BioPAX pathway converted from "Signaling by Receptor Tyrosine Kinases" in the Reactome database. Signaling by Receptor Tyrosine Kinases Receptor tyrosine kinases (RTKs) are a major class of cell surface proteins involved in Signal Transduction. Human cells contain ~60 RTKs, grouped into 20 subfamilies based on their domain architecture. All RTK subfamilies are characterized by an extracellular ligand-binding domain, a single transmembrane region and an intracellular region consisting of the tyrosine kinase domain and additional regulatory and protein interaction domains. In general, RTKs associate into dimers upon ligand binding and are activated by autophosphorylation on conserved intracellular tyrosine residues. Autophosphorylation increases the catalytic efficiency of the receptor and provides binding sites for the assembly of downstream signaling complexes (reveiwed in Lemmon and Schlessinger, 2010). Common signaling pathways activated downstream of RTK activation include RAF/MAP kinase cascades (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT signaling (reviewed in Manning and Cantley, 2007) and PLC-gamma mediated signaling (reviewed in Patterson et al). Activation of these pathways ultimately results in changes in gene expression and cellular metabolism. Authored: Rothfels, Karen, 2017-05-23 Reviewed: D'Eustachio, Peter, 2017-06-22 Edited: Rothfels, Karen, 2017-05-23 Signaling by EGFR Epidermal Growth Factor Receptor (EGFR) signaling The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1045 in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011. Authored: Jassal, B, Castagnoli, L, 2008-02-28 00:00:00 Reviewed: Muthuswamy, S, Heldin, CH, 2008-02-28 Edited: Orlic-Milacic, Marija, 2011-08-25 LEFT-TO-RIGHT 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Pro-EGF is cleaved to form mature EGF Ligands of the epidermal growth factor receptor (EGFR) are shed from the plasma membrane by metalloproteases. Identification of the sheddases for EGFR ligands using mouse embryonic cells lacking candidate sheddases (a disintegrin and metalloprotease; ADAM) has revealed that ADAM10, -12 and -17 are the sheddases of the EGFR ligands in response to various shedding stimulants such as GPCR agonists, growth factors, cytokines, osmotic stress, wounding and phorbol ester. Among the EGFR ligands, heparin-binding EGF-like growth factor (HB-EGF), EGF and TGF-alpha are the best characterized. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 Pro-EGF pro-EGF precursor Epidermal Growth Factor precursor Reactome DB_ID: 179888 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:P01133 EGF EGF FUNCTION EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture. Magnesiotropic hormone that stimulates magnesium reabsorption in the renal distal convoluted tubule via engagement of EGFR and activation of the magnesium channel TRPM6. Can induce neurite outgrowth in motoneurons of the pond snail Lymnaea stagnalis in vitro (PubMed:10964941).SUBUNIT Interacts with EGFR and promotes EGFR dimerization. Interacts with RHBDF2 (By similarity). Interacts with RHBDF1; may retain EGF in the endoplasmic reticulum and regulates its degradation through the endoplasmic reticulum-associated degradation (ERAD).TISSUE SPECIFICITY Expressed in kidney, salivary gland, cerebrum and prostate.PTM O-glycosylated with core 1-like and core 2-like glycans. It is uncertain if Ser-954 or Thr-955 is O-glycosylated. The modification here shows glycan heterogeneity: HexHexNAc (major) and Hex2HexNAc2 (minor). Homo sapiens NCBI Taxonomy 9606 UniProt P01133 23 EQUAL 1207 EQUAL Reactome Database ID Release 78 179888 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=179888 Reactome R-HSA-179888 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-179888.1 Reactome http://www.reactome.org EGF Epidermal Growth Factor Reactome DB_ID: 179863 extracellular region GENE ONTOLOGY GO:0005576 971 EQUAL 1023 EQUAL Reactome Database ID Release 78 179863 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=179863 Reactome R-HSA-179863 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-179863.1 ACTIVATION ADAM:Zn2+ ADAM metalloprotease:Zinc cofactor Reactome DB_ID: 179842 Zn2+ Zn++ zinc(2+) zinc Zn(II) Reactome DB_ID: 109265 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 78 109265 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=109265 Reactome R-ALL-109265 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-109265.3 COMPOUND C00038 additional information MI MI:0361 1 Converted from EntitySet in Reactome ADAM metalloprotease Reactome DB_ID: 179832 ADAM10(215-824) ADAM 10 metalloprotease ADAM 10 sheddase Reactome DB_ID: 179885 UniProt:O14672 ADAM10 ADAM10 KUZ MADM FUNCTION Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905, PubMed:29224781). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:24990881). Involved in the development and maturation of glomerular and coronary vasculature (By similarity). During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions (By similarity). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146).FUNCTION (Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores.ACTIVITY REGULATION Catalytically inactive when the propeptide is intact and associated with the mature enzyme (By similarity). The disintegrin and cysteine-rich regions modulate access of substrates to exerts an inhibitory effect on the cleavage of ADAM10 substrates (PubMed:29224781).SUBUNIT Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells (PubMed:16239146). Interacts with the clathrin adapter AP2 complex subunits AP2A1, AP2A2, AP2B1, and AP2M1; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with TSPAN33 (via extracellular domain) and (via cytoplasmic domain) with AFDN; interaction with TSPAN33 allows the docking of ADAM10 to zonula adherens through a PDZ11-dependent interaction between TSPAN33 and PLEKHA7 while interaction with AFDN locks ADAM10 at zonula adherens (PubMed:30463011). Forms a ternary complex composed of ADAM10, EPHA4 and CADH1; within the complex, ADAM10 cleaves CADH1 which disrupts adherens junctions (By similarity). Interacts with EPHA2 (By similarity). Interacts with NGF in a divalent cation-dependent manner (PubMed:20164177). Interacts with TSPAN14; the interaction promotes ADAM10 maturation and cell surface expression (PubMed:26686862, PubMed:26668317). Interacts with TSPAN5, TSPAN10, TSPAN15, TSPAN17 and TSPAN33; these interactions regulate ADAM10 substrate specificity (PubMed:26686862). Interacts with DLG1; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with BACE1 (via extracellular domain) (By similarity). Interacts with FAM171A1 (PubMed:30312582).SUBUNIT (Microbial infection) Interacts with S.aureus hly; this interaction is necessary for toxin pore formation, disruption of focal adhesions and S.aureus hly-mediated cytotoxicity.TISSUE SPECIFICITY Expressed in the brain (at protein level) (PubMed:23676497). Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver (PubMed:11511685, PubMed:9016778).INDUCTION In osteoarthritis affected-cartilage.DOMAIN The propeptide keeps the metalloprotease in a latent form via a cysteine switch mechanism. This mechanism may be mediated by a highly conserved cysteine (Cys-173) in the propeptide, which interacts and neutralizes the zinc-coordinating HEXGHXXGXXHD catalytic core of the metalloprotease domain. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.DOMAIN The Cys-rich region C-terminal to the disintegrin domain functions as a substrate-recognition module, it recognizes the EFNA5-EPHA3 complex but not the individual proteins (By similarity). Both Cys-rich and stalk region are necessary for interaction with TSPAN5, TSPAN10, TSPAN14, TSPAN17, TSPAN33 (PubMed:26668317). Stalk region is sufficient for interaction with TSPAN15 (By similarity).PTM The precursor is cleaved by furin and PCSK7. UniProt O14672 215 EQUAL 824 EQUAL Reactome Database ID Release 78 179885 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=179885 Reactome R-HSA-179885 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-179885.1 ADAM12 ADAM 12 metalloprotease ADAM 12 sheddase Reactome DB_ID: 179792 UniProt:O43184 ADAM12 ADAM12 MLTN UNQ346/PRO545 FUNCTION Involved in skeletal muscle regeneration, specifically at the onset of cell fusion. Also involved in macrophage-derived giant cells (MGC) and osteoclast formation from mononuclear precursors (By similarity).SUBUNIT Interacts with alpha-actinin-2 and with syndecans (By similarity). Interacts with SH3PXD2A. Interacts with FST3. Interacts with RACK1; the interaction is required for PKC-dependent translocation of ADAM12 to the cell membrane.TISSUE SPECIFICITY Isoform 1 is expressed in placenta and skeletal, cardiac, and smooth muscle. Isoform 2 seems to be expressed only in placenta or in embryo and fetus. Both forms were expressed in some tumor cells lines. Not detected in brain, lung, liver, kidney or pancreas.DOMAIN The cysteine-rich domain supports cell adhesion through syndecans and triggers signaling events that lead to beta-1 integrin-dependent cell spreading. In carcinomas cells the binding of this domain to syndecans does not allow the integrin-mediated cell spreading.DOMAIN The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.PTM The precursor is cleaved by a furin endopeptidase. UniProt O43184 208 EQUAL 909 EQUAL Reactome Database ID Release 78 179792 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=179792 Reactome R-HSA-179792 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-179792.1 TACE ADAM17 ADAM 17 metalloprotease ADAM 17 sheddase Reactome DB_ID: 179878 UniProt:P78536 ADAM17 ADAM17 CSVP TACE FUNCTION Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form (PubMed:9034191). Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By similarity). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R (PubMed:26876177, PubMed:28060820).SUBUNIT Interacts with MAD2L1, MAPK14 and MUC1 (PubMed:12441351, PubMed:20188673). Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). Interacts with FRMD8 via its interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333).TISSUE SPECIFICITY Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney.INDUCTION In arthritis-affected cartilage.DOMAIN Must be membrane anchored to cleave the different substrates. The cytoplasmic domain is not required for the this activity. Only the catalytic domain is essential to shed TNF and p75 TNFR (By similarity).DOMAIN The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.PTM The precursor is cleaved by a furin endopeptidase.PTM Phosphorylated. Stimulation by growth factor or phorbol 12-myristate 13-acetate induces phosphorylation of Ser-819 but decreases phosphorylation of Ser-791. Phosphorylation at THR-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding. UniProt P78536 215 EQUAL 824 EQUAL Reactome Database ID Release 78 179878 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=179878 Reactome R-HSA-179878 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-179878.1 Reactome Database ID Release 78 179832 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=179832 Reactome R-HSA-179832 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-179832.1 1 Reactome Database ID Release 78 179842 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=179842 Reactome R-HSA-179842 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-179842.1 GENE ONTOLOGY GO:0004222 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 179871 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=179871 Reactome Database ID Release 78 177946 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=177946 Reactome R-HSA-177946 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-177946.1 LEFT-TO-RIGHT AAMP binds EGFR AAMP (Angio-associated migratory cell protein) binds to EGFR. The interaction involves the intracellular domain of EGFR. AAMP binding, through and unknown mechanism, promotes EGFR dimerization, trans-autophosphorylation and downstream signaling, leading to activation of ERKs (MAPK1 and MAPK3) and expression of cyclin D1 (CCND1). Downregulation of AAMP inhibits proliferation of a non-small cell lung cancer (NSCLC) cell line and increases its sensitivity to EGFR-targeted chemotherapeutic drugs, and it also inhibits tumorigenesis in a mouse model (Yao et al. 2019).<br>In addition to lung cancer, AAMP overexpression is also linked with poor prognosis in breast cancer, where AAMP level positively correlates with tumor grade. AAMP is overexpressed in breast ductal carcinoma in situ (DCIS) with necrosis (Adeyinka et al. 2002). Authored: Orlic-Milacic, Marija, 2020-01-29 Reviewed: Yao, Shun, 2020-02-05 Reviewed: Liu, Xiangguo, 2020-02-05 Reviewed: Mulvaney, Eamon P, 2020-02-06 Reviewed: Kinsella, B Therese, 2020-02-06 Edited: Orlic-Milacic, Marija, 2020-02-10 EGFR Epidermal Growth Factor Receptor Reactome DB_ID: 179837 UniProt:P00533 EGFR EGFR ERBB ERBB1 HER1 FUNCTION Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:2790960, PubMed:10805725, PubMed:27153536). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975, PubMed:15611079, PubMed:12297049, PubMed:27153536, PubMed:20837704, PubMed:17909029). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity).FUNCTION Isoform 2 may act as an antagonist of EGF action.FUNCTION (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins.ACTIVITY REGULATION Endocytosis and inhibition of the activated EGFR by phosphatases like PTPRJ and PTPRK constitute immediate regulatory mechanisms. Upon EGF-binding phosphorylates EPS15 that regulates EGFR endocytosis and activity. Moreover, inducible feedback inhibitors including LRIG1, SOCS4, SOCS5 and ERRFI1 constitute alternative regulatory mechanisms for the EGFR signaling. Up-regulated by NEU3-mediated desialylation of N-linked glycan at Asn-528.SUBUNIT Binding of the ligand triggers homo- and/or heterodimerization of the receptor triggering its autophosphorylation. Heterodimer with ERBB2 (PubMed:10805725). Forms a complex with CCDC88A/GIV (via SH2-like regions) and GNAI3 which leads to enhanced EGFR signaling and triggering of cell migration; binding to CCDC88A requires autophosphorylation of the EGFR C-terminal region, and ligand stimulation is required for recruitment of GNAI3 to the complex (PubMed:20462955, PubMed:25187647). Interacts with ERRFI1; inhibits dimerization of the kinase domain and autophosphorylation (PubMed:18046415). Part of a complex with ERBB2 and either PIK3C2A or PIK3C2B (PubMed:10805725). Interacts with GRB2; an adapter protein coupling the receptor to downstream signaling pathways. Interacts with GAB2; involved in signaling downstream of EGFR. Interacts with STAT3; mediates EGFR downstream signaling in cell proliferation. Interacts with RIPK1; involved in NF-kappa-B activation. Interacts (autophosphorylated) with CBL, CBLB and CBLC; involved in EGFR ubiquitination and regulation. Interacts with SOCS5; regulates EGFR degradation through ELOC- and ELOB-mediated ubiquitination and proteasomal degradation. Interacts with PRMT5; methylates EGFR and enhances interaction with PTPN6. Interacts (phosphorylated) with PTPN6; inhibits EGFR-dependent activation of MAPK/ERK. Interacts with COPG1; essential for regulation of EGF-dependent nuclear transport of EGFR by retrograde trafficking from the Golgi to the ER. Interacts with TNK2; this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts with PCNA; positively regulates PCNA (PubMed:17115032). Interacts with PELP1. Interacts with MUC1. Interacts with AP2M1. Interacts with FER. May interact with EPS8; mediates EPS8 phosphorylation. Interacts (via SH2 domains) with GRB2, NCK1 and NCK2 (PubMed:10026169). Interacts with ATXN2. Interacts with GAREM1. Interacts (ubiquitinated) with ANKRD13A/B/D; the interaction is direct and may regulate EGFR internalization after EGF stimulation. Interacts with GPER1; the interaction occurs in an estrogen-dependent manner. Interacts (via C-terminal cytoplasmic kinase domain) with ZPR1 (via zinc fingers). Interacts with RNF115 and RNF126 (PubMed:23418353). Interacts with GPRC5A (via its transmembrane domain) (PubMed:25311788). Interacts with FAM83B; positively regulates EGFR inducing its autophosphorylation in absence of stimulation by EGF (PubMed:23912460). Interacts with LAPTM4B; positively correlates with EGFR activation (PubMed:28479384). Interacts with STX19 (PubMed:16420529). Interacts with CD44 (PubMed:23589287). Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization (PubMed:26988023). Interacts with PIKFYVE (PubMed:17909029). Interacts with NEU3.TISSUE SPECIFICITY Ubiquitously expressed. Isoform 2 is also expressed in ovarian cancers.PTM Phosphorylated on Tyr residues in response to EGF (PubMed:20462955, PubMed:27153536). Phosphorylation at Ser-695 is partial and occurs only if Thr-693 is phosphorylated. Phosphorylation at Thr-678 and Thr-693 by PRKD1 inhibits EGF-induced MAPK8/JNK1 activation. Dephosphorylation by PTPRJ prevents endocytosis and stabilizes the receptor at the plasma membrane. Autophosphorylation at Tyr-1197 is stimulated by methylation at Arg-1199 and enhances interaction with PTPN6. Autophosphorylation at Tyr-1092 and/or Tyr-1110 recruits STAT3. Dephosphorylated by PTPN1 and PTPN2.PTM Monoubiquitinated and polyubiquitinated upon EGF stimulation; which does not affect tyrosine kinase activity or signaling capacity but may play a role in lysosomal targeting (PubMed:27153536). Polyubiquitin linkage is mainly through 'Lys-63', but linkage through 'Lys-48', 'Lys-11' and 'Lys-29' also occurs. Deubiquitination by OTUD7B prevents degradation. Ubiquitinated by RNF115 and RNF126 (By similarity).PTM Palmitoylated on Cys residues by ZDHHC20. Palmitoylation inhibits internalization after ligand binding, and increases the persistence of tyrosine-phosphorylated EGFR at the cell membrane. Palmitoylation increases the amplitude and duration of EGFR signaling.PTM Methylated. Methylation at Arg-1199 by PRMT5 stimulates phosphorylation at Tyr-1197.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. UniProt P00533 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 179837 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=179837 Reactome R-HSA-179837 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-179837.1 AAMP Angio-associated migratory cell protein Reactome DB_ID: 9674636 cytosol GENE ONTOLOGY GO:0005829 UniProt:Q13685 AAMP AAMP FUNCTION Plays a role in angiogenesis and cell migration. In smooth muscle cell migration, may act through the RhoA pathway.TISSUE SPECIFICITY Expressed in metastatic melanoma, liver, skin, kidney, heart, lung, lymph node, skeletal muscle and brain, and also in A2058 melanoma cells and activated T-cells (at protein level). Expressed in blood vessels. Strongly expressed in endothelial cells, cytotrophoblasts, and poorly differentiated. colon adenocarcinoma cells found in lymphatics. UniProt Q13685 1 EQUAL 434 EQUAL Reactome Database ID Release 78 9674636 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=9674636 Reactome R-HSA-9674636 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-9674636.1 EGFR:AAMP Reactome DB_ID: 9674862 1 1 Reactome Database ID Release 78 9674862 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=9674862 Reactome R-HSA-9674862 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-9674862.1 Reactome Database ID Release 78 9674531 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=9674531 Reactome R-HSA-9674531 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-9674531.1 12473591 Pubmed 2002 Analysis of gene expression in ductal carcinoma in situ of the breast Adeyinka, Adewale Emberley, Ethan Niu, Yulian Snell, Linda Murphy, Leigh C Sowter, Heidi Wykoff, Charles C Harris, Adrian L Watson, Peter H Clin. Cancer Res. 8:3788-95 31075398 Pubmed 2019 Angio-associated migratory cell protein interacts with epidermal growth factor receptor and enhances proliferation and drug resistance in human non-small cell lung cancer cells Yao, Shun Shi, Feifei Wang, Yingying Sun, Xiaoyang Sun, Wenbo Zhang, Yifeng Liu, Xianfang Liu, Xiangguo Su, Ling Cell. Signal. 61:10-19 LEFT-TO-RIGHT EGFR binds EGF ligand The prototypic receptor tyrosine kinase (RTK) EGFR is composed of 3 major domains; an extracellular domain linked via a single membrane-spanning domain to a cytoplasmic domain. EGF binds to the extracellular domain from where the signal is transmitted to the cytoplasmic domain. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 Converted from EntitySet in Reactome EGF-like ligands Reactome DB_ID: 9624194 TGFA_HUMAN TGFA(24-98) Protransforming growth factor alpha component recommendedName: Transforming growth factor alpha Reactome DB_ID: 9624183 UniProt:P01135 TGFA TGFA FUNCTION TGF alpha is a mitogenic polypeptide that is able to bind to the EGF receptor/EGFR and to act synergistically with TGF beta to promote anchorage-independent cell proliferation in soft agar.SUBUNIT Interacts with the PDZ domains of MAGI3, SDCBP and SNTA1. The interaction with SDCBP, is required for the targeting to the cell surface. In the endoplasmic reticulum, in its immature form (i.e. with a prosegment and lacking full N-glycosylation), interacts with CNIH. In the Golgi apparatus, may form a complex with CNIH and GORASP2. Interacts (via cytoplasmic C-terminal domain) with NKD2.TISSUE SPECIFICITY Isoform 1, isoform 3 and isoform 4 are expressed in keratinocytes and tumor-derived cell lines. UniProt P01135 24 EQUAL 98 EQUAL Reactome Database ID Release 78 9624183 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=9624183 Reactome R-HSA-9624183 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-9624183.1 AREG_HUMAN AREG(101-187) fullName evidence="8"Amphiregulin Reactome DB_ID: 9624190 UniProt:P15514 AREG AREG AREGB SDGF FUNCTION Ligand of the EGF receptor/EGFR. Autocrine growth factor as well as a mitogen for a broad range of target cells including astrocytes, Schwann cells and fibroblasts.SUBUNIT The immature precursor interacts with CNIH.INDUCTION By phorbol 12-myristate 13-acetate (PMA).MISCELLANEOUS AR is a protein containing cysteines in disulfide linkage(s) that are essential for its biological activity. AR may contain oligosaccharides and/or lipid moieties that are not obligatory for the biological activity.SIMILARITY Belongs to the amphiregulin family. UniProt P15514 101 EQUAL 187 EQUAL Reactome Database ID Release 78 9624190 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=9624190 Reactome R-HSA-9624190 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-9624190.1 Epigen EPGN(23-154) EPGN_HUMAN Reactome DB_ID: 9624187 UniProt:Q6UW88 EPGN EPGN UNQ3072/PRO9904 FUNCTION Promotes the growth of epithelial cells. May stimulate the phosphorylation of EGFR and mitogen-activated protein kinases. UniProt Q6UW88 23 EQUAL 154 EQUAL Reactome Database ID Release 78 9624187 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=9624187 Reactome R-HSA-9624187 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-9624187.1 BTC(32-111) Betacellulin Reactome DB_ID: 1233224 UniProt:P35070 BTC BTC FUNCTION Growth factor that binds to EGFR, ERBB4 and other EGF receptor family members. Potent mitogen for retinal pigment epithelial cells and vascular smooth muscle cells.SUBUNIT Monomer. Interacts with EGFR and ERBB4.TISSUE SPECIFICITY Synthesized in several tissues and tumor cells. Predominantly expressed in pancreas and small intestine. UniProt P35070 32 EQUAL 111 EQUAL Reactome Database ID Release 78 1233224 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=1233224 Reactome R-HSA-1233224 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-1233224.2 Epiregulin EREG(60-108) Reactome DB_ID: 1233233 UniProt:O14944 EREG EREG FUNCTION Ligand of the EGF receptor/EGFR and ERBB4. Stimulates EGFR and ERBB4 tyrosine phosphorylation (PubMed:9419975). Contributes to inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and by stimulating cell proliferation (PubMed:24631357).SUBUNIT Interacts with EGFR and ERBB4.TISSUE SPECIFICITY In normal adults, expressed predominantly in the placenta and peripheral blood leukocytes. High levels were detected in carcinomas of the bladder, lung, kidney and colon. UniProt O14944 60 EQUAL 108 EQUAL Reactome Database ID Release 78 1233233 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=1233233 Reactome R-HSA-1233233 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-1233233.2 HBEGF HBEGF(63-148) HB-EGF Heparin-binding EGF-like growth factors Reactome DB_ID: 1233234 UniProt:Q99075 HBEGF HBEGF DTR DTS HEGFL FUNCTION Growth factor that mediates its effects via EGFR, ERBB2 and ERBB4. Required for normal cardiac valve formation and normal heart function. Promotes smooth muscle cell proliferation. May be involved in macrophage-mediated cellular proliferation. It is mitogenic for fibroblasts, but not endothelial cells. It is able to bind EGF receptor/EGFR with higher affinity than EGF itself and is a far more potent mitogen for smooth muscle cells than EGF. Also acts as a diphtheria toxin receptor.SUBUNIT Interacts with FBLN1 (By similarity). Interacts with EGFR and ERBB4.PTM Several N-termini have been identified by direct sequencing. The forms with N-termini 63, 73 and 74 have been tested and found to be biologically active.PTM O-glycosylated with core 1 or possibly core 8 glycans. Thr-47 is a minor glycosylation site compared to Thr-44. UniProt Q99075 63 EQUAL 148 EQUAL Reactome Database ID Release 78 1233234 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=1233234 Reactome R-HSA-1233234 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-1233234.1 Reactome Database ID Release 78 9624194 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=9624194 Reactome R-HSA-9624194 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-9624194.1 EGFR:EGF-like ligands Reactome DB_ID: 9624419 1 1 Reactome Database ID Release 78 9624419 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=9624419 Reactome R-HSA-9624419 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-9624419.1 Reactome Database ID Release 78 177942 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=177942 Reactome R-HSA-177942 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-177942.4 8639530 Pubmed 1996 Activation of epidermal growth factor receptor by epidermal growth factor Sherrill, JM Kyte, J Biochemistry 35:5705-18 INHIBITION Reactome Database ID Release 78 204695 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=204695 Reactome R-HSA-204695 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-204695.1 LRIG1 Leucine-rich repeats and immunoglobulin-like domains protein 1 precursor LIG1_HUMAN Reactome DB_ID: 197745 UniProt:Q96JA1 LRIG1 LRIG1 LIG1 FUNCTION Acts as a feedback negative regulator of signaling by receptor tyrosine kinases, through a mechanism that involves enhancement of receptor ubiquitination and accelerated intracellular degradation.SUBUNIT Interacts (via extracellular LRR and Ig-like domains) with EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 (via extracellular domain) (PubMed:15282549). The physiological relevance of the interaction is controversial; LRIG1 may have low affinity for EGFR, and interaction may occur only when high levels of both proteins are present (PubMed:25765764).TISSUE SPECIFICITY Widely expressed.INDUCTION By EGF.DOMAIN Contains LRR and Ig-domains that can mediate low-affinity interaction with EGFR (PubMed:25765764). The LRRs and the Ig-domains are each sufficient for EGFR/ERBB1 binding. This interaction is abolished only when both the LRRs and the Ig-domains are deleted (PubMed:15282549). UniProt Q96JA1 35 EQUAL 1093 EQUAL Reactome Database ID Release 78 197745 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=197745 Reactome R-HSA-197745 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-197745.1 LEFT-TO-RIGHT EGFR dimerization EGF and other growth factors induce oligomerization of their specific receptors. Inactive EGFR monomers are in equilibrium with active EGFR dimers and binding of the EGF ligand stabilizes the active dimeric form. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 2 EGF-like ligands:EGFR dimer Reactome DB_ID: 9624420 2 Reactome Database ID Release 78 9624420 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=9624420 Reactome R-HSA-9624420 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-9624420.1 Reactome Database ID Release 78 177922 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=177922 Reactome R-HSA-177922 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-177922.2 LEFT-TO-RIGHT 2.7.10 EGFR autophosphorylation The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Dimerization of EGFR activates its intrinsic protein kinase activity and results in autophosphorylation of 6 tyrosine residues in the cytoplasmic tail of EGFR. Tyrosine autophosphorylation is crucial for normal receptor signalling. Five of these tyrosine residues (Y992, Y1068, Y1086, Y1148 and Y1173) serve as specific binding sites for cytosolic target proteins involved in signal transmission, while the tyrosine residue Y1045 is involved in recruitment of CBL ubiquitin ligase and downregulation of EGFR signaling through degradation of activated EGFR. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 Edited: Orlic-Milacic, Marija, 2011-08-25 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 78 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 78 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 EGF-like ligands:p-6Y EGFR dimer Reactome DB_ID: 9624425 p-6Y-EGFR Phospho-EGFR Phosphorylated Epidermal Growth Factor Receptor Reactome DB_ID: 179803 992 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1045 EQUAL 1068 EQUAL 1086 EQUAL 1148 EQUAL 1173 EQUAL 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 179803 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=179803 Reactome R-HSA-179803 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-179803.1 2 2 Reactome Database ID Release 78 9624425 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=9624425 Reactome R-HSA-9624425 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-9624425.1 ACTIVATION activeUnit: #Protein7 GENE ONTOLOGY GO:0004713 Reactome Database ID Release 78 9624430 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=9624430 Reactome Database ID Release 78 177934 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=177934 Reactome R-HSA-177934 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-177934.2 1688559 Pubmed 1990 Analysis of deletions of the carboxyl terminus of the epidermal growth factor receptor reveals self-phosphorylation at tyrosine 992 and enhanced in vivo tyrosine phosphorylation of cell substrates Walton, GM Chen, WS Rosenfeld, MG Gill, GN J Biol Chem 265:1750-4 2543678 Pubmed 1989 All autophosphorylation sites of epidermal growth factor (EGF) receptor and HER2/neu are located in their carboxyl-terminal tails. Identification of a novel site in EGF receptor. Margolis, BL Lax, I Kris, R Dombalagian, M Honegger, AM Howk, R Givol, D Ullrich, A Schlessinger, J J Biol Chem 264:10667-71 2022652 Pubmed 1991 Internalization and down-regulation of the human epidermal growth factor receptor are regulated by the carboxyl-terminal tyrosines Helin, K Beguinot, L J Biol Chem 266:8363-8 LEFT-TO-RIGHT 2.7.10 Phosphorylation of EGFR by SRC kinase Besides autophosphorylation, EGFR can become tyrosine-phosphorylated by the action of the proto-oncogene tyrosine-protein kinase, c-src. This Src homology 2 (SH2) domain-containing protein is one of many such proteins which bind to phosphorylated sites on EGFR to affect signal transmission into the cell. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 Edited: Orlic-Milacic, Marija, 2011-08-25 12 12 ACTIVATION 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: 65043 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). 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.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 78 65043 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=65043 Reactome R-HSA-65043 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-65043.1 Reactome Database ID Release 78 179862 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=179862 Reactome Database ID Release 78 177937 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=177937 Reactome R-HSA-177937 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-177937.2 8845374 Pubmed 1995 In vitro phosphorylation of the epidermal growth factor receptor autophosphorylation domain by c-src: identification of phosphorylation sites and c-src SH2 domain binding sites Lombardo, CR Consler, TG Kassel, DB Biochemistry 34:16456-66 EGFR interacts with phospholipase C-gamma Activated epidermal growth factor receptors (EGFR) can stimulate phosphatidylinositol (PI) turnover. Activated EGFR can activate phospholipase C-gamma1 (PLC-gamma1, i.e. PLCG1) which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is instrumental in the release of calcium from intracellular stores and DAG is involved in protein kinase C activation. Authored: Jassal, Bijay, 2008-02-13 Reviewed: Heldin, CH, 2008-02-12 09:44:02 LEFT-TO-RIGHT Phospholipase C-gamma1 binds to the activated EGF receptor Inactive phospholipase C-gamma1 (PLCG1) binds to activated epidermal growth factor receptor (EGFR). Authored: Jassal, Bijay, 2008-02-13 Reviewed: Heldin, CH, 2008-02-12 09:44:02 PLC1 PLCG1 Phospholipase C gamma 1 PLC gamma 1 Reactome DB_ID: 202320 UniProt:P19174 PLCG1 PLCG1 PLC1 FUNCTION Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, EGFR, FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Plays a role in actin reorganization and cell migration (PubMed:17229814).ACTIVITY REGULATION Activated by phosphorylation on tyrosine residues.SUBUNIT Interacts with AGAP2 via its SH3 domain. Interacts (via SH2 domain) with RET. Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts (via SH2 domain) with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with LAT (phosphorylated) upon TCR activation. Interacts (via SH3 domain) with the Pro-rich domain of TNK1. Associates with BLNK, VAV1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB in activated T-cells; which inhibits phosphorylation. Interacts with SHB. Interacts (via SH3 domain) with the Arg/Gly-rich-flanked Pro-rich domains of KHDRBS1/SAM68. This interaction is selectively regulated by arginine methylation of KHDRBS1/SAM68. Interacts with INPP5D/SHIP1, THEMIS and CLNK (By similarity). Interacts with AXL, FLT4 and KIT. Interacts with RALGPS1. Interacts (via the SH2 domains) with VIL1 (phosphorylated at C-terminus tyrosine phosphorylation sites). Interacts (via SH2 domain) with PDGFRA and PDGFRB (tyrosine phosphorylated). Interacts with PIP5K1C (By similarity). Interacts with NTRK1 and NTRK2 (phosphorylated upon ligand-binding). Interacts with SYK; activates PLCG1. Interacts with GRB2, LAT and THEMIS upon TCR activation in thymocytes (By similarity). Interacts with TESPA1; the association is increased with prolonged stimulation of the TCR and may facilitate the assembly of the LAT signalosome.SUBUNIT (Microbial infection) Interacts (via SH3 domain) with HEV ORF3 protein.DOMAIN The SH3 domain mediates interaction with CLNK (By similarity). The SH3 domain also mediates interaction with RALGPS1 (PubMed:10747847).PTM Tyrosine phosphorylated in response to signaling via activated FLT3, KIT and PDGFRA (By similarity). Tyrosine phosphorylated by activated FGFR1, FGFR2, FGFR3 and FGFR4. Tyrosine phosphorylated by activated FLT1 and KDR. Tyrosine phosphorylated by activated PDGFRB. The receptor-mediated activation of PLCG1 involves its phosphorylation by tyrosine kinases, in response to ligation of a variety of growth factor receptors and immune system receptors. For instance, SYK phosphorylates and activates PLCG1 in response to ligation of the B-cell receptor. May be dephosphorylated by PTPRJ. Phosphorylated by ITK and TXK on Tyr-783 upon TCR activation in T-cells.PTM Ubiquitinated by CBLB in activated T-cells. UniProt P19174 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 202320 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=202320 Reactome R-HSA-202320 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-202320.1 Activated EGFR:PLC-gamma1 EGF-like ligands:p-6Y-EGFR:PLCG1 Reactome DB_ID: 212717 1 1 Reactome Database ID Release 78 212717 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=212717 Reactome R-HSA-212717 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-212717.2 Reactome Database ID Release 78 212706 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=212706 Reactome R-HSA-212706 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-212706.2 2472219 Pubmed 1989 Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro Meisenhelder, J Suh, PG Rhee, SG Hunter, Tony Cell 57:1109-22 2153914 Pubmed 1990 Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor Margolis, B Bellot, F Honegger, AM Ullrich, A Schlessinger, J Zilberstein, A Mol Cell Biol 10:435-41 LEFT-TO-RIGHT 2.7.10 EGFR activates PLC-gamma1 by phosphorylation EGFR phosphorylates PLC-gamma1, thus activating it. Authored: Jassal, Bijay, 2008-02-13 Reviewed: Heldin, CH, 2008-02-12 09:44:02 4 4 Activated EGFR:Phospho-PLC-gamma1 EGF-like ligand:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1 Reactome DB_ID: 212703 p-PLCG1 p-4Y-PLCG1 p-Y1253,Y472,Y771,Y783-PLCG1 p-Y472,771,783,1253-PLCG1 p4Y-PLCG1 Phospho-Phospholipase C gamma 1 Phospho-PLC gamma 1 Reactome DB_ID: 167679 472 EQUAL 771 EQUAL 783 EQUAL 1253 EQUAL 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 167679 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=167679 Reactome R-HSA-167679 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-167679.2 1 1 Reactome Database ID Release 78 212703 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=212703 Reactome R-HSA-212703 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-212703.2 ACTIVATION activeUnit: #Protein17 Reactome Database ID Release 78 212705 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=212705 Reactome Database ID Release 78 212710 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=212710 Reactome R-HSA-212710 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-212710.1 1689311 Pubmed 1990 Identification of two epidermal growth factor-sensitive tyrosine phosphorylation sites of phospholipase C-gamma in intact HSC-1 cells Wahl, MI Nishibe, S Kim, JW Kim, H Rhee, SG Carpenter, G J Biol Chem 265:3944-8 LEFT-TO-RIGHT Active PLC-gamma1 dissociates from EGFR Once activated PLC-gamma1 dissociates from EGFR, it can hydrolyze PIP2. Authored: Jassal, Bijay, 2008-02-13 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Reactome Database ID Release 78 212713 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=212713 Reactome R-HSA-212713 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-212713.2 10579907 Pubmed 1999 Phospholipase C-gamma as a signal-transducing element Carpenter, G Ji, Q Exp Cell Res 253:15-24 Reactome Database ID Release 78 212718 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=212718 Reactome R-HSA-212718 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-212718.2 1501243 Pubmed 1992 Epidermal growth factor receptor: elements of intracellular communication Hernández-Sotomayor, SM Carpenter, G J Membr Biol 128:81-9 GENE ONTOLOGY GO:0007165 gene ontology term for cellular process MI MI:0359 GRB2 events in EGFR signaling Autophosphorylated EGFR tyrosine residues are docking sites for many downstream effectors in EGFR signaling. The adaptor protein GRB2 binds to phosphotyrosine residues in the C-tail of EGFR through its SH2 domain. GRB2 is constitutively associated with SOS, a guanine nucleotide exchange factor of RAS. GRB2 binding to phosphorylated EGFR results in the recruitment of SOS to the plasma membrane where it comes in proximity to RAS. This mechanism has been seen to be the model for RAS activation. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 LEFT-TO-RIGHT GRB2-1 binds SOS1 In the cytoplasm of unstimulated cells, SOS1 is found in a complex with GRB2. The interaction occurs between the carboxy terminal domain of SOS1 and the Src homology 3 (SH3) domains of GRB2. Authored: Charalambous, M, 2005-01-07 11:17:43 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Schmidt, EE, 0000-00-00 00:00:00 Edited: Orlic-Milacic, Marija, 2011-08-25 Ash-L GRB2-1 GRB2 isoform 1 Growth factor receptor-bound protein 2 SH2/SH3 adapter GRB2 ASH protein Reactome DB_ID: 74686 UniProt:P62993-1 GRB2 GRB2 ASH FUNCTION Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.SUBUNIT Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated) (PubMed:10026169, PubMed:19836242). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect (By similarity). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS1, IRS4, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains (PubMed:8388384, PubMed:8491186, PubMed:9553137, PubMed:11433379). It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1 (PubMed:8493579, PubMed:7664271). Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1 (PubMed:7664271). Interacts with phosphorylated MET (PubMed:11063574, PubMed:11827484). Interacts with phosphorylated TOM1L1 (By similarity). Interacts with the phosphorylated C-terminus of SH2B2 (PubMed:9233773). Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation (By similarity) (PubMed:9489702, PubMed:12359715, PubMed:12486104, PubMed:12514734). Interacts with NISCH, PTPNS1 and REPS2 (PubMed:9062191, PubMed:9422736, PubMed:11912194). Interacts with syntrophin SNTA1 (By similarity). Interacts (via SH3 domains) with REPS1 (By similarity). Interacts (via SH3 domains) with PIK3C2B (PubMed:11533253). Interacts with CBL and CBLB (PubMed:10022120, PubMed:10086340). Interacts with AJUBA and CLNK (By similarity). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2 (PubMed:8723348, PubMed:9108392, PubMed:9484780, PubMed:10942756, PubMed:12171928). Interacts with PTPN11 (By similarity). Interacts with PRNP (By similarity). Interacts with RALGPS1 (PubMed:10747847). Interacts with HCST (PubMed:16582911). Interacts with KDR (By similarity). Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts with GAPT and PTPRE (PubMed:10980613, PubMed:18559951). Interacts (via SH2 domain) with KIF26A (PubMed:19914172). Interacts (via SH3 2) with GAB2 (PubMed:19523899). Interacts with ADAM15 (PubMed:18296648). Interacts with THEMIS2 (By similarity). Interacts (via SH2 domain) with AXL (phosphorylated) (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with KIT (phosphorylated) (PubMed:15526160, PubMed:16129412). Interacts with PTPRJ and BCR (PubMed:12475979, PubMed:15302586). Interacts with PTPN23 (PubMed:21179510). Interacts with FLT4 (tyrosine phosphorylated) (PubMed:15102829). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:8798570, PubMed:12925710). Part of a complex including TNK2, GRB2, LTK and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:8262059). Interacts with ERBB4 (PubMed:10867024). Interacts with NTRK1 (phosphorylated upon ligand-binding) (PubMed:15488758). Interacts with PTK2/FAK1 (tyrosine phosphorylated) (PubMed:9148935). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) (PubMed:20521079). Interacts (via SH3 domains) with GAREM1 isoform 1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation (PubMed:19509291). Interacts with DAB2 (By similarity). Interacts with TESPA1 (PubMed:22561606). Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1 (By similarity). Interacts with CD28 (PubMed:24098653). Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA (By similarity). Interacts with ASAP3 (phosphorylated form) (PubMed:22027826). Interacts (via SH2 domain) with PTPRH (phosphorylated form) (By similarity). Interacts with PTPRO (phosphorylated form) (By similarity). Interacts with PTPRB (phosphorylated form) (By similarity). Interacts (via SH3 domain 2) with PRR14 (via proline-rich region) (PubMed:27041574). Interacts with FCRL6 (tyrosine phosphorylated form) (PubMed:20933011). Interacts with RHEX (via tyrosine-phosphorylated form) (PubMed:25092874). Interacts with DENND2B (PubMed:29030480). Interacts with SPRY2 (PubMed:17974561). Interacts with LRRC8A (By similarity).SUBUNIT (Microbial infection) Interacts (via SH3 domain) with hepatitis E virus/HEV ORF3 protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus/HCV protein NS5A via its SH3 domains.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL46.DOMAIN The SH3 domains mediate interaction with RALGPS1 and SHB.SIMILARITY Belongs to the GRB2/sem-5/DRK family.CAUTION Was shown to interact with ZDHHC19, leading to recruitment of STAT3. However, this study was later retracted. UniProt Isoform P62993-1 1 EQUAL 217 EQUAL Reactome Database ID Release 78 74686 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=74686 Reactome R-HSA-74686 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-74686.2 SOS1 Son of sevenless protein homolog 1 SOS-1 Reactome DB_ID: 64847 UniProt:Q07889 SOS1 SOS1 FUNCTION Promotes the exchange of Ras-bound GDP by GTP (PubMed:8493579). Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (PubMed:17339331). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (By similarity).SUBUNIT Interacts (via C-terminus) with GRB2 (via SH3 domain) (PubMed:8493579, PubMed:7664271). Forms a complex with phosphorylated MUC1 and GRB2 (via its SH3 domains) (PubMed:7664271). Interacts with phosphorylated LAT2 (PubMed:12486104). Interacts with NCK1 and NCK2 (PubMed:10026169). Part of a complex consisting of ABI1, EPS8 and SOS1 (By similarity). Interacts (Ser-1134 and Ser-1161 phosphorylated form) with YWHAB and YWHAE (PubMed:22827337).TISSUE SPECIFICITY Expressed in gingival tissues.PTM Phosphorylation at Ser-1134 and Ser-1161 by RPS6KA3 create YWHAB and YWHAE binding sites and which contribute to the negative regulation of EGF-induced MAPK1/3 phosphorylation. UniProt Q07889 1 EQUAL 1333 EQUAL Reactome Database ID Release 78 64847 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=64847 Reactome R-HSA-64847 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-64847.2 GRB2-1:SOS1 Reactome DB_ID: 109797 1 1 Reactome Database ID Release 78 109797 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=109797 Reactome R-HSA-109797 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-109797.3 Reactome Database ID Release 78 109813 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=109813 Reactome R-HSA-109813 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-109813.1 8479541 Pubmed 1993 Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Li, N Batzer, A Daly, R Yajnik, V Skolnik, E Margolis, B Schlessinger, J Nature 363:85-8 LEFT-TO-RIGHT GRB2:SOS1 complex binds to EGF:EGFR complex Cytoplasmic target proteins containing the SH2 domain can bind to activated EGFR. One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 tyrosine autophosphorylation sites on the receptor. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 GRB2:SOS-EGF-Phospho-EGFR dimer EGF-like ligands:p-6Y-EGFR:GRB2:SOS1 Reactome DB_ID: 179820 1 1 Reactome Database ID Release 78 179820 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=179820 Reactome R-HSA-179820 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-179820.2 Reactome Database ID Release 78 177943 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=177943 Reactome R-HSA-177943 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-177943.2 7527043 Pubmed 1994 Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells Okutani, T Okabayashi, Y Kido, Y Sugimoto, Y Sakaguchi, K Matuoka, K Takenawa, T Kasuga, M J Biol Chem 269:31310-4 7518560 Pubmed 1994 Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor Batzer, AG Rotin, D Urena, JM Skolnik, EY Schlessinger, J Mol Cell Biol 14:5192-201 LEFT-TO-RIGHT SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:GRB2:SOS1) The guanine nucleotide exchange factor SOS1 interacts with EGFR through the adaptor protein, GRB2. Upon formation of this complex, SOS activates RAS by promoting GDP release and GTP binding. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 p21 RAS:GDP Reactome DB_ID: 109796 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 78 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 Converted from EntitySet in Reactome mature p21 RAS Reactome DB_ID: 9649715 Ki-Ras S-Farn-Me-PalmS KRAS4A p21A (K-Ras 2A) Transforming protein p21A K-Ras 2A c-K-ras Reactome DB_ID: 9647915 UniProt:P01116-1 KRAS KRAS KRAS2 RASK2 FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:20949621). Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838). Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner (PubMed:24623306).ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP). Interaction with SOS1 promotes exchange of bound GDP by GTP.SUBUNIT Interacts with PHLPP. Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (when farnesylated) with PDE6D; this promotes dissociation from the cell membrane (PubMed:23698361). Interacts with SOS1 (PubMed:22431598). Interacts (when farnesylated) with GPR31 (PubMed:28619714).PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.PTM (Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL.DISEASE Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.DISEASE KRAS mutations are involved in cancer development.SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt Isoform P01116-1 186 EQUAL S-farnesyl-L-cysteine methyl ester MOD MOD:01116 179 EQUAL S-palmitoyl-L-cysteine MOD MOD:00115 1 EQUAL 186 EQUAL Reactome Database ID Release 78 9647915 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=9647915 Reactome R-HSA-9647915 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-9647915.1 p21/N-Ras S-Farn-Me PalmS NRAS Transforming protein N-Ras Reactome DB_ID: 9647910 UniProt:P01111 NRAS NRAS HRAS1 FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).SUBUNIT Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (active GTP-bound form) with RASSF7 (PubMed:21278800).PTM Palmitoylated by the ZDHHC9-GOLGA7 complex (PubMed:16000296). Depalmitoylated by ABHD17A, ABHD17B and ABHD17C (PubMed:26701913). A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi (PubMed:16000296, PubMed:15705808, PubMed:2661017, PubMed:26701913).PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.PTM Phosphorylation at Ser-89 by STK19 enhances NRAS-association with its downstream effectors.PTM (Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL.MISCELLANEOUS Mutations which change AA 12, 13 or 61 activate the potential of Ras to transform cultured cells and are implicated in a variety of human tumors.SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt P01111 186 EQUAL 181 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 78 9647910 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=9647910 Reactome R-HSA-9647910 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-9647910.1 Ras S-Farn-Me-2xPalmS HRAS p21/H-RAS-1 Transforming protein p21/H-Ras-1 c-H-ras Reactome DB_ID: 9647912 UniProt:P01112 HRAS HRAS HRAS1 FUNCTION Involved in the activation of Ras protein signal transduction (PubMed:22821884). Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:12740440, PubMed:14500341, PubMed:9020151).ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).SUBUNIT In its GTP-bound form interacts with PLCE1 (PubMed:11022048). Interacts with TBC1D10C (PubMed:17230191). Interacts with RGL3 (By similarity). Interacts with HSPD1 (By similarity). Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14 (By similarity). Interacts (active GTP-bound form) with RGS14 (via RBD 1 domain) (By similarity). Forms a signaling complex with RASGRP1 and DGKZ (PubMed:11257115). Interacts with RASSF5 (PubMed:18596699). Interacts with PDE6D (PubMed:11980706). Interacts with IKZF3 (PubMed:10369681). Interacts with RACK1 (PubMed:14500341). Interacts with PIK3CG; the interaction is required for membrane recruitment and beta-gamma G protein dimer-dependent activation of the PI3K gamma complex PIK3CG:PIK3R6 (By similarity). Interacts with RAPGEF2 (PubMed:10608844, PubMed:11598133).TISSUE SPECIFICITY Widely expressed.PTM Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi.PTM S-nitrosylated; critical for redox regulation. Important for stimulating guanine nucleotide exchange. No structural perturbation on nitrosylation.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation.PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.PTM (Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL (PubMed:8626586, PubMed:8626575, PubMed:9632667, PubMed:19744486). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to inhibit Ras signaling (PubMed:8626586, PubMed:8626575, PubMed:9632667).DISEASE Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors.SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt P01112 186 EQUAL 181 EQUAL 184 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 78 9647912 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=9647912 Reactome R-HSA-9647912 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-9647912.1 Ki-Ras S-Farn-Me KRAS4B p21A (K-Ras 2A) Transforming protein p21A K-Ras 2A c-K-ras Reactome DB_ID: 9647815 UniProt:P01116-2 KRAS KRAS KRAS2 RASK2 FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:20949621). Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838). Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner (PubMed:24623306).ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP). Interaction with SOS1 promotes exchange of bound GDP by GTP.SUBUNIT Interacts with PHLPP. Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (when farnesylated) with PDE6D; this promotes dissociation from the cell membrane (PubMed:23698361). Interacts with SOS1 (PubMed:22431598). Interacts (when farnesylated) with GPR31 (PubMed:28619714).PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.PTM (Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL.DISEASE Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.DISEASE KRAS mutations are involved in cancer development.SIMILARITY Belongs to the small GTPase superfamily. Ras family. UniProt Isoform P01116-2 186 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 78 9647815 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=9647815 Reactome R-HSA-9647815 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-9647815.1 Reactome Database ID Release 78 9649715 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=9649715 Reactome R-HSA-9649715 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-9649715.1 1 Reactome Database ID Release 78 109796 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=109796 Reactome R-HSA-109796 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-109796.2 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 78 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 p21 RAS:GTP Reactome DB_ID: 109783 1 1 Reactome Database ID Release 78 109783 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=109783 Reactome R-HSA-109783 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-109783.2 ACTIVATION activeUnit: #Protein22 GENE ONTOLOGY GO:0005085 Reactome Database ID Release 78 177932 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=177932 Reactome Database ID Release 78 177938 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=177938 Reactome R-HSA-177938 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-177938.1 8493579 Pubmed 1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2 Chardin, P Camonis, JH Gale, NW Van Aelst, L Schlessinger, J Wigler, Michael H Bar-Sagi, Dafna Science 260:1338-43 Reactome Database ID Release 78 179812 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=179812 Reactome R-HSA-179812 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-179812.2 11706405 Pubmed 2001 GRB2: a pivotal protein in signal transduction Tari, AM Lopez-Berestein, G Semin Oncol 28:142-7 11498013 Pubmed 2001 Internalization of the epidermal growth factor receptor: role in signalling Sorkin, A Biochem Soc Trans 29:480-4 SHC1 events in EGFR signaling GRB2 can bind EGFR directly or through another SH2-containing protein, SHC1. This association leads to RAS activation. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 LEFT-TO-RIGHT SHC1 binds to the phosphorylated EGF receptor:ligand complex SHC1 (Src homology 2 domain-containing) transforming protein can bind to either phosphorylated tyrosine 1148 (p-Y1148) and/or tyrosine 1173 (p-Y1173) sites on the EGF receptor. The N-terminal phosphotyrosine binding domain (PBD) of SHC1, also known as the phosphotyrosine interaction (PI) domain, binds to phosphorylated p-Y1148 of EGFR, which is part of the NPXpY motif. The SH2 domain of SHC1 binds to p-Y1173 of EGFR (Batzer et al. 1995, Songyang et al. 1995, Sakaguchi et al. 1998). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 SHC SHC1 SHC1 p66 SHC transforming protein Reactome DB_ID: 74680 UniProt:P29353 SHC1 SHC1 SHC SHCA FUNCTION Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Isoform p46Shc and isoform p52Shc, once phosphorylated, couple activated receptor tyrosine kinases to Ras via the recruitment of the GRB2/SOS complex and are implicated in the cytoplasmic propagation of mitogenic signals. Isoform p46Shc and isoform p52Shc may thus function as initiators of the Ras signaling cascade in various non-neuronal systems. Isoform p66Shc does not mediate Ras activation, but is involved in signal transduction pathways that regulate the cellular response to oxidative stress and life span. Isoform p66Shc acts as a downstream target of the tumor suppressor p53 and is indispensable for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. The expression of isoform p66Shc has been correlated with life span (By similarity). Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis.SUBUNIT Interacts with CPNE3; this interaction may mediate the binding of CPNE3 with ERBB2 (PubMed:20010870). Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR in vitro via the PID domain. Once activated, binds to GRB2. Interacts with tyrosine-phosphorylated CD3T and DDR2. Interacts with the N-terminal region of SH2B2. Interacts with phosphorylated LRP1 and IRS4. Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with TRIM31. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTT (By similarity). Interacts with ALK, GAB2, GRB7 and KIT. Interacts with FLT4 (tyrosine-phosphorylated). Interacts with EPHB1 and GRB2; activates the MAPK/ERK cascade to regulate cell migration. Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with ERBB4. Interacts with TEK/TIE2 (tyrosine-phosphorylated). Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. Interacts with PTK2/FAK1. Interacts with CEACAM1; this interaction is CEACAM1-phosphorylation-dependent and mediates interaction with EGFR or INSR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity). Interacts (via PID domain) with PEAK1 (when phosphorylated at 'Tyr-1188') (PubMed:23846654). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 UL46.TISSUE SPECIFICITY Widely expressed. Expressed in neural stem cells but absent in mature neurons.DOMAIN In response to a variety of growth factors, isoform p46Shc and isoform p52Shc bind to phosphorylated Trk receptors through their phosphotyrosine binding (PID) and/or SH2 domains. The PID and SH2 domains bind to specific phosphorylated tyrosine residues in the Asn-Pro-Xaa-Tyr(P) motif of the Trk receptors. Isoform p46Shc and isoform p52Shc are in turn phosphorylated on three tyrosine residues within the extended proline-rich domain. These phosphotyrosines act as docking site for GRB2 and thereby are involved in Ras activation (By similarity).PTM Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to FLT4 and KIT signaling. Isoform p46Shc and isoform p52Shc are phosphorylated on tyrosine residues of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36 by PRKCB upon treatment with insulin, hydrogen peroxide or irradiation with ultraviolet light (By similarity). Tyrosine phosphorylated in response to FLT3 signaling (By similarity). Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity). Tyrosine phosphorylated by ligand-activated ALK. Tyrosine phosphorylated by ligand-activated PDGFRB. Tyrosine phosphorylated by TEK/TIE2. May be tyrosine phosphorylated by activated PTK2/FAK1; tyrosine phosphorylation was seen in an astrocytoma biopsy, where PTK2/FAK1 kinase activity is high, but not in normal brain tissue. Isoform p52Shc dephosphorylation by PTPN2 may regulate interaction with GRB2. UniProt P29353 1 EQUAL 583 EQUAL Reactome Database ID Release 78 74680 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=74680 Reactome R-HSA-74680 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-74680.1 EGF-like ligands:p-6Y EGFR:SHC1 Reactome DB_ID: 9624427 1 1 Reactome Database ID Release 78 9624427 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=9624427 Reactome R-HSA-9624427 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-9624427.1 Reactome Database ID Release 78 177925 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=177925 Reactome R-HSA-177925 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-177925.3 7541030 Pubmed 1995 The phosphotyrosine interaction domain of SHC recognizes tyrosine-phosphorylated NPXY motif Songyang, Z Margolis, B Chaudhuri, M Shoelson, S E Cantley, Lewis C J. Biol. Chem. 270:14863-6 7542744 Pubmed 1995 The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor Batzer, A G Blaikie, P Nelson, K Schlessinger, J Margolis, B Mol. Cell. Biol. 15:4403-9 9544989 Pubmed 1998 Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells Sakaguchi, K Okabayashi, Y Kido, Y Kimura, S Matsumura, Y Inushima, K Kasuga, M Mol Endocrinol 12:536-43 LEFT-TO-RIGHT 2.7.10.1 SHC1 phosphorylation by phosphorylated EGFR Once bound to EGFR, SHC1 is phosphorylated on two tyrosines (Y349, Y350). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 2 2 EGF:Phospho-EGFR:Phospho-SHC EGF-like ligands:p-6Y-EGFR:p-Y349,350-SHC1 Reactome DB_ID: 180337 p-Y349,Y350-SHC1 Phospho-SHC transforming protein Reactome DB_ID: 180276 349 EQUAL 350 EQUAL 1 EQUAL 583 EQUAL Reactome Database ID Release 78 180276 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=180276 Reactome R-HSA-180276 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-180276.1 1 1 Reactome Database ID Release 78 180337 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=180337 Reactome R-HSA-180337 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-180337.2 ACTIVATION activeUnit: #Protein7 GENE ONTOLOGY GO:0004714 Reactome Database ID Release 78 9624433 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=9624433 Reactome Database ID Release 78 177933 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=177933 Reactome R-HSA-177933 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-177933.2 8036006 Pubmed 1994 Potent SHC tyrosine phosphorylation by epidermal growth factor at low receptor density or in the absence of receptor autophosphorylation sites Soler, C Alvarez, CV Beguinot, L Carpenter, G Oncogene 9:2207-15 7535773 Pubmed 1995 Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2 VanderKuur, J Allevato, G Billestrup, N Norstedt, G Carter-Su, C J Biol Chem 270:7587-93 LEFT-TO-RIGHT GRB2:SOS1 binds to phosphorylated SHC1 in complex with EGFR The tyrosine sites on SHC1 become possible binding sites for the GRB2:SOS1 complex. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 GRB2:SOS-Phospho-SHC:EGF:Phospho-EGFR dimer EGF-like ligands:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1 Reactome DB_ID: 180331 1 1 Reactome Database ID Release 78 180331 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=180331 Reactome R-HSA-180331 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-180331.2 Reactome Database ID Release 78 177936 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=177936 Reactome R-HSA-177936 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-177936.1 LEFT-TO-RIGHT SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:SHC1:GRB2:SOS1) Son of sevenless homolog 1 (SOS1) is the guanine nucleotide exchange factor (GEF) for rat sarcoma (RAS) protein. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 ACTIVATION activeUnit: #Protein22 Reactome Database ID Release 78 180290 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=180290 Reactome Database ID Release 78 177945 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=177945 Reactome R-HSA-177945 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-177945.1 Reactome Database ID Release 78 180336 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=180336 Reactome R-HSA-180336 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-180336.2 8755247 Pubmed 1996 Not all Shc's roads lead to Ras Bonfini, L Migliaccio, E Pelicci, G Lanfrancone, L Pelicci, PG Trends Biochem Sci 21:257-61 GAB1 signalosome GAB1 is recruited to the activated EGFR indirectly, through GRB2. GAB1 acts as an adaptor protein that enables formation of an active PIK3, through recruitment of PIK3 regulatory subunit PIK3R1 (also known as PI3Kp85), which subsequently recruits PIK3 catalytic subunit PIK3CA (also known as PI3Kp110). PIK3, in complex with EGFR, GRB2 and GAB1, catalyzes phosphorylation of PIP2 and its conversion to PIP3, which leads to the activation of the AKT signaling. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 LEFT-TO-RIGHT Binding of GRB2 to GAB1 GRB2 (Growth factor receptor-bound protein 2) binds to GAB1 (GRB2-associated binding protein 1). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 GAB1 GRB2-associated binding protein 1 Reactome DB_ID: 179795 UniProt:Q13480 GAB1 GAB1 FUNCTION Adapter protein that plays a role in intracellular signaling cascades triggered by activated receptor-type kinases. Plays a role in FGFR1 signaling. Probably involved in signaling by the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR). Involved in the MET/HGF-signaling pathway (PubMed:29408807).SUBUNIT Interacts with GRB2 and with other SH2-containing proteins (PubMed:15010462). Interacts with phosphorylated LAT2 (PubMed:12486104). Interacts with PTPRJ (PubMed:12475979). Identified in a complex containing FRS2, GRB2, GAB1, PIK3R1 and SOS1. Interacts (phosphorylated) with PTPN11 (PubMed:15010462). Interacts with HCK (PubMed:15010462). Part of a tripartite complex containing GAB1, METTL13 and SPRY2 (PubMed:29408807). Interacts with METTL13 (PubMed:29408807).PTM Phosphorylated in response to FGFR1 activation. Phosphorylated on tyrosine residue(s) by the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR). Tyrosine phosphorylation of GAB1 mediates interaction with several proteins that contain SH2 domains. Phosphorylated on tyrosine residues by HCK upon IL6 signaling.SIMILARITY Belongs to the GAB family. UniProt Q13480 1 EQUAL 694 EQUAL Reactome Database ID Release 78 179795 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=179795 Reactome R-HSA-179795 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-179795.1 GRB2:GAB1 Reactome DB_ID: 179849 1 1 Reactome Database ID Release 78 179849 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=179849 Reactome R-HSA-179849 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-179849.1 Reactome Database ID Release 78 177920 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=177920 Reactome R-HSA-177920 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-177920.1 12766170 Pubmed 2003 Grb2-independent recruitment of Gab1 requires the C-terminal lobe and structural integrity of the Met receptor kinase domain Lock, LS Frigault, MM Saucier, C Park, M J Biol Chem 278:30083-90 10913131 Pubmed 2000 Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases Lock, LS Royal, I Naujokas, MA Park, M J Biol Chem 275:31536-45 LEFT-TO-RIGHT GRB2:GAB1 binds to phosphorylated EGFR The regulatory subunit of PIK3 mediates the association of GAB1 and receptor protein-tyrosine kinases such as the EGF receptor, which can phosphorylate GAB1. It appears that the PIK3 regulatory subunit acts as an adaptor protein allowing GAB1 to serve as a substrate for several tyrosine kinases. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 Converted from EntitySet in Reactome GRB2:GAB1,GRB2:GAB1:PIP3 Reactome DB_ID: 9038397 GRB2:GAB1:PIP3 PIP3:GAB1:GRB2 Reactome DB_ID: 180282 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 [ChEBI:16618] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate PIP3 ChEBI CHEBI:16618 Reactome Database ID Release 78 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 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-179838.3 COMPOUND C05981 1 Reactome Database ID Release 78 180282 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=180282 Reactome R-HSA-180282 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-180282.2 Reactome Database ID Release 78 9038397 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=9038397 Reactome R-HSA-9038397 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-9038397.3 GAB1:GRB2-EGF-Phospho-EGFR dimer EGF-like ligands:p-6Y-EGFR:GRB2:GAB1 Reactome DB_ID: 180348 1 1 Reactome Database ID Release 78 180348 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=180348 Reactome R-HSA-180348 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-180348.3 Reactome Database ID Release 78 177941 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=177941 Reactome R-HSA-177941 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-177941.3 9356464 Pubmed 1997 Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor Holgado-Madruga, M Moscatello, DK Emlet, DR Dieterich, R Wong, AJ Proc Natl Acad Sci U S A 94:12419-24 LEFT-TO-RIGHT GAB1 binds phosphatidylinositol-3,4,5-trisphosphate The pleckstrin homology (PH) domain of GAB1 binds to PIP3 and can target GAB1 to the plasma membrane in response to EGF stimulation. This mechanism provides a positive feedback loop with respect to PI3K activation, to enhance EGFR signalling. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 Reactome Database ID Release 78 179467 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=179467 Reactome R-HSA-179467 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-179467.2 10648629 Pubmed 2000 A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling Rodrigues, GA Falasca, M Zhang, Z Ong, SH Schlessinger, J Mol Cell Biol 20:1448-59 LEFT-TO-RIGHT 2.7.10 GAB1 phosphorylation by EGFR kinase EGFR kinase phosphorylates the phosphorylation sites tyrosine 627 and 659 on GAB1 Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 5 GRB2:Phospho GAB1-EGF-Phospho-EGFR dimer EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1 Reactome DB_ID: 180286 Converted from EntitySet in Reactome GRB2:p-5Y-GAB1,GRB2:p-5Y-GAB1:PIP3 Reactome DB_ID: 9038398 GRB2:Phospho-GAB1 Reactome DB_ID: 180304 1 p-5Y-GAB1 Phospho-GAB1 Phosphorylated GRB2-associated binding protein 1 Reactome DB_ID: 180344 627 EQUAL 659 EQUAL 447 EQUAL 472 EQUAL 589 EQUAL 1 EQUAL 694 EQUAL Reactome Database ID Release 78 180344 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=180344 Reactome R-HSA-180344 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-180344.1 1 Reactome Database ID Release 78 180304 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=180304 Reactome R-HSA-180304 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-180304.1 GRB2:p-5Y-GAB1:PIP3 Reactome DB_ID: 9038396 1 1 Reactome Database ID Release 78 9038396 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=9038396 Reactome R-HSA-9038396 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-9038396.1 Reactome Database ID Release 78 9038398 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=9038398 Reactome R-HSA-9038398 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-9038398.2 1 1 Reactome Database ID Release 78 180286 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=180286 Reactome R-HSA-180286 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-180286.3 5 ACTIVATION activeUnit: #Protein32 Reactome Database ID Release 78 180302 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=180302 Converted from EntitySet in Reactome Phosphorylated EGFR dimer Reactome DB_ID: 180285 p-Y1086,Y1101-EGFR SRC-Phosphorylated EGFR Phosphorylated Epidermal Growth Factor Receptor Reactome DB_ID: 179868 1101 EQUAL 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 179868 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=179868 Reactome R-HSA-179868 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-179868.1 Reactome Database ID Release 78 180285 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=180285 Reactome R-HSA-180285 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-180285.1 Reactome Database ID Release 78 177930 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=177930 Reactome R-HSA-177930 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-177930.2 9890893 Pubmed 1999 Identification of tyrosine phosphorylation sites in human Gab-1 protein by EGF receptor kinase in vitro Lehr, S Kotzka, J Herkner, A Klein, E Siethoff, C Knebel, B Noelle, V Bruning, JC Klein, HW Meyer, HE Krone, W Muller-Wieland, D Biochemistry 38:151-9 15231819 Pubmed 2004 Ligand regulates epidermal growth factor receptor kinase specificity: activation increases preference for GAB1 and SHC versus autophosphorylation sites Fan, YX Wong, L Deb, TB Johnson, GR J Biol Chem 279:38143-50 LEFT-TO-RIGHT PI3K binds to EGF:EGFR:GRB2:GAB1 The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 PIK3CA:PIK3R1 Reactome DB_ID: 1806218 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).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 78 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 1 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 78 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 1 Reactome Database ID Release 78 1806218 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=1806218 Reactome R-HSA-1806218 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-1806218.1 EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1:PI3K EGF:Phospho-EGFR-GRB2:p-5Y-GAB1:PI3Kreg:PI3Kcat Reactome DB_ID: 179791 1 1 Reactome Database ID Release 78 179791 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=179791 Reactome R-HSA-179791 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-179791.4 Reactome Database ID Release 78 177927 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=177927 Reactome R-HSA-177927 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-177927.2 11606067 Pubmed 2001 Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein Onishi-Haraikawa, Y Funaki, M Gotoh, N Shibuya, M Inukai, K Katagiri, H Fukushima, Y Anai, M Ogihara, T Sakoda, H Ono, H Kikuchi, M Oka, Y Asano, T Biochem Biophys Res Commun 288:476-82 21827948 Pubmed 2011 Dynamics of the phosphoinositide 3-kinase p110? interaction with p85? and membranes reveals aspects of regulation distinct from p110? Burke, John E Vadas, Oscar Berndt, Alex Finegan, Tara Perisic, O Williams, RL Structure 19:1127-37 19805105 Pubmed 2009 A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane Mandelker, Diana Gabelli, Sandra B Schmidt-Kittler, Oleg Zhu, Jiuxiang Cheong, Ian Huang, Chuan-Hsiang Kinzler, KW Vogelstein, B Amzel, L Mario Proc. Natl. Acad. Sci. U.S.A. 106:16996-7001 LEFT-TO-RIGHT 2.7.1.153 PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3) The kinase activity of PIK3 mediates the phosphorylation of PIP2 to form PIP3 Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 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 [ChEBI:18348] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate PIP2 ChEBI CHEBI:18348 Reactome Database ID Release 78 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 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-179856.3 COMPOUND C04637 ACTIVATION activeUnit: #Protein35 GENE ONTOLOGY GO:0046934 Reactome Database ID Release 78 179881 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=179881 Reactome Database ID Release 78 177939 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=177939 Reactome R-HSA-177939 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-177939.2 LEFT-TO-RIGHT Activation of SHP2 through the binding to phospho-Gab1 The SH2 domains repress phosphatase activity of SHP2. Binding of these domains to phosphotyrosine-containing proteins relieves this autoinhibition, possibly by inducing a conformational change in the enzyme. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 SHP2 PTPN11 SHP2 protein Reactome DB_ID: 162563 UniProt:Q06124 PTPN11 PTPN11 PTP2C SHPTP2 FUNCTION Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus (PubMed:10655584, PubMed:18559669, PubMed:18829466, PubMed:26742426, PubMed:28074573). Positively regulates MAPK signal transduction pathway (PubMed:28074573). Dephosphorylates GAB1, ARHGAP35 and EGFR (PubMed:28074573). Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity (PubMed:18559669). Dephosphorylates CDC73 (PubMed:26742426). Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification (By similarity).SUBUNIT Interacts with phosphorylated LIME1 and BCAR3. Interacts with SHB and INPP5D/SHIP1 (By similarity). Interacts with MILR1 (tyrosine-phosphorylated). Interacts with FLT1 (tyrosine-phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-phosphorylated), KIT and GRB2. Interacts with PDGFRA (tyrosine phosphorylated). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with PTPNS1 and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts with FCRL4, FCRL6 and ANKHD1. Interacts with KIR2DL1; the interaction is enhanced by ARRB2. Interacts with GAB2. Interacts with TERT; the interaction retains TERT in the nucleus. Interacts with PECAM1 and FER. Interacts with EPHA2 (activated); participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream signaling. Interacts with ROS1; mediates PTPN11 phosphorylation. Interacts with PDGFRB (tyrosine phosphorylated); this interaction increases the PTPN11 phosphatase activity. Interacts with GAREM1 isoform 1 (tyrosine phosphorylated); the interaction increases MAPK/ERK activity and does not affect the GRB2/SOS complex formation. Interacts with CDC73 (PubMed:26742426). Interacts with CEACAM1 (via cytoplasmic domain); this interaction depends on the monomer/dimer equilibrium and is phosphorylation-dependent (By similarity). Interacts with MPIG6B (via ITIM motif) (PubMed:23112346). Interacts with SIGLEC10 (By similarity). Interacts with FCRL3 (via phosphorylated ITIM motifs) (PubMed:11162587, PubMed:19843936).TISSUE SPECIFICITY Widely expressed, with highest levels in heart, brain, and skeletal muscle.DOMAIN The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme.PTM Phosphorylated on Tyr-542 and Tyr-580 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins. Phosphorylated upon activation of the receptor-type kinase FLT3. Phosphorylated upon activation of the receptor-type kinase PDGFRA (By similarity). Phosphorylated by activated PDGFRB.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily. UniProt Q06124 1 EQUAL 597 EQUAL Reactome Database ID Release 78 162563 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=162563 Reactome R-HSA-162563 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-162563.2 SHP2-GRB2:Phospho GAB1-EGF-Phospho-EGFR dimer EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2 Reactome DB_ID: 180269 1 1 Reactome Database ID Release 78 180269 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=180269 Reactome R-HSA-180269 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-180269.3 Reactome Database ID Release 78 177944 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=177944 Reactome R-HSA-177944 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-177944.1 14701753 Pubmed 2004 Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB activation through Gab1 in glioblastoma cells Kapoor, GS Zhan, Y Johnson, GR O'Rourke, DM Mol Cell Biol 24:823-36 11323411 Pubmed 2001 Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2 Cunnick, JM Mei, L Doupnik, CA Wu, J J Biol Chem 276:24380-7 LEFT-TO-RIGHT Dephosphorylation of Gab1 by SHP2 Phosphorylated GAB1 can bind PI3 kinase by its regulatory alpha subunit. SHP2 dephosphorylation of the tyrosine residues 447, 472 and 589 on GAB1 means PI3 kinase can no longer bind to the complex in the plasma membrane and cannot be activated. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 29356 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=29356 Reactome R-ALL-29356 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-29356.5 COMPOUND C00001 3 EGF-like ligands:p-6Y-EGFR:GRB2:p-Y627,659-GAB1:SHP2 SHP2-GRB2:Phospho GAB1(dephos)-EGF-Phospho-EGFR dimer Reactome DB_ID: 180503 1 1 Converted from EntitySet in Reactome GRB2:p-Y627,Y659-GAB1,GRB2:p-Y627,Y659-GAB1:PIP3 Reactome DB_ID: 9038479 GRB2:Phospho-GAB1(partially dephosphorylated) Reactome DB_ID: 180511 1 p-Y627,Y659-GAB1 Phospho-GAB1(-Y447, Y472, Y589) Phosphorylated GRB2-associated binding protein 1 Reactome DB_ID: 180496 1 EQUAL 694 EQUAL Reactome Database ID Release 78 180496 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=180496 Reactome R-HSA-180496 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-180496.1 1 Reactome Database ID Release 78 180511 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=180511 Reactome R-HSA-180511 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-180511.1 GRB2:p-GAB1(partially dephosphorylated):PIP3 Reactome DB_ID: 9038477 1 1 Reactome Database ID Release 78 9038477 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=9038477 Reactome R-HSA-9038477 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-9038477.2 Reactome Database ID Release 78 9038479 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=9038479 Reactome R-HSA-9038479 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-9038479.2 1 Reactome Database ID Release 78 180503 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=180503 Reactome R-HSA-180503 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-180503.3 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 29372 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 78 29372 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=29372 Reactome R-ALL-29372 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-29372.4 COMPOUND C00009 3 ACTIVATION activeUnit: #Protein36 GENE ONTOLOGY GO:0004726 Reactome Database ID Release 78 180501 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=180501 Reactome Database ID Release 78 177924 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=177924 Reactome R-HSA-177924 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-177924.1 10734310 Pubmed 2000 Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis Gual, P Giordano, S Williams, TA Rocchi, S Van Obberghen, E Comoglio, PM Oncogene 19:1509-18 LEFT-TO-RIGHT SHP2 dephosphorylates Tyr 992 on EGFR The tyrosine-protein phosphatase SHP2 is a positive effector of EGFR signalling. SHP2 inhibits the tyrosine-dependent translocation of RasGAP (catalyses Ras inactivation) to the plasma membrane, thereby keeping it away from Ras-GTP (its substrate). This inhibition is achieved by the dephosphorylation of a RasGAP binding site on the EGF receptor. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 EGF-like ligands:p-5Y-EGFR:GRB2:p-5Y-GAB1:SHP2 SHP2:GRB2:Phospho GAB1-EGF-Phospho-EGFR (-Y992) dimer Reactome DB_ID: 180326 EGF-like ligands:Phospho-EGFR (-Y992) dimer Reactome DB_ID: 180343 EGF-like ligands:Phospho-EGFR (- Y992) Reactome DB_ID: 180277 1 p-4Y-EGFR p-Y1068,Y1086,Y1148,Y1173-EGFR Phospho-EGFR (dephos Y992) Phosphorylated Epidermal Growth Factor Receptor with dephosphorylated Y992 Reactome DB_ID: 180287 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 180287 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=180287 Reactome R-HSA-180287 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-180287.1 1 Reactome Database ID Release 78 180277 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=180277 Reactome R-HSA-180277 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-180277.2 2 Reactome Database ID Release 78 180343 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=180343 Reactome R-HSA-180343 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-180343.2 1 1 1 Reactome Database ID Release 78 180326 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=180326 Reactome R-HSA-180326 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-180326.3 ACTIVATION activeUnit: #Protein36 Reactome Database ID Release 78 177935 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=177935 Reactome R-HSA-177935 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-177935.1 14560030 Pubmed 2003 Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling Agazie, YM Hayman, MJ Mol Cell Biol 23:7875-86 LEFT-TO-RIGHT Dephosphorylation of PAG by SHP2 Dephosphorylation of CBP/PAG negatively regulates the recruitment of the Src inhibiting kinase, Csk. Src is not negatively regulated by phosphorylation by Csk. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 p-CBP p-Y317-PAG1 p-PAG1 Reactome DB_ID: 180494 UniProt:Q9NWQ8 PAG1 PAG1 CBP PAG FUNCTION Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Promotes CSK activation and recruitment to lipid rafts, which results in LCK inhibition. Inhibits immunological synapse formation by preventing dynamic arrangement of lipid raft proteins. May be involved in cell adhesion signaling.SUBUNIT Interacts with FYN. When phosphorylated, interacts with CSK. Interacts with SLC9A3R1/EBP50. In resting T-cells, part of a PAG1-SLC9A3R1-MSN complex which is disrupted upon TCR activation. Interacts with LYN on plasma membrane lipid rafts. Identified in a complex with LYN and STAT3.TISSUE SPECIFICITY Ubiquitously expressed. Present in germinal center B-cells, plasma cells, T-cells, monocytes and platelets (at protein level).PTM Palmitoylated.PTM Phosphorylated by FYN on Tyr-317 in resting T-cells; which promotes interaction with CSK. Dephosphorylated by PTPRC/CD45 upon TCR activation; which leads to CSK dissociation. May also be dephosphorylated by PTPN11. Hyperphosphorylated in mast cells upon FCER1 activation. Phosphorylated by LYN. UniProt Q9NWQ8 317 EQUAL 1 EQUAL 432 EQUAL Reactome Database ID Release 78 180494 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=180494 Reactome R-HSA-180494 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-180494.1 PAG1 Reactome DB_ID: 180500 1 EQUAL 432 EQUAL Reactome Database ID Release 78 180500 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=180500 Reactome R-HSA-180500 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-180500.1 ACTIVATION activeUnit: #Protein36 Reactome Database ID Release 78 177926 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=177926 Reactome R-HSA-177926 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-177926.2 14967142 Pubmed 2004 Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment Zhang, Si Qing Yang, Wentian Kontaridis, Maria I Bivona, Trever G Wen, Gengyun Araki, Toshiyuki Luo, Jincai Thompson, Julie A Schraven, Burkhart L Philips, Mark R Neel, Benjamin G Mol. Cell 13:341-55 LEFT-TO-RIGHT Sustained activation of SRC kinase by SHP2 SHP2 can dephosphorylate paxillin, which leads to Csk dissociation from the paxillin-Src complex and Src activation. Src is an SHP2 effector in EGF-stimulated Erk activation and cell migration. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Paxillin:CSK:Src complex p-Y-PXN:CSK:MyrG,p-Y530-SRC Reactome DB_ID: 180522 CSK Tyrosine-protein kinase CSK Reactome DB_ID: 180499 UniProt:P41240 CSK CSK FUNCTION Non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN, CSK or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. Suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several positive effectors such as FYN or LCK.SUBUNIT Homodimer (via SH3-domain) (PubMed:19888460). Interacts with PTPN22 (PubMed:15208781). Interacts with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1; these interactions serve to recruit CSK to the membrane where it can phosphorylate and inhibit Src-family kinases (PubMed:11433379, PubMed:10790433, PubMed:14610046, PubMed:10838081). Interacts with SRCIN1 (PubMed:17525734). Interacts with RHOH (PubMed:20851766). Interacts (via SH2 domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-107' (PubMed:21930792). Interacts (via SH2 domain) with PRAG1 (when phosphorylated at 'Tyr-391'); this interaction prevents translocation of CSK from the cytoplasm to the membrane leading to increased activity of CSK (By similarity).TISSUE SPECIFICITY Expressed in lung and macrophages.DOMAIN The architecture of this protein is similar to that of Src-family kinases (SFKs) with one N-terminal SH3 domain, one SH2 domain, and a C-terminal kinase domain.PTM Phosphorylated at Ser-364 by PKA, leading to increased activity. Autophosphorylated.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. CSK subfamily. UniProt P41240 1 EQUAL 450 EQUAL Reactome Database ID Release 78 180499 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=180499 Reactome R-HSA-180499 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-180499.1 1 p(Y530)-SRC MyrG,p-Y530-SRC Inactive SRC (phosphorylated Y530) Reactome DB_ID: 377598 UniProt:P12931 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). 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.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 P12931 530 EQUAL 2 EQUAL N-myristoylglycine MOD MOD:00068 2 EQUAL 536 EQUAL Reactome Database ID Release 78 377598 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=377598 Reactome R-HSA-377598 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-377598.2 1 p-Y-PXN Reactome DB_ID: 9031680 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 78 9031680 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=9031680 Reactome R-HSA-9031680 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-9031680.1 1 Reactome Database ID Release 78 180522 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=180522 Reactome R-HSA-180522 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-180522.2 PXN:MyrG-SRC Paxillin:Src complex Reactome DB_ID: 180523 MyrG-SRC Reactome DB_ID: 8876922 2 EQUAL 536 EQUAL Reactome Database ID Release 78 8876922 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=8876922 Reactome R-HSA-8876922 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-8876922.2 1 PXN Paxillin Reactome DB_ID: 180493 1 EQUAL 591 EQUAL Reactome Database ID Release 78 180493 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=180493 Reactome R-HSA-180493 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-180493.1 1 Reactome Database ID Release 78 180523 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=180523 Reactome R-HSA-180523 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-180523.2 ACTIVATION activeUnit: #Protein36 Reactome Database ID Release 78 177923 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=177923 Reactome R-HSA-177923 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-177923.2 14665621 Pubmed 2004 Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor Ren, Y Meng, S Mei, L Zhao, ZJ Jove, R Wu, J J Biol Chem 279:8497-505 15574420 Pubmed 2005 A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation Montagner, A Yart, A Dance, M Perret, B Salles, JP Raynal, P J Biol Chem 280:5350-60 Reactome Database ID Release 78 180292 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=180292 Reactome R-HSA-180292 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-180292.3 15550174 Pubmed 2004 The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway Mattoon, DR Lamothe, B Lax, I Schlessinger, J BMC Biol 2:24 EGFR downregulation Regulation of receptor tyrosine kinase (RTK) activity is implicated in the control of almost all cellular functions. One of the best understood RTKs is epidermal growth factor receptor (EGFR). Growth factors can bind to EGFR and activate it to initiate signalling cascades within the cell. EGFRs can also be recruited to clathrin-coated pits which can be internalised into endocytic vesicles. From here, EGFRs can either be recycled back to the plasma membrane or directed to lysosomes for destruction.This provides a mechanism by which EGFR signalling is negatively regulated and controls the strength and duration of EGFR-induced signals. It also prevents EGFR hyperactivation as commonly seen in tumorigenesis.<br><br>The proto-oncogene Cbl can negatively regulate EGFR signalling. The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation. All Cbl proteins have a unique domain that recognises phosphorylated tyrosine residues on activated EGFRs. They also direct the ubiquitination and degradation of activated EGFRs by recruiting ubiquitin-conjugation enzymes. Cbl proteins function by specifically targeting activated EGFRs and mediating their down-regulation, thus providing a means by which signaling processes can be negatively regulated.<br><br>Cbl also promotes receptor internalization via it's interaction with an adaptor protein, CIN85 (Cbl-interacting protein of 85kDa). CIN85 binds to Cbl via it's SH3 domain and is enhanced by the EGFR-induced tyrosine phosphorylation of Cbl. The proline-rich region of CIN85 interacts with endophilins which are regulatory components of clathrin-coated vesicles (CCVs). Endophilins bind to membranes and induce membrane curvature, in conjunction with other proteins involved in CCV formation. The rapid recruitment of endophilin to the activated receptor complex by CIN85 is the mechanism which controls receptor internalization. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 LEFT-TO-RIGHT Binding of CBL to EGFR Phosphorylation at tyrosine Y1045 of EGFR creates a major docking site for E3 ubiquitin-protein ligase, CBL (Casitas B-lineage lymphoma proto- oncogene) and is required to sort the EGFR to lysosomes for degradation. The E3 ligase CBL plays a crucial role in these events as it dually participates in early events of internalization via a CIN85-endophilin dependent mechanism and endocytic sorting by mediating multiple monoubiquitylation of the receptor. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 CBL CBL E3 ubiquitin protein ligase Signal transduction protein CBL Proto-oncogene c-CBL Casitas B-lineage lymphoma proto-oncogene Reactome DB_ID: 112199 UniProt:P22681 CBL CBL CBL2 RNF55 FUNCTION Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome (PubMed:17094949). Ubiquitinates SPRY2 (PubMed:17094949, PubMed:17974561). Ubiquitinates EGFR (PubMed:17974561). Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Forms homodimers; IFT20 promotes the formation of stable homodimers (PubMed:29237719). Interacts (phosphorylated at Tyr-731) with PIK3R1. Associates with NCK via its SH3 domain. The phosphorylated C-terminus interacts with CD2AP via its second SH3 domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region. Also interacts with SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2 (By similarity). Interacts with CBLB (PubMed:29237719). Interacts with ALK, AXL, BLK, FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with ATX2 (By similarity). Interacts with TEK/TIE2 (tyrosine phosphorylated). Interacts with SH3KBP1 and this interaction is inhibited in the presence of SHKBP1 (By similarity). Interacts with SIGLEC10 (By similarity). Interacts with IFT20 (PubMed:29237719). Interacts with SPRY2; the interaction inhibits CBL-mediated ubiquitination of EGFR (PubMed:17974561).SUBUNIT (Microbial infection) Interacts with M.tuberculosis LpqN, which influences the balance between intrinsic antibacterial and antiviral defense.DOMAIN The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.DOMAIN The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.PTM Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and ZAP70 (By similarity). Phosphorylated on tyrosine residues in response to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR and FGR. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by HCK.PTM Ubiquitinated, leading to its degradation via the proteasome (PubMed:11896602, PubMed:20094046). Ubiquitination is negatively regulated by IFT20 (PubMed:29237719).MISCELLANEOUS This protein has one functional calcium-binding site. UniProt P22681 1 EQUAL 906 EQUAL Reactome Database ID Release 78 112199 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=112199 Reactome R-HSA-112199 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-112199.1 2 EGF-like ligands:p-6Y-EGFR:CBL EGF:Phospho-EGFR (Y1045) dimer:CBL Reactome DB_ID: 182960 2 1 Reactome Database ID Release 78 182960 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=182960 Reactome R-HSA-182960 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-182960.4 Reactome Database ID Release 78 183055 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=183055 Reactome R-HSA-183055 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-183055.4 15475003 Pubmed 2004 Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation Grovdal, LM Stang, E Sorkin, A Madshus, IH Exp Cell Res 300:388-95 LEFT-TO-RIGHT 2.7.10 Phosphorylation of CBL (EGFR:CBL) EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 2 2 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL Reactome DB_ID: 182953 p-Y371-CBL Phospho-CBL CBL E3 ubiquitin protein ligase Signal transduction protein CBL Proto-oncogene c-CBL Casitas B-lineage lymphoma proto-oncogene Reactome DB_ID: 182940 371 EQUAL 1 EQUAL 906 EQUAL Reactome Database ID Release 78 182940 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=182940 Reactome R-HSA-182940 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-182940.1 2 2 2 Reactome Database ID Release 78 182953 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=182953 Reactome R-HSA-182953 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-182953.3 ACTIVATION activeUnit: #Protein7 Reactome Database ID Release 78 183047 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=183047 Reactome Database ID Release 78 182969 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=182969 Reactome R-HSA-182969 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-182969.1 7657591 Pubmed 1995 Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation Galisteo, ML Dikic, I Batzer, AG Langdon, WY Schlessinger, J J Biol Chem 270:20242-5 15117950 Pubmed 2004 Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations Kassenbrock, CK Anderson, SM J Biol Chem 279:28017-27 LEFT-TO-RIGHT 6.3.2.19 CBL binds and ubiquitinates phosphorylated Sprouty Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL.The CBL-mediated ubiquitination of Sprouty targets the protein for degradation by the 26S proteosome. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 Converted from EntitySet in Reactome SPRY1/2 Sprouty Reactome DB_ID: 182909 SPRY1 Sprouty 1 Reactome DB_ID: 182908 UniProt:O43609 SPRY1 SPRY1 FUNCTION Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2 (By similarity). Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells (By similarity).SUBUNIT Forms heterodimers with SPRY2 (By similarity). Interacts with TESK1 (By similarity). Interacts with CAV1 (via C-terminus) (By similarity).DOMAIN The Cys-rich domain is responsible for the localization of the protein to the membrane ruffles.SIMILARITY Belongs to the sprouty family. UniProt O43609 1 EQUAL 319 EQUAL Reactome Database ID Release 78 182908 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=182908 Reactome R-HSA-182908 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-182908.1 SPRY2 Sprouty 2 Reactome DB_ID: 182949 UniProt:O43597 SPRY2 SPRY2 FUNCTION Antagonist of fibroblast growth factor (FGF) pathways via inhibition of FGF-mediated phosphorylation of ERK1/2 (By similarity). Thereby acts as an antagonist of FGF-induced retinal lens fiber differentiation, may inhibit limb bud outgrowth and may negatively modulate respiratory organogenesis (By similarity). Inhibits TGFB-induced epithelial-to-mesenchymal transition in retinal lens epithelial cells (By similarity). Inhibits CBL/C-CBL-mediated EGFR ubiquitination (PubMed:17974561).SUBUNIT Forms heterodimers with SPRY1 (By similarity). Part of a tripartite complex containing GAB1, METTL13 and SPRY2 (PubMed:29408807). Interacts with METTL13 (PubMed:29408807).Interacts with RAF1 (PubMed:12717443). Interacts (via C-terminus) with TESK1 (via C-terminus); the interaction disrupts SPRY2 interaction with GRB2, potentially via disruption of SPRY2 serine dephosphorylation (PubMed:17974561). Interacts with PPP2R1A/PP2A-A and PPP2CA/PP2A-C; the interaction with PPP2CA/PP2A-C is inhibited by interaction with TESK1, possibly by vesicular sequestration of SPRY2 (PubMed:17974561). Inhibition of the interaction with the serine/threonine-protein phosphatase 2A (PP2A) holoenzyme results in loss of PP2A-mediated dephosphorylation, resulting in the loss of SPRY2 interaction with GRB2 (PubMed:17974561). Interacts with GRB2 (PubMed:17974561). Interacts with CBL/C-CBL; the interaction inhibits CBL-mediated ubiquitination of EGFR (PubMed:17974561). Interacts (via C-terminus) with CAV1 (via C-terminus) (PubMed:16877379).DOMAIN The Cys-rich domain is responsible for the localization of the protein to the membrane ruffles.PTM Cleaved at Pro-144 by the prolyl endopeptidase FAP (seprase) activity (in vitro).SIMILARITY Belongs to the sprouty family. UniProt O43597 1 EQUAL 315 EQUAL Reactome Database ID Release 78 182949 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=182949 Reactome R-HSA-182949 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-182949.1 Reactome Database ID Release 78 182909 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=182909 Reactome R-HSA-182909 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-182909.1 Converted from EntitySet in Reactome Ub ubiquitin Reactome DB_ID: 113595 RPS27A RPS27A(1-76) ubiquitin (RPS27A) Reactome DB_ID: 939205 UniProt:P62979 RPS27A RPS27A UBA80 UBCEP1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P62979 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939205 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=939205 Reactome R-HSA-939205 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-939205.1 UBA52 UBA52(1-76) ubiquitin (UBA52) Reactome DB_ID: 939203 UniProt:P62987 UBA52 UBA52 UBCEP2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62987 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939203 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=939203 Reactome R-HSA-939203 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-939203.1 UBB UBB(1-76) ubiquitin (UBB 1) Reactome DB_ID: 939214 UniProt:P0CG47 UBB UBB SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG47 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939214 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=939214 Reactome R-HSA-939214 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-939214.1 UBB(77-152) ubiquitin (UBB 2) Reactome DB_ID: 939213 77 EQUAL 152 EQUAL Reactome Database ID Release 78 939213 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=939213 Reactome R-HSA-939213 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-939213.1 UBB(153-228) ubiquitin (UBB 3) Reactome DB_ID: 939230 153 EQUAL 228 EQUAL Reactome Database ID Release 78 939230 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=939230 Reactome R-HSA-939230 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-939230.1 UBC UBC(1-76) ubiquitin (UBC 1) Reactome DB_ID: 939188 UniProt:P0CG48 UBC UBC MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG48 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939188 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=939188 Reactome R-HSA-939188 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-939188.1 UBC(77-152) ubiquitin (UBC 2) Reactome DB_ID: 939164 77 EQUAL 152 EQUAL Reactome Database ID Release 78 939164 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=939164 Reactome R-HSA-939164 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-939164.1 UBC(153-228) ubiquitin (UBC 3) Reactome DB_ID: 939258 153 EQUAL 228 EQUAL Reactome Database ID Release 78 939258 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=939258 Reactome R-HSA-939258 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-939258.1 UBC(229-304) ubiquitin (UBC 4) Reactome DB_ID: 939192 229 EQUAL 304 EQUAL Reactome Database ID Release 78 939192 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=939192 Reactome R-HSA-939192 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-939192.1 UBC(305-380) ubiquitin (UBC 5) Reactome DB_ID: 939232 305 EQUAL 380 EQUAL Reactome Database ID Release 78 939232 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=939232 Reactome R-HSA-939232 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-939232.1 UBC(381-456) ubiquitin (UBC 6) Reactome DB_ID: 939191 381 EQUAL 456 EQUAL Reactome Database ID Release 78 939191 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=939191 Reactome R-HSA-939191 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-939191.1 UBC(457-532) ubiquitin (UBC 7) Reactome DB_ID: 939184 457 EQUAL 532 EQUAL Reactome Database ID Release 78 939184 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=939184 Reactome R-HSA-939184 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-939184.1 UBC(533-608) ubiquitin (UBC 8) Reactome DB_ID: 939239 533 EQUAL 608 EQUAL Reactome Database ID Release 78 939239 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=939239 Reactome R-HSA-939239 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-939239.1 UBC(609-684) ubiquitin (UBC 9) Reactome DB_ID: 939165 609 EQUAL 684 EQUAL Reactome Database ID Release 78 939165 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=939165 Reactome R-HSA-939165 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-939165.1 Reactome Database ID Release 78 113595 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=113595 Reactome R-HSA-113595 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-113595.1 EGF-like ligands:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2 EGF:Phospho-EGFR (Y1045) dimer:CBL:Phospho-Sprouty ubiquitinated Reactome DB_ID: 182939 Ub-p-Y53/55-SPRY1/2 Phospho-SPROUTY ubiquitinated Reactome DB_ID: 182967 Converted from EntitySet in Reactome Phospho-Sprouty p-Y53/55-SPRY1/2 Reactome DB_ID: 182963 p-Y53-SPRY1 Phospho-Sprouty 1 Reactome DB_ID: 182933 53 EQUAL 1 EQUAL 319 EQUAL Reactome Database ID Release 78 182933 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=182933 Reactome R-HSA-182933 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-182933.1 p-Y55-SPRY2 Y55-phospho Sprouty 2 hSpry2-phosphoY55 Reactome DB_ID: 182950 55 EQUAL 1 EQUAL 315 EQUAL Reactome Database ID Release 78 182950 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=182950 Reactome R-HSA-182950 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-182950.1 Reactome Database ID Release 78 182963 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=182963 Reactome R-HSA-182963 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-182963.1 1 1 Reactome Database ID Release 78 182967 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=182967 Reactome R-HSA-182967 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-182967.1 1 1 Reactome Database ID Release 78 182939 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=182939 Reactome R-HSA-182939 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-182939.2 ACTIVATION activeUnit: #Protein69 GENE ONTOLOGY GO:0004842 Reactome Database ID Release 78 183074 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=183074 p-Y371-CBL Phospho-CBL CBL E3 ubiquitin protein ligase Signal transduction protein CBL Proto-oncogene c-CBL Casitas B-lineage lymphoma proto-oncogene Reactome DB_ID: 182923 1 EQUAL 906 EQUAL Reactome Database ID Release 78 182923 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=182923 Reactome R-HSA-182923 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-182923.1 Reactome Database ID Release 78 183089 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=183089 Reactome R-HSA-183089 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-183089.1 12593796 Pubmed 2003 hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl Hall, AB Jura, N DaSilva, J Jang, YJ Gong, D Bar-Sagi, Dafna Curr Biol 13:308-14 LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of stimulated EGFR (CBL) CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain. Receptor-type tyrosine-protein phosphatase kappa (PTPRK/RPTPk/DEP1) dephosphorylates EGFR, thereby inhibiting receptor ubiquitylation (Ub) by c-CBL, which decelerates the rate of receptor internalization and diminishes MAPK signals generated at the membrane and in endosomes. PTPRK disrupts physical association of ubiquitin ligase complex with EGFR and impairs its internalization (Tarcic et al. 2009, Xu et al. 2005). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 2 EGF-like ligands:Ub-p-6Y-EGFR:p-Y371-CBL EGF:Phospho-EGFR (Y1045) dimer Ubiquitinated:Phospho-CBL Reactome DB_ID: 182930 2 2 2 2 Reactome Database ID Release 78 182930 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=182930 Reactome R-HSA-182930 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-182930.3 ACTIVATION activeUnit: #Protein69 Reactome Database ID Release 78 182993 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=182993 Reactome R-HSA-182993 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-182993.1 10514377 Pubmed 1999 The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase Joazeiro, Claudio A Wing, SS Huang, H Leverson, JD Hunter, T Liu, YC Science 286:309-12 15021893 Pubmed 2004 Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases Marmor, MD Yarden, Y Oncogene 23:2057-70 LEFT-TO-RIGHT CBL binds to GRB2 CBL binds multiple signalling proteins including GRB2. The CBL:GRB2 complex translocates to the plasma membrane where it can bind to GRB2-specific docking sites on the EGF receptor. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 CBL:GRB2 Reactome DB_ID: 182910 1 1 Reactome Database ID Release 78 182910 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=182910 Reactome R-HSA-182910 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-182910.1 Reactome Database ID Release 78 183052 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=183052 Reactome R-HSA-183052 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-183052.1 8621719 Pubmed 1996 p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase Panchamoorthy, G Fukazawa, T Miyake, S Soltoff, S Reedquist, K Druker, B Shoelson, S Cantley, Lewis C Band, H J Biol Chem 271:3187-94 LEFT-TO-RIGHT Localization of CBL:GRB2 to the membrane Upon EGF stimulation and consequent EGFR phosphorylation, GRB2 binds phosphorylated tyrosines Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 2 EGF-like ligands:p-6Y-EGFR:CBL:GRB2 EGF:Phospho-EGFR (Y1045) dimer:CBL:GRB2 Reactome DB_ID: 182928 2 1 Reactome Database ID Release 78 182928 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=182928 Reactome R-HSA-182928 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-182928.3 Reactome Database ID Release 78 183067 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=183067 Reactome R-HSA-183067 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-183067.2 11823423 Pubmed 2002 A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling Waterman, H Katz, M Rubin, C Shtiegman, K Lavi, S Elson, A Jovin, T Yarden, Y EMBO J 21:303-13 LEFT-TO-RIGHT 2.7.10 Phosphorylation of CBL (EGFR:GRB2:CBL) EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 2 2 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:GRB2 EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:GRB2 Reactome DB_ID: 182948 2 2 2 2 Reactome Database ID Release 78 182948 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=182948 Reactome R-HSA-182948 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-182948.2 ACTIVATION activeUnit: #Protein7 Reactome Database ID Release 78 182979 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=182979 Reactome Database ID Release 78 183058 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=183058 Reactome R-HSA-183058 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-183058.1 LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of stimulated EGFR (CBL:GRB2) CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain. Receptor-type tyrosine-protein phosphatase kappa (PTPRK/RPTPk/DEP1) dephosphorylates EGFR, thereby inhibiting receptor ubiquitylation (Ub) by c-CBL, which decelerates the rate of receptor internalization and diminishes MAPK signals generated at the membrane and in endosomes. PTPRK disrupts physical association of ubiquitin ligase complex with EGFR and impairs its internalization (Tarcic et al. 2009, Xu et al. 2005). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 2 EGF-like ligands:Ub-p-6Y-EGFR:p-Y371-CBL:GRB2 EGF:Phospho-EGFR (Y1045) dimer Ubiquitinated:Phospho-CBL:GRB2 Reactome DB_ID: 182945 2 2 2 p-Y371-CBL:GRB2 Reactome DB_ID: 182964 1 1 Reactome Database ID Release 78 182964 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=182964 Reactome R-HSA-182964 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-182964.1 2 Reactome Database ID Release 78 182945 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=182945 Reactome R-HSA-182945 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-182945.2 ACTIVATION activeUnit: #Protein69 Reactome Database ID Release 78 183039 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=183039 Reactome Database ID Release 78 183036 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=183036 Reactome R-HSA-183036 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-183036.2 INHIBITION Reactome Database ID Release 78 6785334 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=6785334 Reactome R-HSA-6785334 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-6785334.1 PTPRK Receptor-type protein-tyrosine phosphatase kappa precursor RPTPk RPTP kappa Reactome DB_ID: 6785699 UniProt:Q15262 PTPRK PTPRK PTPK FUNCTION Regulation of processes involving cell contact and adhesion such as growth control, tumor invasion, and metastasis. Negative regulator of EGFR signaling pathway. Forms complexes with beta-catenin and gamma-catenin/plakoglobin. Beta-catenin may be a substrate for the catalytic activity of PTPRK/PTP-kappa.TISSUE SPECIFICITY High levels in lung, brain and colon; less in liver, pancreas, stomach, kidney, placenta and mammary carcinoma.PTM This protein undergoes proteolytic processing.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Receptor class 2B subfamily. UniProt Q15262 27 EQUAL 1439 EQUAL Reactome Database ID Release 78 6785699 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=6785699 Reactome R-HSA-6785699 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-6785699.1 LEFT-TO-RIGHT Sprouty lures CBL away from EGFR The NEYTEG motif is very similar to the CBL binding motif around Tyr-1045 in EGFR. Tyrosine-phosphorylated Sprouty (hSpry) binds to CBL, which then cannot ubiquitinate EGFR. Sprouty acts as a decoy to lure CBL away from EGFR and targets it for degradation. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 CBL:SPRY1/2 CBL:Sprouty Reactome DB_ID: 182914 1 1 Reactome Database ID Release 78 182914 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=182914 Reactome R-HSA-182914 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-182914.1 Reactome Database ID Release 78 182988 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=182988 Reactome R-HSA-182988 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-182988.2 12234920 Pubmed 2002 Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling Wong, ES Fong, CW Lim, J Yusoff, P Low, BC Langdon, WY Guy, GR EMBO J 21:4796-808 12593795 Pubmed 2003 Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops Rubin, C Litvak, V Medvedovsky, H Zwang, Y Lev, S Yarden, Y Curr Biol 13:297-307 LEFT-TO-RIGHT CDC42:GTP binds CBL:Beta-Pix CDC42 lures CBL away from the receptor Activated CDC42 binds to Beta-Pix (p85Cool-1), a protein that directly associates with CBL. This inhibits the binding of CBL to the EGF receptor and thus prevents CBL from catalyzing receptor ubiquitination. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 Beta-Pix:CDC42:GTP Cool/Pix:CDC42-GTP Reactome DB_ID: 182917 CDC42:GTP CDC42-GTP Reactome DB_ID: 182921 CDC42 Cell division control protein 42 homolog CDC42_HUMAN Reactome DB_ID: 449545 UniProt:P60953 CDC42 CDC42 FUNCTION Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. Regulates the bipolar attachment of spindle microtubules to kinetochores before chromosome congression in metaphase (PubMed:15642749). Regulates cell migration (PubMed:17038317). In neurons, plays a role in the extension and maintenance of the formation of filopodia, thin and actin-rich surface projections (PubMed:14978216). Required for DOCK10-mediated spine formation in Purkinje cells and hippocampal neurons. Facilitates filopodia formation upon DOCK11-activation (By similarity). Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Also plays a role in phagocytosis through organization of the F-actin cytoskeleton associated with forming phagocytic cups (PubMed:26465210).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.SUBUNIT Interacts with CDC42EP1, CDC42EP2, CDC42EP3, CDC42EP4, CDC42EP5, CDC42SE1, CDC42SE2, PARD6A, PARD6B and PARD6G (in a GTP-dependent manner) (PubMed:10490598, PubMed:10816584, PubMed:10954424, PubMed:11260256). Interacts with activated CSPG4 and with BAIAP2 (PubMed:10587647, PubMed:11130076). Interacts with activated CSPG4 and with BAIAP2 (By similarity). Interacts with DOCK11/Zizimin2; the interaction activates CDC42 by exchanging GDP for GTP (By similarity). Interacts with DOCK9; the interaction activates CDC42 by exchanging GDP for GTP (PubMed:12172552, PubMed:19745154). Interacts with DOCK8 (via DHR-2 domain); the interaction activates CDC42 by exchanging GDP for GTP (PubMed:12172552). Interacts with IQGAP1 (By similarity). Interacts with NET1 and ARHGAP33/TCGAP (By similarity). Part of a complex with PARD3, PARD6A or PARD6B and PRKCI or PRKCZ (PubMed:11260256). The GTP-bound form interacts with CCPG1 (By similarity). Interacts with USP6 (PubMed:12612085). Interacts with NEK6 (PubMed:20873783). Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas (PubMed:17038317). Interacts with ITGB1BP1 (PubMed:11807099). Interacts with ARHGDIA; this interaction inactivates and stabilizes CDC42 (PubMed:23434736). Interacts with ARHGDIB; this maintains CDC42 in the inactive, GDP-bound form (PubMed:7512369). Interacts (in GTP-bound form) with FNBP1L and ABI1, but only in the presence of FNBP1L (PubMed:19798448). May interact with ARHGEF16; responsible for the activation of CDC42 by the viral protein HPV16 E6 (PubMed:21139582).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 Phosphorylated by SRC in an EGF-dependent manner, this stimulates the binding of the Rho-GDP dissociation inhibitor RhoGDI.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 CDC42 and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-35 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-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).SIMILARITY Belongs to the small GTPase superfamily. Rho family. CDC42 subfamily. UniProt P60953 1 EQUAL 188 EQUAL Reactome Database ID Release 78 449545 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=449545 Reactome R-HSA-449545 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-449545.1 1 1 Reactome Database ID Release 78 182921 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=182921 Reactome R-HSA-182921 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-182921.1 1 PIX ARHGEF7 Beta-Pix COOL1 Reactome DB_ID: 430346 UniProt:Q14155 ARHGEF7 ARHGEF7 COOL1 KIAA0142 P85SPR PAK3BP PIXB Nbla10314 FUNCTION Acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling. Functions in cell migration, attachment and cell spreading. Promotes targeting of RAC1 to focal adhesions (By similarity). May function as a positive regulator of apoptosis. Downstream of NMDA receptors and CaMKK-CaMK1 signaling cascade, promotes the formation of spines and synapses in hippocampal neurons.SUBUNIT Interacts with PAK kinases through the SH3 domain. Interacts with GIT1 and TGFB1I1. Interacts with PTK2/FAK1 and RAC1. Interacts with ITCH and PARVB (By similarity). Interacts with unphosphorylated PAK1. Interacts with SCRIB; interaction is direct and may play a role in regulation of apoptosis. Interacts with FRMPD4 (via N-terminus). Interacts with CaMK1. Interacts with BIN2. Isoform 1 and isoform 5 interact with SNX27. Interacts with YWHAZ (By similarity).PTM Phosphorylated by PTK2/FAK1; this promotes interaction with RAC1 (By similarity). Phosphorylated on Ser-694 by CaMK1; enhancement of GEF activity and downstream activation of RAC1. UniProt Q14155 1 EQUAL 803 EQUAL Reactome Database ID Release 78 430346 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=430346 Reactome R-HSA-430346 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-430346.1 1 Reactome Database ID Release 78 182917 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=182917 Reactome R-HSA-182917 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-182917.1 CBL:Beta-Pix:CDC42:GTP CBL:Cool/Pix:CDC42:GTP Reactome DB_ID: 182956 1 1 Reactome Database ID Release 78 182956 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=182956 Reactome R-HSA-182956 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-182956.2 Reactome Database ID Release 78 183094 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=183094 Reactome R-HSA-183094 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-183094.3 14505571 Pubmed 2003 Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation Wu, WJ Tu, S Cerione, RA Cell 114:715-25 LEFT-TO-RIGHT Beta-Pix pushes CIN85 away from CBL Beta-Pix:CDC42:GTP binds CBL in EGF:p-6Y-EGFR:CBL:CIN85 High concentrations of active CDC42 (bound to GTP) and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 (SH3KBP1) from the CBL complex. This competitive mechanism could block the CIN85-imposed clustering phenomenon on CBL that is required for tighter binding (Schmidt et al. 2006). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Jassal, Bijay, 2016-12-07 2 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:GRB2:CIN85:Endophilin Reactome DB_ID: 182946 2 2 CIN85:endophilin SH3KBP1 tetramer:SH3GLs Reactome DB_ID: 8875480 SH3KBP1 tetramer CIN85 homotetramer Reactome DB_ID: 8875475 CIN85 SH3KBP1 Cbl-interacting protein of 85K Reactome DB_ID: 182957 UniProt:Q96B97 SH3KBP1 SH3KBP1 CIN85 FUNCTION Adapter protein involved in regulating diverse signal transduction pathways. Involved in the regulation of endocytosis and lysosomal degradation of ligand-induced receptor tyrosine kinases, including EGFR and MET/hepatocyte growth factor receptor, through an association with CBL and endophilins. The association with CBL, and thus the receptor internalization, may be inhibited by an interaction with PDCD6IP and/or SPRY2. Involved in regulation of ligand-dependent endocytosis of the IgE receptor. Attenuates phosphatidylinositol 3-kinase activity by interaction with its regulatory subunit (By similarity). May be involved in regulation of cell adhesion; promotes the interaction between TTK2B and PDCD6IP. May be involved in the regulation of cellular stress response via the MAPK pathways through its interaction with MAP3K4. Is involved in modulation of tumor necrosis factor mediated apoptosis. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. Has an essential role in the stimulation of B cell activation (PubMed:29636373).SUBUNIT Can self-associate and form homotetramers. Interacts with CD2, F-actin capping protein, PIK3R3, GRB2, EGFR, MET, BLNK, MAP3K4, PDCD6IP, SPRY2, ARHGAP17, ARHGAP27, MAGI2, CRK, BCAR1, SOS1, ASAP1, ARAP3, HIP1R, SYNJ2, INPP5D and STAP1. Interacts with CBL and CBLB, but does not interact with CBLC. Two molecules of SH3KBP1 seem to bind through their respective SH3 1 domain to one molecule of CBLB. The interaction with CBL or CBLB and EGFR is increased upon EGF stimulation. The interaction with CBL is attenuated by PDCD6IP. Interacts through its proline-rich region with the SH3 domain of endophilins SH3GL1, SH3GL2 and SH3GL3. The SH3KBP1-endophilin complex seems to associate with a complex containing the phosphorylated receptor (EGFR or MET) and phosphorylated CBL. Probably associates with ASAP1 and phosphorylated EGFR. Probably part of a complex consisting of at least SH3KBP1, ASAP1 and ARAP3. Interacts with focal adhesion kinases PTK2/FAK1 AND PTK2B/PYK2, probably as a dimer. Interacts with DAB2 and probably associates with chathrin through its interaction with DAB2. Part of a complex consisting of SH3KBP1, DAB2, and clathrin heavy chain. DAB2 and clathrin dissociate from SH3KBP1 following growth factor treatment, enabling interaction with CBL. Interacts with DDN and probably associates with MAGI2 through its interaction with DDN. Interacts with the SH3 domains of SRC tyrosine-protein kinases SRC, LCK, LYN, FGR, FYN and HCK. Interacts with TRADD, BIRC2, TRAF1, TRAF2 and TNFR1, and the association with a TNFR1-associated complex upon stimulation with TNF-alpha seems to be mediated by SRC. Interacts (via SH3 domains) with SHKBP1 (via PXXXPR motifs) (By similarity). Interaction with CBL is abolished in the presence of SHKBP1 (By similarity). Interacts (via SH3 domains) with ZFP36 (via extreme C-terminal region) (PubMed:20221403). Interacts with MAP3K4; this interaction enhances the association with ZFP36 (PubMed:20221403).TISSUE SPECIFICITY Ubiquitously expressed. Also expressed in some cancer cell lines.PTM Monoubiquitinated by CBL and CBLB after EGF stimulation; probably on its C-terminus. UniProt Q96B97 1 EQUAL 665 EQUAL Reactome Database ID Release 78 182957 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=182957 Reactome R-HSA-182957 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-182957.2 4 Reactome Database ID Release 78 8875475 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=8875475 Reactome R-HSA-8875475 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-8875475.1 1 Converted from EntitySet in Reactome SH3GLs endophilins Reactome DB_ID: 8867746 SH3GL2 dimer Reactome DB_ID: 8867741 SH3GL2 Endophilin Reactome DB_ID: 182958 UniProt:Q99962 SH3GL2 SH3GL2 CNSA2 SH3D2A FUNCTION Implicated in synaptic vesicle endocytosis. May recruit other proteins to membranes with high curvature. Required for BDNF-dependent dendrite outgrowth. Cooperates with SH3GL2 to mediate BDNF-NTRK2 early endocytic trafficking and signaling from early endosomes.SUBUNIT Monomer; in cytoplasm. Homodimer; when associated with membranes (By similarity). Interacts with OPHN1 (By similarity). Interacts with SYNJ1 (PubMed:10542231). Interacts with DNM1 (By similarity). Interacts with MAP4K3; the interaction appears to regulate MAP4K3-mediated JNK activation (By similarity). Interacts with PDCD6IP (PubMed:17350572). Interacts with ATXN2 (PubMed:18602463). Interacts with ADAM9 and ADAM15 cytoplasmic tails (PubMed:10531379). Interacts with BIN2 (PubMed:23285027). Interacts with TMEM108 (By similarity). Interacts with ADGRB2 (PubMed:28891236).TISSUE SPECIFICITY Brain, mostly in frontal cortex. Expressed at high level in fetal cerebellum.DOMAIN An N-terminal amphipathic helix, the BAR domain and a second amphipathic helix inserted into helix 1 of the BAR domain (N-BAR domain) induce membrane curvature and bind curved membranes. The BAR domain dimer forms a rigid crescent shaped bundle of helices with the pair of second amphipathic helices protruding towards the membrane-binding surface.MISCELLANEOUS HeLa cells expressing the N-BAR domain of SH3GL2 show tubulation of the plasma membrane. The N-BAR domain binds liposomes and induces formation of tubules from liposomes. The N-terminal amphipathic helix is required for liposome binding. The second amphipathic helix enhances liposome tubulation.SIMILARITY Belongs to the endophilin family. UniProt Q99962 1 EQUAL 352 EQUAL Reactome Database ID Release 78 182958 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=182958 Reactome R-HSA-182958 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-182958.1 2 Reactome Database ID Release 78 8867741 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=8867741 Reactome R-HSA-8867741 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-8867741.2 SH3GL1 dimer Reactome DB_ID: 8867743 SH3GL1 Endophilin-A2 SH3G1_HUMAN Reactome DB_ID: 8867732 UniProt:Q99961 SH3GL1 SH3GL1 CNSA1 SH3D2B FUNCTION Implicated in endocytosis. May recruit other proteins to membranes with high curvature (By similarity).SUBUNIT Interacts with ARC (By similarity). Interacts with SYNJ1 and DNM1. Interacts with PDCD6IP. Interacts with BIN2.TISSUE SPECIFICITY Ubiquitous. Higher expression in pancreas, placenta, prostate, testis and uterus.DOMAIN An N-terminal amphipathic helix, the BAR domain and a second amphipathic helix inserted into helix 1 of the BAR domain (N-BAR domain) induce membrane curvature and bind curved membranes.DISEASE In some cases of acute leukemia, a translocation results in the formation of a KMT2A/MLL1-EEN fusion gene.SIMILARITY Belongs to the endophilin family. UniProt Q99961 1 EQUAL 368 EQUAL Reactome Database ID Release 78 8867732 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=8867732 Reactome R-HSA-8867732 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-8867732.2 2 Reactome Database ID Release 78 8867743 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=8867743 Reactome R-HSA-8867743 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-8867743.2 SH3GL3 dimer Reactome DB_ID: 8867739 SH3GL3 Endophilin-A3 SH3G3_HUMAN Reactome DB_ID: 8867734 UniProt:Q99963 SH3GL3 SH3GL3 CNSA3 SH3D2C FUNCTION Implicated in endocytosis. May recruit other proteins to membranes with high curvature (By similarity).SUBUNIT Interacts with ARC (By similarity). Interacts with DNM1, SGIP1 and SYNJ1. Interacts with the huntingtin exon 1 protein (HDEX1P) containing a glutamine repeat in the pathological range and promotes formation of insoluble polyglutamine-containing aggregates in vivo. Interacts with DYDC1. Interacts with FASLG. Interacts with ATXN2. Interacts with BIN2.TISSUE SPECIFICITY Brain and testis.DOMAIN An N-terminal amphipathic helix, the BAR domain and a second amphipathic helix inserted into helix 1 of the BAR domain (N-BAR domain) induce membrane curvature and bind curved membranes.SIMILARITY Belongs to the endophilin family. UniProt Q99963 1 EQUAL 347 EQUAL Reactome Database ID Release 78 8867734 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=8867734 Reactome R-HSA-8867734 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-8867734.2 2 Reactome Database ID Release 78 8867739 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=8867739 Reactome R-HSA-8867739 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-8867739.2 Reactome Database ID Release 78 8867746 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=8867746 Reactome R-HSA-8867746 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-8867746.2 1 Reactome Database ID Release 78 8875480 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=8875480 Reactome R-HSA-8875480 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-8875480.1 1 2 2 Reactome Database ID Release 78 182946 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=182946 Reactome R-HSA-182946 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-182946.3 EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP:CIN85 Reactome DB_ID: 8951489 2 1 Reactome Database ID Release 78 8951489 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=8951489 Reactome R-HSA-8951489 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-8951489.3 Reactome Database ID Release 78 183002 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=183002 Reactome R-HSA-183002 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-183002.3 16407834 Pubmed 2006 Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule betaPix Schmidt, MH Husnjak, K Szymkiewicz, I Haglund, K Dikic, I Oncogene 25:3071-8 LEFT-TO-RIGHT CIN85 dissociates from EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP:CIN85 High concentrations of active CDC42 (bound to GTP) and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 (SH3KBP1) from the CBL complex. This competitive mechanism could block the CIN85-imposed clustering phenomenon on CBL that is required for tighter binding (Schmidt et al. 2006). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Jassal, Bijay, 2016-12-07 EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP EGF:Phospho-EGFR (Y1045) dimer:CBL:Cool/Pix:CDC42-GTP Reactome DB_ID: 182932 2 1 Reactome Database ID Release 78 182932 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=182932 Reactome R-HSA-182932 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-182932.2 Reactome Database ID Release 78 8951490 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=8951490 Reactome R-HSA-8951490 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-8951490.2 LEFT-TO-RIGHT 6.3.2.19 CBL escapes CDC42-mediated inhibition by down-regulating the adaptor molecule Beta-Pix Beta-Pix (Cool-1) associates with CBL, which appears to be a critical step in CDC42-mediated inhibition of EGFR ubiquitylation and downregulation. The SH3 domain of Beta-Pix specifically interacts with a proline-arginine motif (PxxxPR) present within CBL, which mediates ubiquitylation and subsequent degradation of Beta-Pix. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 2 Ub-Beta-Pix:CDC42:GTP Cool/Pix Ubiquitinated:CDC42-GTP Reactome DB_ID: 182915 1 1 1 Reactome Database ID Release 78 182915 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=182915 Reactome R-HSA-182915 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-182915.1 2 ACTIVATION activeUnit: #Protein46 Reactome Database ID Release 78 182995 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=182995 Reactome Database ID Release 78 183084 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=183084 Reactome R-HSA-183084 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-183084.2 LEFT-TO-RIGHT Assembly of EGFR complex in clathrin-coated vesicles CBL-CIN85-Endophilin complex mediates ligand-induced down-regulation of the EGF receptor. The BAR domain of endophilin induces membrane curvature. The three SH3 domains of CIN85 bind to atypical proline-arginine motifs (PxxxPR) present in the carboxyl termini of CBL and CBL-b. In this way, CIN85 clusters CBL molecules, which is crucial for efficient EGFR endocytosis and degradation (Soubeyran et al. 2002). Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Reactome Database ID Release 78 182994 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=182994 Reactome R-HSA-182994 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-182994.2 11894095 Pubmed 2002 Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors Soubeyran, P Kowanetz, K Szymkiewicz, I Langdon, WY Dikic, I Nature 416:183-7 LEFT-TO-RIGHT EGFR non-clathrin mediated endocytosis At higher concentrations of ligand, a substantial fraction of the receptor (>50%) is endocytosed through a clathrin independent, lipid-raft-dependent route as the receptor becomes Y1045 phosphorylated and ubiquitnated. Eps15 and Epsin are found in caveolae. Eps15 and Epsin are immunoprecipated with the EGF receptor. Non-clathrin internalization of ubiquitinated EGFR depends on its interaction with proteins harbouring the UIM Ub-interacting motif, as shown through the ablation of three Ub-interacting motif-containing proteins, Eps15, Eps15R and Epsin. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Eps15R EPS15L1 Reactome DB_ID: 182937 UniProt:Q9UBC2 EPS15L1 EPS15L1 EPS15R FUNCTION Seems to be a constitutive component of clathrin-coated pits that is required for receptor-mediated endocytosis. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR seems to require association with DAB2.SUBUNIT Interacts with EPS15, AGFG1/HRB and AGFG2/HRBL. Associates with the clathrin-associated adapter protein complex 2 (AP-2) (By similarity). Interacts with FCHO1. Interacts with FCHO2. Interacts (via EH domains) with DAB2. Interacts with UBQLN1 (via ubiquitin-like domain). Interacts with CAVIN3 (via leucine-zipper domain) (PubMed:19262564). Interacts with REPS2 (PubMed:10393179).PTM Phosphorylated on tyrosine residues by EGFR.CAUTION Studies in clathrin-mediated endocytosis used a siRNA mixture of EPS15 and EPS15L1. UniProt Q9UBC2 2 EQUAL 864 EQUAL Reactome Database ID Release 78 182937 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=182937 Reactome R-HSA-182937 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-182937.1 EPN1 Epsin Reactome DB_ID: 182952 UniProt:Q9Y6I3 EPN1 EPN1 FUNCTION Binds to membranes enriched in phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Modifies membrane curvature and facilitates the formation of clathrin-coated invaginations (By similarity). Regulates receptor-mediated endocytosis (PubMed:10557078, PubMed:10393179).SUBUNIT Monomer. Binds clathrin, ZBTB16/ZNF145 and ITSN1 (By similarity). Binds ubiquitinated proteins (By similarity). Binds AP2A1 and AP2A2. Interacts with RALBP1 in a complex also containing NUMB and TFAP2A during interphase and mitosis. Interacts with AP2B1. Interacts with UBQLN2. Interacts with REPS2; the interaction is direct (PubMed:10557078, PubMed:10764745, PubMed:10393179). Interacts with EPS15; the interaction is direct (PubMed:10764745, PubMed:10393179).DOMAIN The NPF repeat domain is involved in EPS15 binding.DOMAIN The DPW repeat domain is involved in AP2A2 and clathrin binding.DOMAIN The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction with the AP-2 complex subunit AP2B1.PTM Phosphorylated on serine and/or threonine residues in mitotic cells. Phosphorylation reduces interaction with REPS2, AP-2 and the membrane fraction. Depolarization of synaptosomes results in dephosphorylation.PTM Ubiquitinated.SIMILARITY Belongs to the epsin family. UniProt Q9Y6I3 1 EQUAL 576 EQUAL Reactome Database ID Release 78 182952 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=182952 Reactome R-HSA-182952 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-182952.1 EPS15:HGS:STAM Reactome DB_ID: 182947 Converted from EntitySet in Reactome STAM Reactome DB_ID: 182929 STAM STAM1 Signal transducing adapter molecule 1 Reactome DB_ID: 182925 UniProt:Q92783 STAM STAM STAM1 FUNCTION Involved in intracellular signal transduction mediated by cytokines and growth factors. Upon IL-2 and GM-CSL stimulation, it plays a role in signaling leading to DNA synthesis and MYC induction. May also play a role in T-cell development. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with HGS (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes.SUBUNIT Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS (PubMed:11687594, PubMed:9407053, PubMed:19278655). Probably part of a complex at least composed of HSG, STAM and EPS15 (PubMed:12551915). Found in a complex with HGS and E3 ligase ITCH and DTX3L (PubMed:24790097). Interacts with E3 ligase DTX3L; the interaction brings together STAM and HSG, promotes their recruitment to early endosomes and decreases STAM and HGS ubiquitination by ITCH (PubMed:24790097). Interacts with STAMBP/AMSH (PubMed:10383417). Interacts with PDGFRB (PubMed:20494825). Interacts with LITAF; the interaction is direct (PubMed:23166352). Identified in a complex with HGS and LITAF (PubMed:23166352).TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The VHS domain mediates high-avidity binding to Lys63-linked and Lys48-linked polyubiquitinated cargos.PTM Phosphorylated on Tyr-198. Phosphorylated in response to IL2, IL3, IL4, IL7, CSF2/GM-CSF, EGF and PDGFB. Phosphorylated by activated PDGFRB.PTM Ubiquitinated by ITCH.SIMILARITY Belongs to the STAM family. UniProt Q92783 2 EQUAL 540 EQUAL Reactome Database ID Release 78 182925 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=182925 Reactome R-HSA-182925 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-182925.1 STAM2 Signal transducing adapter molecule 2 Reactome DB_ID: 182965 UniProt:O75886 STAM2 STAM2 HBP FUNCTION Involved in intracellular signal transduction mediated by cytokines and growth factors. Upon IL-2 and GM-CSL stimulation, it plays a role in signaling leading to DNA synthesis and MYC induction. May also play a role in T-cell development. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with HGS (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes (By similarity).SUBUNIT Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS. Part of a complex at least composed of HSG, STAM2 and EPS15. Interacts with JAK2 and JAK3. Interacts with ubiquitinated proteins and the deubiquitinating enzyme USP8/UBPY (By similarity). Interacts (via the via the PxVxL motif) with CBX5; the interaction is direct. Interacts with VPS37C. Interacts with ubiquitin; the interaction is direct. Interacts (via UIM domain) with UBQLN1 (via ubiquitin-like domain) (By similarity).TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The VHS and UIM domains mediate the interaction with ubiquitinated proteins.DOMAIN The SH3 domain mediates the interaction with USP8.DOMAIN Contains one Pro-Xaa-Val-Xaa-Leu (PxVxL) motif, which is required for interaction with chromoshadow domains. This motif requires additional residues -7, -6, +4 and +5 of the central Val which contact the chromoshadow domain.PTM Phosphorylated in response to IL-2, GM-CSF, EGF and PDGF.SIMILARITY Belongs to the STAM family. UniProt O75886 1 EQUAL 525 EQUAL Reactome Database ID Release 78 182965 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=182965 Reactome R-HSA-182965 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-182965.1 Reactome Database ID Release 78 182929 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=182929 Reactome R-HSA-182929 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-182929.2 1 EPS15 Eps15 Reactome DB_ID: 182920 UniProt:P42566 EPS15 EPS15 AF1P FUNCTION Involved in cell growth regulation. May be involved in the regulation of mitogenic signals and control of cell proliferation. Involved in the internalization of ligand-inducible receptors of the receptor tyrosine kinase (RTK) type, in particular EGFR. Plays a role in the assembly of clathrin-coated pits (CCPs). Acts as a clathrin adapter required for post-Golgi trafficking. Seems to be involved in CCPs maturation including invagination or budding. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR seems to require association with DAB2.SUBUNIT Interacts with SGIP1 (PubMed:26822536). Interacts with HGS; the interaction bridges the interaction of STAM or STAM2 with EPS15. Isoform 2 interacts with HGS and AP2A2. Part of a complex at least composed of EPS15, HGS, and either STAM or STAM2. Binds AP2A2. Interacts with AP2B1; clathrin competes with EPS15. Binds STON2. Interacts (via its SH3-binding sites) with CRK. Interacts with SH3BP4/TTP. Interacts with ERBB2. Interacts with FCHO1. Interacts with FCHO2. Interacts (via EH domains) with DAB2. Interacts (via UIM repeats) with CORO7 (when ubiquitinated at 'Lys-472'). Interacts (via UIM domains) with UBQLN1 (via ubiquitin-like domain) and can interact with both the ubiquitinated and the non-ubiquitinated forms of UBQLN1. Interacts with UBQLN2 (By similarity) (PubMed:10757979, PubMed:11062555, PubMed:12551915, PubMed:16159959, PubMed:16314522, PubMed:16325581, PubMed:16903783, PubMed:18199683, PubMed:18200045, PubMed:18362181, PubMed:20448150, PubMed:21762413, PubMed:22484487, PubMed:22648170, PubMed:24768539, PubMed:8662907, PubMed:9721102, PubMed:9723620). Interacts with REPS2; the interaction is direct (PubMed:10393179). Interacts with EPN1; the interaction is direct (PubMed:9723620, PubMed:10393179).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein A36.TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The EH domain interacts with Asn-Pro-Phe (NPF) motifs of target proteins.DOMAIN The UIM (ubiquitin-interacting motif) repeats specifically bind 'Lys-33'-linked ubiquitin.PTM Phosphorylation on Tyr-849 is involved in the internalization of EGFR. Not required for membrane translocation after EGF treatment or for targeting to coated pits, but essential for a subsequent step in EGFR endocytosis (By similarity). Phosphorylated on serine upon DNA damage, probably by ATM or ATR.PTM Ubiquitinated.DISEASE A chromosomal aberration involving EPS15 is found in acute leukemias. Translocation t(1;11)(p32;q23) with KMT2A/MLL1. The result is a rogue activator protein.CAUTION Studies in clathrin-mediated endocytosis of ITGB1 and TFR used a siRNA mixture of EPS15 and EPS15L1, and a Dab2 mutant with impaired binding to EH domain-containing proteins EPS15 and ITSN1 suggesting a partially overlapping role of the EH domain-containing proteins. UniProt P42566 1 EQUAL 896 EQUAL Reactome Database ID Release 78 182920 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=182920 Reactome R-HSA-182920 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-182920.2 1 HGS Hepatocyte growth factor-regulated tyrosine kinase substrate HRS Reactome DB_ID: 182954 UniProt:O14964 HGS HGS HRS FUNCTION Involved in intracellular signal transduction mediated by cytokines and growth factors. When associated with STAM, it suppresses DNA signaling upon stimulation by IL-2 and GM-CSF. Could be a direct effector of PI3-kinase in vesicular pathway via early endosomes and may regulate trafficking to early and late endosomes by recruiting clathrin. May concentrate ubiquitinated receptors within clathrin-coated regions. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with STAM (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes. May contribute to the efficient recruitment of SMADs to the activin receptor complex. Involved in receptor recycling via its association with the CART complex, a multiprotein complex required for efficient transferrin receptor recycling but not for EGFR degradation.SUBUNIT Component of the ESCRT-0 complex composed of STAM or STAM2 and HGS. Part of a complex at least composed of HSG, STAM2 (or probably STAM) and EPS15 (PubMed:12551915). Interacts with STAM (PubMed:9407053). Interacts with STAM2 (By similarity). Interacts with EPS15; the interaction is direct, calcium-dependent and inhibited by SNAP25 (By similarity). Identified in a complex with STAM and LITAF (PubMed:23166352). Found in a complex with STAM and E3 ligase ITCH and DTX3L (PubMed:24790097). Interacts with E3 ligase DTX3L; the interaction brings together STAM and HSG, promotes their recruitment to early endosomes and decreases STAM and HGS ubiquitination by ITCH (PubMed:24790097). Interacts with NF2; the interaction is direct (PubMed:10861283). Interacts with ubiquitin; the interaction is direct (By similarity). Interacts with VPS37C (PubMed:15509564). Interacts with SMAD1, SMAD2 and SMAD3 (By similarity). Interacts with TSG101; the interaction mediates the association with the ESCRT-I complex (PubMed:21070952). Interacts with SNAP25; the interaction is direct and decreases with addition of increasing concentrations of free calcium (By similarity). Interacts with SNX1; the interaction is direct (By similarity). Component of a 550 kDa membrane complex at least composed of HGS and SNX1 but excluding EGFR (By similarity). Interacts with TRAK1 (PubMed:18675823). Interacts with TRAK2 (By similarity). Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 (PubMed:15772161). Interacts (via UIM domain) with UBQLN1 (via ubiquitin-like domain) (By similarity). Interacts with ARRDC3 (PubMed:23208550). Identified in a complex containing at least ARRDC4, AVPR2 and HGS (PubMed:23236378). Interacts with LAPTM4B; promotes HGS ubiquitination (PubMed:25588945).TISSUE SPECIFICITY Ubiquitous expression in adult and fetal tissues with higher expression in testis and peripheral blood leukocytes.DOMAIN Has a double-sided UIM that can bind 2 ubiquitin molecules, one on each side of the helix.DOMAIN The FYVE-type zinc finger domain mediates interactions with phosphatidylinositol 3-phosphate in membranes of early endosomes and penetrates bilayers. The FYVE domain insertion into PtdIns(3)P-enriched membranes is substantially increased in acidic conditions.PTM Phosphorylated on Tyr-334. A minor site of phosphorylation on Tyr-329 is detected (By similarity). Phosphorylation occurs in response to EGF, IL-2, GM-CSF and HGF.PTM Ubiquitinated (PubMed:25588945). Ubiquitinated by ITCH (PubMed:14602072, PubMed:24790097). UniProt O14964 1 EQUAL 777 EQUAL Reactome Database ID Release 78 182954 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=182954 Reactome R-HSA-182954 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-182954.3 1 Reactome Database ID Release 78 182947 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=182947 Reactome R-HSA-182947 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-182947.2 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15L1:Eps15 EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15 complex Reactome DB_ID: 182961 1 1 1 1 1 Reactome Database ID Release 78 182961 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=182961 Reactome R-HSA-182961 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-182961.5 Reactome Database ID Release 78 183072 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=183072 Reactome R-HSA-183072 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-183072.2 12072436 Pubmed 2002 A ubiquitin-interacting motif (UIM) is essential for Eps15 and Eps15R ubiquitination Klapisz, E Sorokina, I Lemeer, S Pijnenburg, M Verkleij, AJ van Bergen en Henegouwen, PM J Biol Chem 277:30746-53 15701692 Pubmed 2005 Clathrin-independent endocytosis of ubiquitinated cargos Sigismund, S Woelk, T Puri, C Maspero, E Tacchetti, C Transidico, P Di Fiore, PP Polo, S Proc Natl Acad Sci U S A 102:2760-5 LEFT-TO-RIGHT 6.3.2.19 CBL ubiquitinates Sprouty Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL. The CBL-mediated ubiquitination of Sprouty targets the protein for degradation by the 26S proteasome. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 EGF:Phospho-EGFR dimer:CBL:Phospho-Sprouty EGF-like ligands:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2 Reactome DB_ID: 182935 1 1 Reactome Database ID Release 78 182935 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=182935 Reactome R-HSA-182935 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-182935.2 ACTIVATION Reactome Database ID Release 78 1482936 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=1482936 Reactome Database ID Release 78 183051 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=183051 Reactome R-HSA-183051 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-183051.1 LEFT-TO-RIGHT 6.3.2.19 CBL-mediated ubiquitination of CIN85 The adaptor protein CIN85 is monoubiquitinated by CBL after EGF stimulation. Monoubiquitination is thought to regulate receptor internalization and endosomal sorting. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:Ub-CIN85:Endophilin:Epsin:Eps15L1:Eps15 EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85 ubiquitinated:Endophilin:Epsin:Eps15R:Eps15 complex Reactome DB_ID: 182936 2 2 1 2 Ub-CIN85:endophilin Ub-SH3KBP1 tetramer:SH3GLs Reactome DB_ID: 8934537 Ub-CIN85 Ub-SH3KBP1 tetramer Reactome DB_ID: 8934535 Ub-SH3KBP1 monoUb-CIN85 CIN85 ubiquitinated Reactome DB_ID: 182926 ubiquitinylated lysine MOD MOD:01148 1 EQUAL 665 EQUAL Reactome Database ID Release 78 182926 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=182926 Reactome R-HSA-182926 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-182926.1 4 Reactome Database ID Release 78 8934535 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=8934535 Reactome R-HSA-8934535 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-8934535.1 1 1 Reactome Database ID Release 78 8934537 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=8934537 Reactome R-HSA-8934537 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-8934537.1 1 1 1 Reactome Database ID Release 78 182936 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=182936 Reactome R-HSA-182936 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-182936.4 ACTIVATION activeUnit: #Protein46 Reactome Database ID Release 78 183057 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=183057 Reactome Database ID Release 78 182986 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=182986 Reactome R-HSA-182986 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-182986.2 12218189 Pubmed 2002 Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors Haglund, K Shimokawa, N Szymkiewicz, I Dikic, I Proc Natl Acad Sci U S A 99:12191-6 LEFT-TO-RIGHT Sprouty sequesters CBL away from active EGFR Sprouty can constitutively interact with two SH3 domains of CIN85 whereas the third SH3 domain of CIN85 can still associate with CBL on cell activation with EGF. This allows Sprouty to block CIN85-mediated clustering of CBL molecules, stablization of CBL-EGFR interactions and efficient ubiquitination and down-regulation of EGFR. Authored: Castagnoli, L, 2006-10-10 13:09:34 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Edited: Orlic-Milacic, Marija, 2011-08-25 Converted from EntitySet in Reactome SPRY1/2 Sprouty Reactome DB_ID: 182912 SPRY1 Sprouty 1 Reactome DB_ID: 182944 1 EQUAL 319 EQUAL Reactome Database ID Release 78 182944 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=182944 Reactome R-HSA-182944 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-182944.1 SPRY2 Sprouty 2 Reactome DB_ID: 182924 1 EQUAL 315 EQUAL Reactome Database ID Release 78 182924 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=182924 Reactome R-HSA-182924 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-182924.1 Reactome Database ID Release 78 182912 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=182912 Reactome R-HSA-182912 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-182912.1 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:CIN85:SPRY1/2:Endophilin:Epsin:Eps15L1:EPS15 EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85-Sprouty:Endophilin:Epsin:Eps15R:Eps15 complex Reactome DB_ID: 182931 1 1 Reactome Database ID Release 78 182931 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=182931 Reactome R-HSA-182931 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-182931.5 Reactome Database ID Release 78 182990 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=182990 Reactome R-HSA-182990 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-182990.2 15962011 Pubmed 2005 Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation Haglund, K Schmidt, MH Wong, ES Guy, GR Dikic, I EMBO Rep 6:635-41 LEFT-TO-RIGHT 3.1.3.48 PTPN12 dephosphorylates EGFR at Y1148 (Y1172) PTPN12 protein tyrosine phosphatase dephosphorylates activated EGFR at tyrosine residue Y1148 (Y1148 corresponds to Y1172 in the nascent EGFR sequence which includes the 24 amino acid long signal peptide at the N-terminus). PTPN12-mediated dephosphorylation of activated EGFR inhibits SHC1 recruitment to the p-Y1148 docking site, thus attenuating downstream RAS activation (Sun et al. 2011). The recruitment of SHC1 to p-Y1148 of EGFR is mediated by the N-terminal phosphotyrosine interaction domain (PID) of SHC1 (Batzer et al. 1995, Songyang et al. 1995). Authored: Orlic-Milacic, Marija, 2016-03-10 Reviewed: Ayoub, Emily, 2016-08-04 Reviewed: Tremblay, Michel, 2016-08-04 Edited: Orlic-Milacic, Marija, 2016-08-09 EGF:p-6Y-EGFR dimer EGF:Phospho-EGFR (Y992, Y1068, Y1086, Y1148, Y1173) dimer Reactome DB_ID: 179882 EGF:Phospho-EGFR Reactome DB_ID: 179860 1 1 Reactome Database ID Release 78 179860 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=179860 Reactome R-HSA-179860 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-179860.1 2 Reactome Database ID Release 78 179882 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=179882 Reactome R-HSA-179882 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-179882.2 2 EGF:p-EGFR dimer dephosphorylated at Y1148 (Y1172) Reactome DB_ID: 8864028 EGF:p-Y992,Y1045,Y1068,Y1086,Y1173-EGFR Reactome DB_ID: 8864018 p-Y992,Y1045,Y1068,Y1086,Y1173-EGFR Reactome DB_ID: 8864019 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 8864019 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=8864019 Reactome R-HSA-8864019 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-8864019.1 1 1 Reactome Database ID Release 78 8864018 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=8864018 Reactome R-HSA-8864018 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-8864018.1 2 Reactome Database ID Release 78 8864028 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=8864028 Reactome R-HSA-8864028 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-8864028.1 2 ACTIVATION activeUnit: #Protein89 PTPN12 PTP-PEST Tyrosine-protein phosphatase non-receptor type 12 PTN12_HUMAN Reactome DB_ID: 432933 UniProt:Q05209 PTPN12 PTPN12 FUNCTION Dephosphorylates a range of proteins, and thereby regulates cellular signaling cascades (PubMed:18559503). Dephosphorylates cellular tyrosine kinases, such as ERBB2 and PTK2B/PYK2, and thereby regulates signaling via ERBB2 and PTK2B/PYK2 (PubMed:17329398, PubMed:27134172). Selectively dephosphorylates ERBB2 phosphorylated at 'Tyr-1112', 'Tyr-1196', and/or 'Tyr-1248' (PubMed:27134172).SUBUNIT Interacts with TGFB1I1 (By similarity). Interacts with PSTPIP1 (PubMed:9857189). Interacts with PTK2B/PYK2 (PubMed:17329398). Interacts with LPXN (By similarity). Interacts with SORBS2; this interaction greatly enhances WASF1 dephosphorylation and might mediate partial translocation to focal adhesion sites (PubMed:18559503).PTM Phosphorylated by STK24/MST3 and this results in inhibition of its activity.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class 4 subfamily. UniProt Q05209 1 EQUAL 780 EQUAL Reactome Database ID Release 78 432933 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=432933 Reactome R-HSA-432933 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-432933.2 GENE ONTOLOGY GO:0004725 Reactome Database ID Release 78 8863802 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=8863802 Reactome Database ID Release 78 8864029 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=8864029 Reactome R-HSA-8864029 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-8864029.3 21376233 Pubmed 2011 Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase Sun, Tingting Aceto, Nicola Meerbrey, Kristen L Kessler, Jessica D Zhou, Chunshui Migliaccio, Ilenia Nguyen, Don X Pavlova, Natalya N Botero, Maria Huang, Jian Bernardi, Ronald J Schmitt, Earlene Hu, Guang Li, Mamie Z Dephoure, Noah Gygi, SP Rao, Mitchell Creighton, Chad J Hilsenbeck, Susan G Shaw, Chad A Muzny, Donna Gibbs, Richard A Wheeler, David A Osborne, C Kent Schiff, Rachel Bentires-Alj, Mohamed Elledge, Stephen J Westbrook, Thomas F Cell 144:703-18 GENE ONTOLOGY GO:1901185 LEFT-TO-RIGHT EGFR binds EPS15, EPN1, EPS15L1 EH-containing proteins such as EPS15, EPN1 and EPS15L1 are required for the endocytosis of ligand-activated EGFR (Confalonieri et al, 2000; Huang et al, 2004; reviewed in van Bergen en Henegouwen, 2009). EPS15 and EPN1 bind components of the clathrin coated pit through DPF motifs and likely bind to EGFR through the ubiquitin interacting motifs (UIMs). In this way EH proteins may help cluster activated EGFR into nascent clathrin-coated pits (Kazazic et al, 2009; Benmerah et al, 2000; reviewed in van Bergen en Henegouwen, 2009). Note, however, that EH-containing proteins are also involved in the clathrin-independent endocytosis of EGFR (Sigismund et al, 2005) Authored: Rothfels, Karen, 2016-04-05 Reviewed: Chen, Guang-Chao, 2016-05-06 Edited: Rothfels, Karen, 2016-04-05 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:EPN1:EPS15L1:EPS15:HGS:STAM Reactome DB_ID: 8867034 1 1 1 1 1 Reactome Database ID Release 78 8867034 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=8867034 Reactome R-HSA-8867034 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-8867034.3 Reactome Database ID Release 78 8867044 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=8867044 Reactome R-HSA-8867044 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-8867044.2 10953014 Pubmed 2000 Tyrosine phosphorylation of Eps15 is required for ligand-regulated, but not constitutive, endocytosis Confalonieri, Stefano Salcini, Anna Elisabetta Puri, Claudia Tacchetti, Carlo Di Fiore, Pier Paolo J. Cell Biol. 150:905-12 14985334 Pubmed 2004 Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference Huang, Fangtian Khvorova, A Marshall, William Sorkin, Alexander J. Biol. Chem. 279:16657-61 10652316 Pubmed 2000 Mapping of Eps15 domains involved in its targeting to clathrin-coated pits Benmerah, Alexandre Poupon, Viviane Cerf-Bensussan, Nadine Dautry-Varsat, Alice J. Biol. Chem. 275:3288-95 19814798 Pubmed 2009 Eps15: a multifunctional adaptor protein regulating intracellular trafficking van Bergen En Henegouwen, Paul Mp Cell Commun. Signal 7:24 19054389 Pubmed 2009 Epsin 1 is involved in recruitment of ubiquitinated EGF receptors into clathrin-coated pits Kazazic, Maja Bertelsen, Vibeke Pedersen, Ketil Winther Vuong, Tram Thu Grandal, Michael Vibo Rødland, Marianne Skeie Traub, Linton M Stang, Espen Madshus, Inger Helene Traffic 10:235-45 LEFT-TO-RIGHT 2.7.10 EGFR phosphorylates EPS15 EPS15 is phosphorylated at Y849 by activated EGFR (Confalonieri et al, 2000). While the roles of phosphorylation and ubiquitination in EGFR endocytosis are unclear, emerging evidence suggests that EPS15 phosphorylation may target the activated EGFR complex for endocytosis through a clathrin-mediated route, while dephosphorylation at Y849 may direct the receptor complex into a clathrin-independent route (Confalonieri et al, 2002; de Melker et al, 2004; Li et al, 2015; reviewed in van Bergen en Henegouwen, 2009). Authored: Rothfels, Karen, 2016-04-05 Reviewed: Chen, Guang-Chao, 2016-05-06 Edited: Rothfels, Karen, 2016-04-05 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:EPN1:EPS15L1:p-EPS15:HGS:STAM Reactome DB_ID: 8867035 1 1 1 p-Eps15:HGS:STAM Reactome DB_ID: 8867032 1 1 Eps15 p-Y850 EPS15 Reactome DB_ID: 8867028 850 EQUAL 1 EQUAL 896 EQUAL Reactome Database ID Release 78 8867028 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=8867028 Reactome R-HSA-8867028 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-8867028.2 1 Reactome Database ID Release 78 8867032 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=8867032 Reactome R-HSA-8867032 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-8867032.2 1 1 Reactome Database ID Release 78 8867035 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=8867035 Reactome R-HSA-8867035 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-8867035.3 ACTIVATION activeUnit: #Protein7 Reactome Database ID Release 78 8867039 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=8867039 Reactome Database ID Release 78 8867041 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=8867041 Reactome R-HSA-8867041 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-8867041.2 15465819 Pubmed 2004 Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment de Melker, Annemieke A van der Horst, Gerda Borst, Jannie J. Biol. Chem. 279:55465-73 25263444 Pubmed 2015 Protein tyrosine phosphatase PTPN3 inhibits lung cancer cell proliferation and migration by promoting EGFR endocytic degradation Li, M-Y Lai, P-L Chou, Y-T Chi, A-P Mi, Y-Z Khoo, K-H Chang, G-D Wu, C-W Meng, T-C Chen, Guang-Chao Oncogene 34:3791-803 LEFT-TO-RIGHT 3.1.3.48 PTPN3 dephosphorylates EPS15 While the roles of EGFR and EPS15 phosphorylation and ubiquitination are not completely clear, recent evidence supports the idea that EGFR-mediated phosphorylation of EPS15 promotes the clustering of the activated receptor into clathrin-coated pits, while the dephosphorylated EPS15 targets EGFR for endocytosis through a caveolin-and lipid raft-dependent route (reviewed in van Bergen en Henegouwen, 2009). Consistent with this, overexpression of the phosphatase PTPN3, which dephosphorylates EPS15 in vitro and in vivo, promotes the internalization of EGFR into caveolin-enriched structures and targets it for lysosomal degradation (Li et al, 2015). Authored: Rothfels, Karen, 2016-04-05 Reviewed: Chen, Guang-Chao, 2016-05-06 Edited: Rothfels, Karen, 2016-04-05 ACTIVATION PTPN3 Tyrosine-protein phosphatase non-receptor type 3 ecNumber3.1.3.48/ecNumber PTN3_HUMAN Reactome DB_ID: 5490317 UniProt:P26045 PTPN3 PTPN3 PTPH1 FUNCTION May act at junctions between the membrane and the cytoskeleton. Possesses tyrosine phosphatase activity.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class subfamily. UniProt P26045 1 EQUAL 913 EQUAL Reactome Database ID Release 78 5490317 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=5490317 Reactome R-HSA-5490317 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-5490317.2 Reactome Database ID Release 78 8867049 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=8867049 Reactome Database ID Release 78 8867047 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=8867047 Reactome R-HSA-8867047 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-8867047.2 Reactome Database ID Release 78 182971 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=182971 Reactome R-HSA-182971 6 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-182971.6 14641021 Pubmed 2003 Mechanisms controlling EGF receptor endocytosis and degradation Dikic, I Biochem Soc Trans 31:1178-81 11283727 Pubmed 2001 Cbl: many adaptations to regulate protein tyrosine kinases Thien, CB Langdon, WY Nat Rev Mol Cell Biol 2:294-307 GENE ONTOLOGY GO:0042059 Reactome Database ID Release 78 177929 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=177929 Reactome R-HSA-177929 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-177929.2 21252999 Pubmed 2011 Feedback regulation of EGFR signalling: decision making by early and delayed loops Avraham, R Yarden, Y Nat Rev Mol Cell Biol 12:104-17 15142631 Pubmed 2004 Review of epidermal growth factor receptor biology Herbst, RS Int J Radiat Oncol Biol Phys 59:21-6 12297041 Pubmed 2002 Ligand-induced, receptor-mediated dimerization and activation of EGF receptor Schlessinger, J Cell 110:669-72 10459005 Pubmed 1999 Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways Carpenter, G J Cell Biol 146:697-702 10404636 Pubmed 1999 EGF receptor Wells, A Int J Biochem Cell Biol 31:637-43 GENE ONTOLOGY GO:0007173 Signaling by FGFR Fibroblast Growth Factor Receptor (FGFR) signaling The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.<br><br>Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.<br><br>This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.<br> Authored: de Bono, B, 2007-01-10 10:27:18 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Reviewed: Gotoh, N, 2011-08-26 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 Signaling by FGFR1 Fibroblast Growth Factor Receptor (FGFR) signaling The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.<br><br>Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.<br><br>This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.<br> Authored: de Bono, B, 2007-01-10 10:27:18 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Reviewed: Gotoh, N, 2011-08-26 Reviewed: Grose, Richard P, 2016-01-25 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 FGFR1 ligand binding and activation The vertebrate fibroblast growth factor receptor 1 (FGFR1) is alternatively spliced generating multiple variants that are differentially expressed during embryo development and in the adult body. The restricted expression patterns of FGFR1 isoforms, together with differential expression and binding of specific ligands, leads to activation of common FGFR1 signal transduction pathways, but may result in distinctively different biological responses as a result of differences in cellular context. FGFR1 isoforms are also present in the nucleus in complex with various fibroblast growth factors where they function to regulate transcription of target genes. <br><br>FGFR is probably activated by NCAM very differently from the way by which it is activated by FGFs, reflecting the different conditions for NCAM-FGFR and FGF-FGFR interactions. The affinity of FGF for FGFR is approximately 10e6 times higher than that of NCAM for FGFR. Moreover, in the brain NCAM is constantly present on the cell surface at a much higher (micromolar) concentration than FGFs, which only appear transiently in the extracellular environment in the nanomolar range. Authored: de Bono, B, 2007-01-10 10:27:18 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Reviewed: Grose, Richard P, 2016-01-06 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 FGFR1b ligand binding and activation This pathway depicts the binding of an experimentally-verified range of ligands to FGFR1b. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. Authored: de Bono, B, 2007-01-10 10:27:18 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 LEFT-TO-RIGHT FGFR1b binds to FGF In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. NCAM and other members of the CAM protein family directly or indirectly modulate this interaction in a variety of neural tissues. The details of this interaction in vivo have not been definitively established at the molecular level, but are thought to play a central role in the regulation of the development of these tissues. Authored: de Bono, B, 2007-01-10 10:27:18 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Converted from EntitySet in Reactome FGFR1b-binding FGFs Reactome DB_ID: 189963 FGF1 Fibroblast growth factor-1 Heparin-binding growth factor 1 FGF1_HUMAN Reactome DB_ID: 189856 UniProt:P05230 FGF1 FGF1 FGFA FUNCTION Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. Acts as a ligand for FGFR1 and integrins. Binds to FGFR1 in the presence of heparin leading to FGFR1 dimerization and activation via sequential autophosphorylation on tyrosine residues which act as docking sites for interacting proteins, leading to the activation of several signaling cascades. Binds to integrin ITGAV:ITGB3. Its binding to integrin, subsequent ternary complex formation with integrin and FGFR1, and the recruitment of PTPN11 to the complex are essential for FGF1 signaling. Induces the phosphorylation and activation of FGFR1, FRS2, MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:18441324, PubMed:20422052). Can induce angiogenesis (PubMed:23469107).SUBUNIT Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Found in a complex with FGFBP1, FGF1 and FGF2. Interacts with FGFBP1. Part of a Cu(2+)-dependent multiprotein aggregate containing FGF1, S100A13 and SYT1. Interacts with SYT1. Interacts with S100A13. Interacts with LRRC59. Interacts with CSNKA, CSNKB and FIBP. While binding with LRRC59, CSNKA and FIBP seem mutually exclusive, CSNKB and FIBP may cooperatively interact with FGF1. Forms a ternary complex with FGFR1 and ITGAV:ITGB3 and induces the recruitment of PTPN11 to the complex (PubMed:20422052).TISSUE SPECIFICITY Predominantly expressed in kidney and brain. Detected at much lower levels in heart and skeletal muscle.PTM In the nucleus, phosphorylated by PKC/PRKCD.SIMILARITY Belongs to the heparin-binding growth factors family. UniProt P05230 16 EQUAL 155 EQUAL Reactome Database ID Release 78 189856 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=189856 Reactome R-HSA-189856 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-189856.1 FGF2 FGF2(10-155) Fibroblast growth factor-2 Heparin-binding growth factor 2 FGF2_HUMAN Basic fibroblast growth factor bFGF Reactome DB_ID: 189898 UniProt:P09038 FGF2 FGF2 FGFB FUNCTION Acts as a ligand for FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:8663044). Also acts as an integrin ligand which is required for FGF2 signaling (PubMed:28302677). Binds to integrin ITGAV:ITGB3 (PubMed:28302677). Plays an important role in the regulation of cell survival, cell division, cell differentiation and cell migration (PubMed:8663044, PubMed:28302677). Functions as a potent mitogen in vitro (PubMed:1721615, PubMed:3964259, PubMed:3732516). Can induce angiogenesis (PubMed:23469107, PubMed:28302677). Mediates phosphorylation of ERK1/2 and thereby promotes retinal lens fiber differentiation (PubMed:29501879).SUBUNIT Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Interacts with CSPG4, FGFBP1 and TEC. Found in a complex with FGFBP1, FGF1 and FGF2. Interacts with FGFBP3 (PubMed:18669637). Interacts with integrin ITGAV:ITGB3; the interaction is required for FGF2 signaling (PubMed:28302677). Interacts with SNORC (via the extracellular domain) (By similarity). Interacts with glypican GPC3 (By similarity).TISSUE SPECIFICITY Expressed in granulosa and cumulus cells. Expressed in hepatocellular carcinoma cells, but not in non-cancerous liver tissue.PTM Phosphorylation at Tyr-215 regulates FGF2 unconventional secretion.PTM Several N-termini starting at positions 94, 125, 126, 132, 143 and 162 have been identified by direct sequencing.MISCELLANEOUS This protein binds heparin more strongly than does aFGF.SIMILARITY Belongs to the heparin-binding growth factors family. UniProt P09038 10 EQUAL 155 EQUAL Reactome Database ID Release 78 189898 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=189898 Reactome R-HSA-189898 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-189898.1 FGF3 Fibroblast growth factor-3 INT-2 proto-oncogene protein FGF3_HUMAN Reactome DB_ID: 189886 UniProt:P11487 FGF3 FGF3 INT2 FUNCTION Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. Required for normal ear development.SUBUNIT Interacts with FGFR1 and FGFR2. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.SIMILARITY Belongs to the heparin-binding growth factors family. UniProt P11487 18 EQUAL 239 EQUAL Reactome Database ID Release 78 189886 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=189886 Reactome R-HSA-189886 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-189886.1 FGF10 Fibroblast growth factor-10 Reactome DB_ID: 189869 UniProt:O15520 FGF10 FGF10 FUNCTION Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation. Required for normal branching morphogenesis. May play a role in wound healing.SUBUNIT Interacts with FGFR1 and FGFR2. Interacts with FGFBP1.SIMILARITY Belongs to the heparin-binding growth factors family. UniProt O15520 38 EQUAL 208 EQUAL Reactome Database ID Release 78 189869 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=189869 Reactome R-HSA-189869 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-189869.1 FGF22 Fibroblast growth factor-22 FGFM_HUMAN Reactome DB_ID: 189877 UniProt:Q9HCT0 FGF22 FGF22 UNQ2500/PRO5800 FUNCTION Plays a role in the fasting response, glucose homeostasis, lipolysis and lipogenesis. Can stimulate cell proliferation (in vitro). May be involved in hair development.SUBUNIT Interacts with FGFR1 and FGFR2. Interacts with FGFBP1.SIMILARITY Belongs to the heparin-binding growth factors family. UniProt Q9HCT0 23 EQUAL 170 EQUAL Reactome Database ID Release 78 189877 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=189877 Reactome R-HSA-189877 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-189877.1 Reactome Database ID Release 78 189963 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=189963 Reactome R-HSA-189963 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-189963.1 2 HS Heparan Sulphate heparan sulfate Reactome DB_ID: 190915 heparan sulfate [ChEBI:28815] heparan sulfate N-Acetylheparan sulfate Heparin monosulfate Heparatan sulfate Heparitin monosulfate Heparan sulphate Heparan N-sulfate Heparitin sulfate Heparin sulfate ChEBI CHEBI:28815 Reactome Database ID Release 78 190915 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=190915 Reactome R-ALL-190915 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-190915.3 FGFR1b Fibroblast growth factor receptor 1b FGR1_HUMAN Reactome DB_ID: 189878 UniProt:P11362-19 FGFR1 FGFR1 BFGFR CEK FGFBR FLG FLT2 HBGFR FUNCTION Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.ACTIVITY REGULATION Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by sequential autophosphorylation on tyrosine residues. Inhibited by ARQ 069; this compound maintains the kinase in an inactive conformation and inhibits autophosphorylation. Inhibited by PD173074.SUBUNIT Monomer. Homodimer after ligand binding. Interacts predominantly with FGF1 and FGF2, but can also interact with FGF3, FGF4, FGF5, FGF6, FGF8, FGF10, FGF19, FGF21, FGF22 and FGF23 (in vitro) (PubMed:1697263, PubMed:1722683, PubMed:8663044, PubMed:9655399, PubMed:12181353, PubMed:16597617, PubMed:17623664). Ligand specificity is determined by tissue-specific expression of isoforms, and differences in the third Ig-like domain are crucial for ligand specificity. Affinity for fibroblast growth factors (FGFs) is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Likewise, KLB increases the affinity for FGF19, FGF21 and FGF23 (PubMed:19966287). Interacts (phosphorylated on Tyr-766) with PLCG1 (via SH2 domains) (PubMed:1656221, PubMed:1379697, PubMed:21765395). Interacts with FRS2 (PubMed:21765395). Interacts with RPS6KA1 (PubMed:15117958). Interacts (via C-terminus) with NEDD4 (via WW3 domain) (PubMed:21765395). Interacts with KL (By similarity). Interacts with SHB (via SH2 domain) (PubMed:12181353). Interacts with GRB10 (PubMed:10454568). Interacts with ANOS1; this interaction does not interfere with FGF2-binding to FGFR1, but prevents binding of heparin-bound FGF2 (PubMed:19696444). Interacts with SOX2 and SOX3. Interacts with FLRT1, FLRT2 and FLRT3 (By similarity). Found in a ternary complex with FGF1 and ITGAV:ITGB3 (PubMed:20422052, PubMed:18441324).TISSUE SPECIFICITY Detected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform 17, isoform 18 and isoform 19 are not detected in these cells.DOMAIN The second and third Ig-like domains directly interact with fibroblast growth factors (FGF) and heparan sulfate proteoglycans. Isoforms lacking the first Ig-like domain have higher affinity for fibroblast growth factors (FGF) and heparan sulfate proteoglycans than isoforms with all three Ig-like domains.PTM Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer and proceeds in a highly ordered manner. Initial autophosphorylation at Tyr-653 increases the kinase activity by a factor of 50 to 100. After this, Tyr-583 becomes phosphorylated, followed by phosphorylation of Tyr-463, Tyr-766, Tyr-583 and Tyr-585. In a third stage, Tyr-654 is autophosphorylated, resulting in a further tenfold increase of kinase activity. Phosphotyrosine residues provide docking sites for interacting proteins and so are crucial for FGFR1 function and its regulation.PTM Ubiquitinated. FGFR1 is rapidly ubiquitinated by NEDD4 after autophosphorylation, leading to internalization and lysosomal degradation. CBL is recruited to activated FGFR1 via FRS2 and GRB2, and mediates ubiquitination and subsequent degradation of FGFR1.PTM N-glycosylated in the endoplasmic reticulum. The N-glycan chains undergo further maturation to an Endo H-resistant form in the Golgi apparatus.DISEASE Chromosomal aberrations involving FGFR1 are a cause of chromosome 8p11 myeloproliferative syndrome. Translocation t(8;13)(p11;q12) with ZMYM2. Translocation t(6;8)(q27;p11) with CEP43. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. Translocation t(8;9)(p12;q33) with CNTRL. Translocation t(2;8)(q12;p11) with RANBP2. Chromosome 8p11 myeloproliferative syndrome is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, CEP43-FGFR1 or FGFR1-CEP43 may exhibit constitutive kinase activity and be responsible for the transforming activity. The fusion protein CNTRL-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. UniProt Isoform P11362-19 2 EQUAL 822 EQUAL Reactome Database ID Release 78 189878 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=189878 Reactome R-HSA-189878 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-189878.2 2 FGFR1b homodimer bound to FGF Reactome DB_ID: 190226 FGFR1b homodimer Reactome DB_ID: 190228 2 Reactome Database ID Release 78 190228 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=190228 Reactome R-HSA-190228 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-190228.1 1 2 1 Reactome Database ID Release 78 190226 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=190226 Reactome R-HSA-190226 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-190226.1 Reactome Database ID Release 78 190245 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=190245 Reactome R-HSA-190245 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-190245.3 12791257 Pubmed 2003 Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP Kiselyov, VV Skladchikova, G Hinsby, AM Jensen, PH Kulahin, N Soroka, V Pedersen, N Tsetlin, V Poulsen, FM Berezin, V Bock, E Structure 11:691-701 16709412 Pubmed 2006 The neural cell adhesion molecule binds to fibroblast growth factor receptor 2 Christensen, C Lauridsen, JB Berezin, V Bock, E Kiselyov, VV FEBS Lett 580:3386-90 16597617 Pubmed 2006 Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. Zhang, X Ibrahimi, OA Olsen, SK Umemori, H Mohammadi, M Ornitz, DM J Biol Chem 281:15694-700 15863029 Pubmed 2005 Structural basis for fibroblast growth factor receptor activation Mohammadi, M Olsen, SK Ibrahimi, OA Cytokine Growth Factor Rev 16:107-37 7917292 Pubmed 1994 Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin Williams, EJ Furness, J Walsh, FS Doherty, P Neuron 13:583-94 16045455 Pubmed 2005 Structural biology of NCAM homophilic binding and activation of FGFR Kiselyov, VV Soroka, V Berezin, V Bock, E J Neurochem 94:1169-79 ACTIVATION Reactome Database ID Release 78 190317 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=190317 Reactome R-HSA-190317 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-190317.1 LEFT-TO-RIGHT 2.7.10 Autocatalytic phosphorylation of FGFR1b Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Authored: de Bono, B, 2007-01-10 10:27:18 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 16 16 Activated FGFR1b homodimer Reactome DB_ID: 190430 2 p-8Y-FGFR1b dimer Reactome DB_ID: 5656340 FGR1_HUMAN p-8Y-FGFR1b Fibroblast growth factor receptor 1b Reactome DB_ID: 5656338 463 EQUAL 583 EQUAL 585 EQUAL 653 EQUAL 654 EQUAL 730 EQUAL 766 EQUAL 776 EQUAL 2 EQUAL 822 EQUAL Reactome Database ID Release 78 5656338 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=5656338 Reactome R-HSA-5656338 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-5656338.2 2 Reactome Database ID Release 78 5656340 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=5656340 Reactome R-HSA-5656340 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-5656340.1 1 1 Reactome Database ID Release 78 190430 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=190430 Reactome R-HSA-190430 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-190430.1 ACTIVATION Reactome Database ID Release 78 190428 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=190428 Reactome Database ID Release 78 190427 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=190427 Reactome R-HSA-190427 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-190427.2 8622701 Pubmed 1996 Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction Mohammadi, M Dikic, I Sorokin, A Burgess, WH Jaye, M Schlessinger, J Mol Cell Biol 16:977-89 1656221 Pubmed 1991 A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1 Mohammadi, M Honegger, AM Rotin, D Fischer, R Bellot, F Li, W Dionne, CA Jaye, M Rubinstein, M Schlessinger, J Mol Cell Biol 11:5068-78 1379698 Pubmed 1992 Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis Mohammadi, M Dionne, CA Li, W Li, N Spivak, T Honegger, AM Jaye, M Schlessinger, J Nature 358:681-4 16507368 Pubmed 2006 Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction Furdui, CM Lew, ED Schlessinger, J Anderson, KS Mol Cell 21:711-7 Reactome Database ID Release 78 190370 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=190370 Reactome R-HSA-190370 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-190370.2 GENE ONTOLOGY GO:0008543 FGFR1c ligand binding and activation This pathway depicts the binding of an experimentally-verified range of ligands to FGFR1c. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. Authored: de Bono, B, 2007-01-10 10:27:18 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Reviewed: Grose, Richard P, 2016-01-06 LEFT-TO-RIGHT FGFR1c binds to FGF In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Authored: de Bono, B, 2007-01-10 10:27:18 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 FGFR1c FGFR1-1 Fibroblast growth factor receptor 1c FGR1_HUMAN FGFR1 isoform 1 Reactome DB_ID: 189897 UniProt:P11362-1 FGFR1 FGFR1 BFGFR CEK FGFBR FLG FLT2 HBGFR FUNCTION Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.ACTIVITY REGULATION Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by sequential autophosphorylation on tyrosine residues. Inhibited by ARQ 069; this compound maintains the kinase in an inactive conformation and inhibits autophosphorylation. Inhibited by PD173074.SUBUNIT Monomer. Homodimer after ligand binding. Interacts predominantly with FGF1 and FGF2, but can also interact with FGF3, FGF4, FGF5, FGF6, FGF8, FGF10, FGF19, FGF21, FGF22 and FGF23 (in vitro) (PubMed:1697263, PubMed:1722683, PubMed:8663044, PubMed:9655399, PubMed:12181353, PubMed:16597617, PubMed:17623664). Ligand specificity is determined by tissue-specific expression of isoforms, and differences in the third Ig-like domain are crucial for ligand specificity. Affinity for fibroblast growth factors (FGFs) is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Likewise, KLB increases the affinity for FGF19, FGF21 and FGF23 (PubMed:19966287). Interacts (phosphorylated on Tyr-766) with PLCG1 (via SH2 domains) (PubMed:1656221, PubMed:1379697, PubMed:21765395). Interacts with FRS2 (PubMed:21765395). Interacts with RPS6KA1 (PubMed:15117958). Interacts (via C-terminus) with NEDD4 (via WW3 domain) (PubMed:21765395). Interacts with KL (By similarity). Interacts with SHB (via SH2 domain) (PubMed:12181353). Interacts with GRB10 (PubMed:10454568). Interacts with ANOS1; this interaction does not interfere with FGF2-binding to FGFR1, but prevents binding of heparin-bound FGF2 (PubMed:19696444). Interacts with SOX2 and SOX3. Interacts with FLRT1, FLRT2 and FLRT3 (By similarity). Found in a ternary complex with FGF1 and ITGAV:ITGB3 (PubMed:20422052, PubMed:18441324).TISSUE SPECIFICITY Detected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform 17, isoform 18 and isoform 19 are not detected in these cells.DOMAIN The second and third Ig-like domains directly interact with fibroblast growth factors (FGF) and heparan sulfate proteoglycans. Isoforms lacking the first Ig-like domain have higher affinity for fibroblast growth factors (FGF) and heparan sulfate proteoglycans than isoforms with all three Ig-like domains.PTM Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer and proceeds in a highly ordered manner. Initial autophosphorylation at Tyr-653 increases the kinase activity by a factor of 50 to 100. After this, Tyr-583 becomes phosphorylated, followed by phosphorylation of Tyr-463, Tyr-766, Tyr-583 and Tyr-585. In a third stage, Tyr-654 is autophosphorylated, resulting in a further tenfold increase of kinase activity. Phosphotyrosine residues provide docking sites for interacting proteins and so are crucial for FGFR1 function and its regulation.PTM Ubiquitinated. FGFR1 is rapidly ubiquitinated by NEDD4 after autophosphorylation, leading to internalization and lysosomal degradation. CBL is recruited to activated FGFR1 via FRS2 and GRB2, and mediates ubiquitination and subsequent degradation of FGFR1.PTM N-glycosylated in the endoplasmic reticulum. The N-glycan chains undergo further maturation to an Endo H-resistant form in the Golgi apparatus.DISEASE Chromosomal aberrations involving FGFR1 are a cause of chromosome 8p11 myeloproliferative syndrome. Translocation t(8;13)(p11;q12) with ZMYM2. Translocation t(6;8)(q27;p11) with CEP43. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. Translocation t(8;9)(p12;q33) with CNTRL. Translocation t(2;8)(q12;p11) with RANBP2. Chromosome 8p11 myeloproliferative syndrome is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, CEP43-FGFR1 or FGFR1-CEP43 may exhibit constitutive kinase activity and be responsible for the transforming activity. The fusion protein CNTRL-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. UniProt Isoform P11362-1 22 EQUAL 822 EQUAL Reactome Database ID Release 78 189897 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=189897 Reactome R-HSA-189897 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-189897.1 2 Converted from EntitySet in Reactome FGFR1c-binding FGFs Reactome DB_ID: 189953 FGF4 Fibroblast growth factor-4 FGF4_HUMAN Reactome DB_ID: 189907 UniProt:P08620 FGF4 FGF4 HST HSTF1 KS3 FUNCTION Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. Required for normal limb and cardiac valve development during embryogenesis.SUBUNIT Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.SIMILARITY Belongs to the heparin-binding growth factors family. UniProt P08620 31 EQUAL 206 EQUAL Reactome Database ID Release 78 189907 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=189907 Reactome R-HSA-189907 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-189907.1 FGF5-1 Fibroblast growth factor-5 isoform 1 FGF5_HUMAN Reactome DB_ID: 189903 UniProt:P12034-1 FGF5 FGF5 FUNCTION Plays an important role in the regulation of cell proliferation and cell differentiation. Required for normal regulation of the hair growth cycle. Functions as an inhibitor of hair elongation by promoting progression from anagen, the growth phase of the hair follicle, into catagen the apoptosis-induced regression phase (By similarity).SUBUNIT Interacts with FGFR1 and FGFR2. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.TISSUE SPECIFICITY Expressed in neonatal brain.DEVELOPMENTAL STAGE Can transform NIH 3T3 cells.SIMILARITY Belongs to the heparin-binding growth factors family. UniProt Isoform P12034-1 18 EQUAL 268 EQUAL Reactome Database ID Release 78 189903 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=189903 Reactome R-HSA-189903 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-189903.1 FGF6 Fibroblast growth factor-6 FGF6_HUMAN Reactome DB_ID: 189881 UniProt:P10767 FGF6 FGF6 HST2 HSTF2 FUNCTION Plays an important role in the regulation of cell proliferation, cell differentiation, angiogenesis and myogenesis, and is required for normal muscle regeneration.SUBUNIT Interacts with FGFR1, FGFR2 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.TISSUE SPECIFICITY Leukemia cell lines with platelet/ megakaryocytic differentiation potential.SIMILARITY Belongs to the heparin-binding growth factors family. UniProt P10767 38 EQUAL 208 EQUAL