vascular functions such as vascular dilation and angiogenesis (Murohara et al. 1998, Ziche at al. 1997). NO has been reported to be a downstream mediator in the angiogenic response mediated by VEGF, but the mechanism by which NO promotes neovessel formation is not clear (Babaei & Stewart 2002). Persistent vasodilation and increase in vascular permeability in the existing vasculature is observed during the early steps of angiogenesis, suggesting that these hemodynamic changes are indispensable during an angiogenic processes. NO production by VEGF can occur either through the activation of PI3K or through a PLC-gamma dependent manner. Once activated both pathways converge on AKT phosphorylation of eNOS, releasing NO (Lin & Sessa 2006). VEGF also regulates vascular permeability by promoting VE-cadherin endocytosis at the cell surface through a VEGFR-2-Src-Vav2-Rac-PAK signalling axis. Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 LEFT-TO-RIGHT RAC1 binds PAK1-3 Activated Rac1 binds to and stimulates the kinase activity of PAK1-3 (p21 activated kinases 1-3). PAK dimers are arranged in head-to-tail fashion, in which the kinase domain of one molecule is inhibited by the regulatory domain of the other molecule and vice versa. Binding of activated Rac1 breaks the PAK dimer and removes the trans-inhibition (Knaus et al. 1998, Parrini et al. 2002). PAK activated by Rac1 in turn phosphorylates VE-cadherin thereby promoting the beta-arestin-dependent endocytosis of VE-cadherin. This consequently disassemblies intracellular junctions leading to vascular permeability (Gavard & Gutkind 2006). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 Converted from EntitySet in Reactome PAK1,2,3 dimer Reactome DB_ID: 399856 PAK1 dimer Reactome DB_ID: 445002 PAK1 p21-activated kinase Reactome DB_ID: 162629 UniProt:Q13153 PAK1 PAK1 FUNCTION Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes (PubMed:11896197, PubMed:30290153). Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion (PubMed:25766321). In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling (PubMed:23260667). In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in F-actin stabilization (By similarity). In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity). Along with GIT1, positively regulates microtubule nucleation during interphase (PubMed:27012601).ACTIVITY REGULATION Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, and enables activation by phosphorylation of Thr-423 (PubMed:10995762, PubMed:11804587, PubMed:15893667, PubMed:9032240). Phosphorylation of Thr-84 by OXSR1 inhibits activation (By similarity).SUBUNIT Homodimer; homodimerization results in autoinhibition (PubMed:30290153). Active as monomer. Interacts with GIT1 (PubMed:27012601). Component of cytoplasmic complexes, which also contains PXN, ARHGEF7 and GIT1. Interacts with NISCH (By similarity). Interacts with DVL1; mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering (By similarity). Binds to the caspase-cleaved p110 isoform of CDC2L1 and CDC2L2, p110C, but not the full-length proteins (PubMed:12624090). Interacts with ARHGEF7 (PubMed:27012601, PubMed:16101281). Interacts tightly with GTP-bound but not GDP-bound CDC42/P21 and RAC1 (By similarity). Interacts with SCRIB (PubMed:18716323). Interacts with PDPK1 (PubMed:10995762). Interacts (via kinase domain) with RAF1 (PubMed:11733498). Interacts with NCK1 and NCK2 (PubMed:10026169). Interacts with TBCB (PubMed:15831477). Interacts with BRSK2 (By similarity). Interacts with SNAI1 (PubMed:15833848). Interacts with CIB1 isoform 2 (PubMed:23503467). Interacts with CIB1 (via N-terminal region); the interaction is direct, promotes PAK1 activity and occurs in a calcium-dependent manner. Interacts with INPP5K (PubMed:26940976). Interacts with gamma-tubulin (PubMed:27012601).TISSUE SPECIFICITY Overexpressed in gastric cancer cells and tissues (at protein level) (PubMed:25766321).PTM Autophosphorylated in trans, meaning that in a dimer, one kinase molecule phosphorylates the other one. Activated by autophosphorylation at Thr-423 in response to a conformation change, triggered by interaction with GTP-bound CDC42 or RAC1. Activated by phosphorylation at Thr-423 by BRSK2 and by PDPK1. Phosphorylated by JAK2 in response to PRL; this increases PAK1 kinase activity. Phosphorylated at Ser-21 by PKB/AKT; this reduces interaction with NCK1 and association with focal adhesion sites. Upon DNA damage, phosphorylated at Thr-212 and translocates to the nucleoplasm (PubMed:23260667). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (By similarity).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.CAUTION The interaction between DSCAM, PAK1 and RAC1 has beend described. This article has been withdrawn by the authors.CAUTION There are data describing interaction and regulation by the product of CRIPAK, a putative single exon gene (PubMed:16278681). However, considering all available data there is no sufficient supporting evidence for the existence of such protein. UniProt Q13153 1 EQUAL 545 EQUAL Reactome Database ID Release 83 162629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=162629 Reactome R-HSA-162629 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-162629.1 2 Reactome Database ID Release 83 445002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=445002 Reactome R-HSA-445002 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-445002.1 PAK2 dimer Reactome DB_ID: 2685645 PAK2 Reactome DB_ID: 211604 UniProt:Q13177 PAK2 PAK2 FUNCTION Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation (PubMed:7744004, PubMed:19273597, PubMed:19923322, PubMed:9171063, PubMed:12853446, PubMed:16617111). Acts as downstream effector of the small GTPases CDC42 and RAC1 (PubMed:7744004). Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues (PubMed:7744004). Full-length PAK2 stimulates cell survival and cell growth (PubMed:7744004). Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration (PubMed:21317288). Phosphorylates JUN and plays an important role in EGF-induced cell proliferation (PubMed:21177766). Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP (PubMed:21724829). Phosphorylates CASP7, thereby preventing its activity (PubMed:21555521, PubMed:27889207). Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis (PubMed:19273597, PubMed:19923322). On the other hand, apoptotic stimuli such as DNA damage lead to caspase-mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment that translocates to the nucleus and promotes cellular apoptosis involving the JNK signaling pathway (PubMed:9171063, PubMed:12853446, PubMed:16617111). Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation (PubMed:15234964).ACTIVITY REGULATION Activated by binding small G proteins (By similarity). Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-402 and allows the kinase domain to adopt an active structure (By similarity). Following caspase cleavage, autophosphorylated PAK-2p34 is constitutively active (PubMed:9786869).SUBUNIT Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1 (PubMed:20696164). Interacts with SH3MD4 (PubMed:16374509). Interacts with SCRIB (PubMed:18716323). Interacts with ARHGEF7 and GIT1 (PubMed:19273597). PAK-2p34 interacts with ARHGAP10 (PubMed:15471851).SUBUNIT (Microbial infection) Interacts with and activated by HIV-1 Nef.TISSUE SPECIFICITY Ubiquitously expressed. Higher levels seen in skeletal muscle, ovary, thymus and spleen.PTM Full-length PAK2 is autophosphorylated when activated by CDC42/p21. Following cleavage, both peptides, PAK-2p27 and PAK-2p34, become highly autophosphorylated, with PAK-2p27 being phosphorylated on serine and PAK-2p34 on threonine residues, respectively. Autophosphorylation of PAK-2p27 can occur in the absence of any effectors and is dependent on phosphorylation of Thr-402, because PAK-2p27 is acting as an exogenous substrate.PTM During apoptosis proteolytically cleaved by caspase-3 or caspase-3-like proteases to yield active PAK-2p34.PTM Ubiquitinated, leading to its proteasomal degradation.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt Q13177 2 EQUAL 524 EQUAL Reactome Database ID Release 83 211604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211604 Reactome R-HSA-211604 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-211604.1 2 Reactome Database ID Release 83 2685645 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2685645 Reactome R-HSA-2685645 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2685645.1 PAK3 dimer Reactome DB_ID: 5669154 PAK3 Serine/threonine-protein kinase PAK 3 PAK3_HUMAN Reactome DB_ID: 428457 UniProt:O75914 PAK3 PAK3 OPHN3 FUNCTION Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments. May also be involved in early neuronal development. In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity).ACTIVITY REGULATION Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-436 and allows the kinase domain to adopt an active structure (By similarity).SUBUNIT Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Shows highly specific binding to the SH3 domains of phospholipase C-gamma and of adapter protein NCK. Interacts with the C-terminal of APP (By similarity). Interacts with ARHGEF6 and ARHGEF7. Interacts with GIT1 and GIT2 (PubMed:10896954).TISSUE SPECIFICITY Restricted to the nervous system. Highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus.PTM Autophosphorylated when activated by CDC42/p21.PTM Neddylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt O75914 1 EQUAL 559 EQUAL Reactome Database ID Release 83 428457 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428457 Reactome R-HSA-428457 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428457.1 2 Reactome Database ID Release 83 5669154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5669154 Reactome R-HSA-5669154 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5669154.1 Reactome Database ID Release 83 399856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399856 Reactome R-HSA-399856 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399856.1 2 2 x p-VAV family:PIP3:RAC1:GTP:PAK 1-3 Reactome DB_ID: 5357447 1 2 Reactome Database ID Release 83 5357447 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357447 Reactome R-HSA-5357447 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357447.1 Reactome Database ID Release 83 5357483 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357483 Reactome R-HSA-5357483 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357483.2 9705280 Pubmed 1998 Structural requirements for PAK activation by Rac GTPases Knaus, UG Wang, Y Reilly, AM Warnock, D Jackson, JH J Biol Chem 273:21512-8 11804587 Pubmed 2002 Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1 Parrini, MC Lei, M Harrison, SC Mayer, BJ Mol Cell 9:73-83 17060906 Pubmed 2006 VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin Gavard, Julie Gutkind, J Silvio Nat. Cell Biol. 8:1223-34 LEFT-TO-RIGHT PAK1-3 dimer disassociates Binding of Rac1 increases p21 activated kinases 1-3 (PAK1-3) kinase activity and breaks the PAK dimer into monomers. Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 p-VAV family:PIP3:RAC1:GTP:PAK 1-3 Reactome DB_ID: 5357487 Converted from EntitySet in Reactome PAK1,2,3 Reactome DB_ID: 390765 Reactome Database ID Release 83 390765 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=390765 Reactome R-HSA-390765 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-390765.1 1 1 Reactome Database ID Release 83 5357487 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357487 Reactome R-HSA-5357487 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357487.1 2 Reactome Database ID Release 83 5357445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357445 Reactome R-HSA-5357445 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357445.1 LEFT-TO-RIGHT 2.7.11.1 PAK1-3 autophosphorylates Increased PAK1-3 catalytic activity is associated with autophosphorylation of key residues, including one site in the regulatory portion (S144 in PAK1) and another in the so-called activation loop (T423 in PAK1). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 2 2 Converted from EntitySet in Reactome p-S,T-PAK1,2,3 Reactome DB_ID: 399836 p-S144,T423-PAK1 Reactome DB_ID: 399819 144 EQUAL 423 EQUAL O-phospho-L-threonine MOD MOD:00047 1 EQUAL 545 EQUAL Reactome Database ID Release 83 399819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399819 Reactome R-HSA-399819 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399819.1 p-S141,T402-PAK2 Reactome DB_ID: 399824 141 EQUAL 402 EQUAL 1 EQUAL 524 EQUAL Reactome Database ID Release 83 399824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399824 Reactome R-HSA-399824 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399824.1 p-PAK3 p-S154,T436-PAK3 phospho-PAK3 Reactome DB_ID: 5357471 154 EQUAL 436 EQUAL 1 EQUAL 559 EQUAL Reactome Database ID Release 83 5357471 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357471 Reactome R-HSA-5357471 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357471.1 Reactome Database ID Release 83 399836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=399836 Reactome R-HSA-399836 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-399836.1 ACTIVATION Reactome Database ID Release 83 5357467 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357467 Reactome Database ID Release 83 5357472 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357472 Reactome R-HSA-5357472 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357472.2 11278486 Pubmed 2001 The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity Chong, C Tan, L Lim, L Manser, E J Biol Chem 276:17347-53 10075701 Pubmed 1999 Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation Gatti, A Huang, Z Tuazon, PT Traugh, JA J Biol Chem 274:8022-8 LEFT-TO-RIGHT 2.7.11.1 PAK1-3 phosphorylates VE-cadherin Activated PAK then phosphorylates a serene residue (S665) within a conserved motif in the cytoplasmic tail of VE-cadherin. VE-cadherin is also phosphorylated by c-Src in a manner dependent on TSAD (Sun et al. 2012, Lambeng et al. 2005). Serine-phosphorylated VE-cadherin recruits beta-arrestin 2 which promotes the internalization of VE-cadherin into clathrin-coated pits. This process leads to the disassembly of endothelial-cell junctions, resulting in the enhanced permeability of the blood-vessel wall (Gavard & Gutkind 2006). Authored: Garapati, P V, 2013-08-30 Reviewed: Welsh, Michael, Berger, Philipp, Ballmer-Hofer, Kurt, 2014-05-12 Edited: Garapati, P V, 2013-08-30 VE-cadherin-Catenin complex Reactome DB_ID: 5357454 CTNND1 p120 catenin Reactome DB_ID: 418996 UniProt:O60716 CTNND1 CTNND1 KIAA0384 FUNCTION Key regulator of cell-cell adhesion that associates with and regulates the cell adhesion properties of both C-, E- and N-cadherins, being critical for their surface stability (PubMed:14610055, PubMed:20371349). Beside cell-cell adhesion, regulates gene transcription through several transcription factors including ZBTB33/Kaiso2 and GLIS2, and the activity of Rho family GTPases and downstream cytoskeletal dynamics (PubMed:10207085, PubMed:20371349). Implicated both in cell transformation by SRC and in ligand-induced receptor signaling through the EGF, PDGF, CSF-1 and ERBB2 receptors (PubMed:17344476).SUBUNIT Belongs to a multiprotein cell-cell adhesion complex that also contains E-cadherin/CDH1, alpha-catenin/CTNNA1, beta-catenin/CTNNB1, and gamma-catenin/JUP (PubMed:20371349, PubMed:15240885). Component of a cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (PubMed:28051089). Binds to the C-terminal fragment of PSEN1 and mutually competes for CDH1. Interacts with ZBTB33 (PubMed:10207085). Interacts with GLIS2 (PubMed:17344476). Interacts with FER (PubMed:7623846). Interacts with NANOS1 (via N-terminal region) (PubMed:17047063). Interacts (via N-terminus) with GNA12; the interaction regulates CDH1-mediated cell-cell adhesion (PubMed:15240885). Interacts with GNA13 (PubMed:15240885). Interacts with CCDC85B (PubMed:25009281). Interacts with PLPP3; negatively regulates the PLPP3-mediated stabilization of CTNNB1 (PubMed:20123964).TISSUE SPECIFICITY Expressed in vascular endothelium. Melanocytes and melanoma cells primarily express the long isoform 1A, whereas keratinocytes express shorter isoforms, especially 3A. The shortest isoform 4A, is detected in normal keratinocytes and melanocytes, and generally lost from cells derived from squamous cell carcinomas or melanomas. The C-terminal alternatively spliced exon B is present in the p120ctn transcripts in the colon, intestine and prostate, but lost in several tumor tissues derived from these organs.INDUCTION Induced in vascular endothelium by wounding. This effect is potentiated by prior laminar shear stress, which enhances wound closure.DOMAIN A possible nuclear localization signal exists in all isoforms where Asp-626--631-Arg are deleted.DOMAIN ARM repeats 1 to 5 mediate interaction with cadherins.PTM Phosphorylated by FER and other protein-tyrosine kinases. Phosphorylated at Ser-288 by PAK5. Dephosphorylated by PTPRJ.SIMILARITY Belongs to the beta-catenin family. UniProt O60716 1 EQUAL 968 EQUAL Reactome Database ID Release 83 418996 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=418996 Reactome R-HSA-418996 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-418996.1 1 CTNNA1 alpha-catenin Reactome DB_ID: 191735 UniProt:P35221 CTNNA1 CTNNA1 FUNCTION Associates with the cytoplasmic domain of a variety of cadherins. The association of catenins to cadherins produces a complex which is linked to the actin filament network, and which seems to be of primary importance for cadherins cell-adhesion properties. Can associate with both E- and N-cadherins. Originally believed to be a stable component of E-cadherin/catenin adhesion complexes and to mediate the linkage of cadherins to the actin cytoskeleton at adherens junctions. In contrast, cortical actin was found to be much more dynamic than E-cadherin/catenin complexes and CTNNA1 was shown not to bind to F-actin when assembled in the complex suggesting a different linkage between actin and adherens junctions components. The homodimeric form may regulate actin filament assembly and inhibit actin branching by competing with the Arp2/3 complex for binding to actin filaments. Involved in the regulation of WWTR1/TAZ, YAP1 and TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity). May play a crucial role in cell differentiation.SUBUNIT Monomer and homodimer; the monomer preferentially binds to CTNNB1 and the homodimer to actin (By similarity). Component of an cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (PubMed:28051089). Possible component of an E-cadherin/ catenin adhesion complex together with E-cadherin/CDH1 and beta-catenin/CTNNB1 or gamma-catenin/JUP; the complex is located to adherens junctions (By similarity). The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex (By similarity). Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1 (By similarity). Binds AFDN and F-actin (By similarity). Interacts with ARHGAP21 (PubMed:16184169). Interacts with AJUBA (PubMed:12417594). Interacts with LIMA1 (PubMed:18093941). Interacts with vinculin/VCL (PubMed:26691986).TISSUE SPECIFICITY Expressed ubiquitously in normal tissues.PTM Sumoylated.PTM Phosphorylation seems to contribute to the strength of cell-cell adhesion rather than to the basic capacity for cell-cell adhesion.DISEASE Germline CTNNA1 truncating mutations have been detected in patients with hereditary diffuse gastric cancer (HDGC) and may play a role in disease susceptibility. Diffuse gastric cancer is a malignant disease characterized by poorly differentiated infiltrating lesions resulting in thickening of the stomach. Malignant tumors start in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body.SIMILARITY Belongs to the vinculin/alpha-catenin family. UniProt P35221 2 EQUAL 906 EQUAL Reactome Database ID Release 83 191735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191735 Reactome R-HSA-191735 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-191735.1 1 CDH5 VE-cadherin Cadherin-5 Reactome DB_ID: 418992 UniProt:P33151 CDH5 CDH5 FUNCTION Cadherins are calcium-dependent cell adhesion proteins (By similarity). They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types (PubMed:21269602). This cadherin may play a important role in endothelial cell biology through control of the cohesion and organization of the intercellular junctions (By similarity). It associates with alpha-catenin forming a link to the cytoskeleton (PubMed:10861224). Acts in concert with KRIT1 and PALS1 to establish and maintain correct endothelial cell polarity and vascular lumen (By similarity). These effects are mediated by recruitment and activation of the Par polarity complex and RAP1B (PubMed:20332120). Required for activation of PRKCZ and for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction (PubMed:20332120).SUBUNIT Interacts (via cadherin 5 domain) with PTPRB (By similarity). Interacts with TRPC4 (PubMed:19996314). Interacts with KRIT1 (PubMed:20332120). Interacts with PARD3 (By similarity). Interacts with RTN4 (isoform B) (PubMed:21183689). Interacts with PALS1; the interaction promotes PALS1 localization to cell junctions and is required for CDH5-mediated vascular lumen formation and endothelial cell (PubMed:27466317).TISSUE SPECIFICITY Endothelial tissues and brain.DOMAIN Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain.PTM Phosphorylated on tyrosine residues by KDR/VEGFR-2. Dephosphorylated by PTPRB (By similarity).PTM O-glycosylated. UniProt P33151 48 EQUAL 784 EQUAL Reactome Database ID Release 83 418992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=418992 Reactome R-HSA-418992 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-418992.1 1 Converted from EntitySet in Reactome Beta-catenin/gamma catenin Reactome DB_ID: 418993 Converted from EntitySet in Reactome beta-catenin Reactome DB_ID: 191731 CTNNB1 Catenin beta-1 CTNB1_HUMAN Reactome DB_ID: 9038440 UniProt:P35222 CTNNB1 CTNNB1 CTNNB OK/SW-cl.35 PRO2286 FUNCTION Key downstream component of the canonical Wnt signaling pathway (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). Involved in the regulation of cell adhesion, as component of an E-cadherin:catenin adhesion complex (By similarity). Acts as a negative regulator of centrosome cohesion (PubMed:18086858). Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization (PubMed:21262353). Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2 (PubMed:18957423). Disrupts PML function and PML-NB formation by inhibiting RANBP2-mediated sumoylation of PML (PubMed:22155184). Promotes neurogenesis by maintaining sympathetic neuroblasts within the cell cycle (By similarity). Involved in chondrocyte differentiation via interaction with SOX9: SOX9-binding competes with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity).SUBUNIT Two separate complex-associated pools are found in the cytoplasm. The majority is present as component of an E-cadherin:catenin adhesion complex composed of at least E-cadherin/CDH1 and beta-catenin/CTNNB1, and possibly alpha-catenin/CTNNA1; the complex is located to adherens junctions. The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex. Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1. Another cytoplasmic pool is part of a large complex containing AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. Wnt-dependent activation of DVL antagonizes the action of GSK3B. When GSK3B activity is inhibited the complex dissociates, CTNNB1 is dephosphorylated and is no longer targeted for destruction. The stabilized protein translocates to the nucleus, where it binds TCF/LEF-1 family members, BCL9, BCL9L and possibly also RUVBL1 and CHD8. Binds CTNNBIP and EP300. CTNNB1 forms a ternary complex with LEF1 and EP300 that is disrupted by CTNNBIP1 binding. Interacts with TAX1BP3 (via the PDZ domain); this interaction inhibits the transcriptional activity of CTNNB1. Interacts with AJAP1, BAIAP1, CARM1, CTNNA3, CXADR and PCDH11Y. Binds SLC9A3R1. Interacts with GLIS2 and MUC1. Interacts with SLC30A9. Interacts with XIRP1. Interacts directly with AXIN1; the interaction is regulated by CDK2 phosphorylation of AXIN1. Interacts with SCRIB. Interacts with RAPGEF2. Interacts with PTPRU (via the cytoplasmic juxtamembrane domain). Interacts with EMD. Interacts with TNIK and TCF7L2. Interacts with SESTD1 and TRPC4. Interacts with CAV1. Interacts with TRPV4. The TRPV4 and CTNNB1 complex can interact with CDH1. Interacts with VCL. Interacts with PTPRJ. Interacts with PKT7 and CDK2. Interacts with FAT1 (via the cytoplasmic domain). Interacts with NANOS1 and NDRG2. Interacts with isoform 1 of NEK2. Interacts with both isoform 1 and isoform 2 of CDK5. Interacts with PTK6. Interacts with SOX7; this interaction may lead to proteasomal degradation of active CTNNB1 and thus inhibition of Wnt/beta-catenin-stimulated transcription. Identified in a complex with HINT1 and MITF. Interacts with FHIT. The CTNNB1 and TCF7L2/TCF4 complex interacts with PML (isoform PML-4). Interacts with FERMT2. Identified in a complex with TCF7L2/TCF4 and FERMT2 (PubMed:29739711, PubMed:22699938). Interacts with RORA. May interact with P-cadherin/CDH3. Interacts with RNF220 (PubMed:25266658). Interacts with CTNND2 (PubMed:25807484). Interacts (via the C-terminal region) with CBY1 (PubMed:12712206, PubMed:16424001). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422). Interacts with DLG5 (By similarity). Interacts with FAM53B; promoting translocation to the nucleus (PubMed:25183871). Interacts with TMEM170B (PubMed:29367600). Interacts with AHI1 (PubMed:21623382). Interacts with GID8 (PubMed:28829046). Component of an cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (PubMed:28051089). Forms a complex comprising APPL1, RUVBL2, APPL2, HDAC1 and HDAC2 (PubMed:19433865). Interacts with IRF2BPL; mediates the ubiquitination and degradation of CTNNB1 (PubMed:29374064). Interacts with AMFR (By similarity). Interacts with LMBR1L (PubMed:31073040). Interacts with SOX30; prevents interaction of CTNNB1 with TCF7L2/TCF4 and leads to inhibition of Wnt signaling (PubMed:29739711). Interacts with SOX9; inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity). Interacts with SPN/CD43 cytoplasmic tail (PubMed:15003504). Interacts (when phosphorylated at Tyr-333) with isoform M2 of PKM (PKM2); promoting transcription activation (PubMed:22056988). Interacts with PKP2 (via HEAD domain) (PubMed:11790773). Interacts with CDH1 (PubMed:11790773).SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein vPK; this interaction inhibits the Wnt signaling pathway.TISSUE SPECIFICITY Expressed in several hair follicle cell types: basal and peripheral matrix cells, and cells of the outer and inner root sheaths. Expressed in colon. Present in cortical neurons (at protein level). Expressed in breast cancer tissues (at protein level) (PubMed:29367600).PTM Phosphorylation at Ser-552 by AMPK promotes stabilizion of the protein, enhancing TCF/LEF-mediated transcription (By similarity). Phosphorylation by GSK3B requires prior phosphorylation of Ser-45 by another kinase (PubMed:10966653, PubMed:12051714, PubMed:12027456). Phosphorylation proceeds then from Thr-41 to Ser-37 and Ser-33 (PubMed:12077367, PubMed:25169422). Phosphorylated by NEK2 (PubMed:18086858). EGF stimulates tyrosine phosphorylation (PubMed:10187801). Phosphorylated on Ser-33 and Ser-37 by HIPK2 and GSK3B, this phosphorylation triggers proteasomal degradation (PubMed:20307497). Phosphorylation on Ser-191 and Ser-246 by CDK5 (PubMed:17009320). Phosphorylation by CDK2 regulates insulin internalization (PubMed:21262353). Phosphorylation by PTK6 at Tyr-64, Tyr-142, Tyr-331 and/or Tyr-333 with the predominant site at Tyr-64 is not essential for inhibition of transcriptional activity (PubMed:20026641). Phosphorylation by SRC at Tyr-333 promotes interaction with isoform M2 of PKM (PKM2); promoting transcription activation (PubMed:22056988).PTM Ubiquitinated by the SCF(BTRC) E3 ligase complex when phosphorylated by GSK3B, leading to its degradation (PubMed:12077367). Ubiquitinated by a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X, leading to its subsequent proteasomal degradation (PubMed:11389839, PubMed:11389840, PubMed:20307497). Ubiquitinated and degraded following interaction with SOX9 (By similarity).PTM S-nitrosylation at Cys-619 within adherens junctions promotes VEGF-induced, NO-dependent endothelial cell permeability by disrupting interaction with E-cadherin, thus mediating disassembly adherens junctions.PTM O-glycosylation at Ser-23 decreases nuclear localization and transcriptional activity, and increases localization to the plasma membrane and interaction with E-cadherin CDH1.PTM Deacetylated at Lys-49 by SIRT1.PTM Phosphorylated at Thr-556 by herpes virus 1/HHV-1 leading to CTNNB1 inhibition.DISEASE Activating mutations in CTNNB1 have oncogenic activity resulting in tumor development. Somatic mutations are found in various tumor types, including colon cancers, ovarian and prostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma (HCC). HBs are malignant embryonal tumors mainly affecting young children in the first three years of life.DISEASE A chromosomal aberration involving CTNNB1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1.SIMILARITY Belongs to the beta-catenin family.CAUTION A paper showing an interaction with TBP and phosphorylation at Tyr-86 and Tyr-654 has been retracted due to panel duplication in several figures. UniProt P35222 1 EQUAL 781 EQUAL Reactome Database ID Release 83 9038440 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9038440 Reactome R-HSA-9038440 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9038440.1 Reactome Database ID Release 83 191731 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191731 Reactome R-HSA-191731 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-191731.2 JUP Junction plakoglobin PLAK_HUMAN Catenin gamma CTNNG Desmoplakin III Desmoplakin-3 Gamma-catenin DP3 Reactome DB_ID: 437260 UniProt:P14923 JUP JUP CTNNG DP3 FUNCTION Common junctional plaque protein. The membrane-associated plaques are architectural elements in an important strategic position to influence the arrangement and function of both the cytoskeleton and the cells within the tissue. The presence of plakoglobin in both the desmosomes and in the intermediate junctions suggests that it plays a central role in the structure and function of submembranous plaques. Acts as a substrate for VE-PTP and is required by it to stimulate VE-cadherin function in endothelial cells. Can replace beta-catenin in E-cadherin/catenin adhesion complexes which are proposed to couple cadherins to the actin cytoskeleton (By similarity).SUBUNIT Homodimer. Component of an E-cadherin/catenin adhesion complex composed of at least E-cadherin/CDH1 and gamma-catenin/JUP, and possibly alpha-catenin/CTNNA1; the complex is located to adherens junctions. The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex. Interacts with MUC1. Interacts with CAV1 (By similarity). Interacts with PTPRJ. Interacts with DSG1. Interacts with DSC1 and DSC2. Interacts with PKP2 (PubMed:11790773, PubMed:22781308).DOMAIN The entire ARM repeats region mediates binding to CDH1/E-cadherin. The N-terminus and first three ARM repeats are sufficient for binding to DSG1. The N-terminus and first ARM repeat are sufficient for association with CTNNA1. DSC1 association requires both ends of the ARM repeat region.PTM May be phosphorylated by FER.SIMILARITY Belongs to the beta-catenin family. UniProt P14923 1 EQUAL 745 EQUAL Reactome Database ID Release 83 437260 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437260 Reactome R-HSA-437260 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-437260.2 Reactome Database ID Release 83 418993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=418993 Reactome R-HSA-418993 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-418993.1 1 Reactome Database ID Release 83 5357454 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357454 Reactome R-HSA-5357454 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357454.1 p-S665-VE-cadherin-Catenin complex Reactome DB_ID: 5357459 1 1 Cadherin-5 p-S665-VE-cadherin p-S665-CDH5 Reactome DB_ID: 5357435 665 EQUAL 48 EQUAL 784 EQUAL Reactome Database ID Release 83 5357435 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357435 Reactome R-HSA-5357435 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357435.1 1 1 Reactome Database ID Release 83 5357459 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357459 Reactome R-HSA-5357459 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357459.1 ACTIVATION Reactome Database ID Release 83 5357431 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357431 Reactome Database ID Release 83 5357477 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357477 Reactome R-HSA-5357477 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357477.2 15662029 Pubmed 2005 Vascular endothelial-cadherin tyrosine phosphorylation in angiogenic and quiescent adult tissues Lambeng, Nathalie Wallez, Yann Rampon, Christine Cand, Francine Christé, Georges Gulino-Debrac, Danielle Vilgrain, Isabelle Huber, Philippe Circ. Res. 96:384-91 LEFT-TO-RIGHT PIP3 recruits PDPK1 to the membrane PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Edited: Matthews, L, 2012-08-03 PDK1 PDPK1 3-phosphoinositide dependent protein kinase-1 Reactome DB_ID: 202210 UniProt:O15530 PDPK1 PDPK1 PDK1 FUNCTION Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.ACTIVITY REGULATION Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-373 and Tyr-376 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-241 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin.SUBUNIT Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-241 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.TISSUE SPECIFICITY Appears to be expressed ubiquitously. The Tyr-9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast.INDUCTION Stimulated by insulin, and the oxidants hydrogen peroxide and peroxovanadate.DOMAIN The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization.DOMAIN The PIF-pocket is a small lobe in the catalytic domain required by the enzyme for the binding to the hydrophobic motif of its substrates. It is an allosteric regulatory site that can accommodate small compounds acting as allosteric inhibitors.PTM Phosphorylation on Ser-241 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-241, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2 (By similarity). Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-241 and palmitate-induced phosphorylation at Ser-529 and Ser-501 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-354 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-394 and Ser-398 by MAP3K5.PTM Autophosphorylated; autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2.PTM Monoubiquitinated in the kinase domain, deubiquitinated by USP4.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily. UniProt O15530 1 EQUAL 556 EQUAL Reactome Database ID Release 83 202210 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202210 Reactome R-HSA-202210 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202210.1 PDK1:PIP3 PDPK1:PIP3 Reactome DB_ID: 377179 1 PDK1 PDPK1 3-phosphoinositide dependent protein kin