Signaling by ERBB2 (Homo sapiens)

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154163, 33, 4115917, 355, 1149639252641323252814, 19, 20, 24, 27...424305, 11, 404261-3, 7, 8, 14...2626101093, 41439432NRG1 NRG1/2P-ERBB3 EGFp-EGFRp-ERBB2GRB2GAB1PIK3R1 Ub NRGs/EGFLsp-ERBB4cyt1p-7Y-ERBB2 CDC37 NRG1/2 NRGs/EGF-like ligands EGF-like ligands NRGs/EGFLsp-ERBB4p-7Y-ERBB2 Phosphorylated p-6Y-ERBB2 heterodimers CDC37 EGFp-6Y-EGFRp-7Y-ERBB2 NRGs/EGFLsp-ERBB4cyt1p-ERBB2PIK3R1 GRB2SOS1 CDC37 P-ERBB4cyt1 GRB2GAB1 NRGs/EGFLsp-ERBB4cyt2p-7Y-ERBB2 p21 RASGDP EGFp-6Y-EGFRp-6Y-ERBB2 P-ERBB4cyt1 NRGs/EGF-like ligandsP-ERBB4cyt1 NRGs/EGF-like ligandsP-ERBB4cyt1 Ub NRGs/EGFLsp-ERBB4cyt1p-6Y-ERBB2 GRB2SOS1 NRGs/EGF-like ligandsp-ERBB4cyt2 NRGs/EGFLsp-ERBB4cyt2p-6Y-ERBB2 NRG1 Ub-ERBB2ERBB2IPUb-HSP90CDC37 GRB2GAB1 Ub-RNF41 Ub NRGs/EGF-like ligands HSP90 p21 RASGTP NRGs/EGFLsp-ERBB4cyt1p-ERBB2PIK3R1 NRG1/2 Ub-RNF41p-USP8 GRB2GAB1 EGFp-EGFRp-ERBB2GRB2GAB1 NRG1/2p-ERBB3p-ERBB2PIK3R1 Phosphorylated ERBB2ERBB4 heterodimers EGFp-EGFRp-ERBB2GRB2GAB1PIK3R1 EGFp-EGFRp-ERBB2GRB2GAB1PI3K SHC1Phosphorylated ERBB2 heterodimers NRGs/EGFLsp-ERBB4p-ERBB2GRB2SOS1 Ub EGFp-EGFRp-ERBB2PLCG1 CDC37 NRG1/2 Phosphorylated ERBB2ERBB4 heterodimers NRG1/2p-10Y-ERBB3p-ERBB2RNF41 Ub-ERBB2ERBB2IPHSP90CDC37 Ub-ERBB3 EGF-like ligands p-Y349,350-SHC1Phosphorylated ERBB2 heterodimers NRG1/2P-ERBB3 NRGs/EGFLsp-ERBB4cyt1p-ERBB2PI3K NRG1/2p-ERBB3p-ERBB2PI3K GRB2SOS1 p21 RAS NRGs/EGF-like ligandsp-ERBB4cyt2 HSP90 NRG1/2p-ERBB3p-ERBB2PIK3R1 EGFp-EGFRp-ERBB2GRB2GAB1 GRB2GAB1 Phosphorylated ERBB2 heterodimersMATK GRB2SOS1 p21 RAS NRG1/2Ub-p-10Y-ERBB3p-ERBB2 EGFp-EGFRp-ERBB2GRB2GAB1 Ub EGFp-6Y-EGFR cytosolNRG1 Ub ERBB3RNF41 HSP90 ERBB2ERBB2IPHSP90CDC37 Phosphorylated p-Y877-ERBB2 heterodimers EGFp-6Y-EGFR HSP90 NRGs/EGFLsp-ERBB4p-6Y-ERBB2 GRB2SOS1p-Y349,350-SHC1Phosphorylated ERBB2 heterodimers NRG1/2ERBB3 NRG1/2p-10Y-ERBB3p-ERBB2GRB7 NRG1/2p-10Y-ERBB3p-Y,877-ERBB2 p-Y349,350-SHC1Phosphorylated ERBB2 heterodimers EGFp-EGFRp-ERBB2GRB2SOS1 Ub-RNF41 NRG1/2p-10Y-ERBB3p-Y-ERBB2 UBCUBCEGFRAF/MAP kinase cascadeCDC37UbUBCERBB3-1 p-7Y-ERBB2 p21 RASGDPSHC1HBEGFUb-ERBB2ERBB2IPUb-HSP90CDC37p-Y419/420/426-N-myristoyl-SRC/FYN/YES1p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform UBBUBCGRB2GAB1NRG1 MATKGAB1 RNF41 HRASUBBGAB1 NRG1-10 UBBGRB7 EGFp-EGFRp-ERBB2GRB2SOS1UBCUBCATPNRAS p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform UBCSHC1Phosphorylated ERBB2 heterodimersUBBERBB2 STUB1GRB2-1 ADPUBBp-T945-USP8PIK3CA NRG2 ERBB3-1 UbNRGs/EGFLsp-ERBB4cyt1p-ERBB2PIK3R1UBCPIK3R1ERBB2 UbPhosphorylated ERBB2EGFR heterodimersATPEpiregulin Ub-RNF41NRG1-10 ADPPICDC37SOS1 HBEGFGAB1 Phosphorylated p-Y877-ERBB2 heterodimersUBCLigand-Activated EGFR/ERBB3/ERBB4UBCADPERBB2ERBB2IPHSP90CDC37RPS27AUBCUBCUBCNRGs/EGFLsp-ERBB4cyt1p-ERBB2PI3KUBBRNF41 UBCGRB2-1 ERBB2IP UBBMATK NRG2 p-6Y-ERBB2 GRB2-1 UBCPIK3R1 UBA52UBBERBB2 heterodimersUBBUBCUBBGRB2-1 NRG1/2ERBB3UBCUBCp-Y349,350-SHC1Phosphorylated ERBB2 heterodimersEGFUBCUb-ERBB2ERBB2IPHSP90CDC37Phosphorylated ERBB2ERBB4 heterodimersActive AKTUbPIK3R1 NRAS Ub-RNF41p-USP8UBCNRG1/2p-10Y-ERBB3p-ERBB2RNF41NRGs/EGFLsp-ERBB4p-ERBB2GRB2SOS1EGFp-EGFRp-ERBB2GRB2GAB1PIK3R1UBBUBA52GDP NRG1 p-Y,Y877-ERBB2 Phosphorylated ERBB2ERBB3 heterodimersUBBUBCRPS27APLCG1SOS1 UBCUBBGTPUBCUBCGRB2-1 p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform UBCUBCEGFp-EGFRp-ERBB2GRB2GAB1PI3Kp-6Y-EGFR UBCPIK3CA ADPGTP RNF41RNF41 PIPhosphorylated ERBB2ERBB4cyt1 heterodimersATPPLCG1UBCRPS27ACDC37Betacellulin p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform ERBB2IPRPS27ANRG1/2Ub-p-10Y-ERBB3p-ERBB2HSP90NRG1 UbNRG2 ERBB3-1PIK3R1 ATPUbUBBSOS1 ADPERBB2 RNF41 Ub-ERBB3UBCUBCUSP8KRASNRG1/2ATPATPPhosphorylated p-6Y-ERBB2 heterodimersPIK3R1UBBHSP90AA1 PIK3R1 ERBB3RNF41p-T945-USP8 UBA52UBBEpiregulin UBCUBCUBCRPS27Ap-Y-ERBB2 p-10Y-ERBB3-1 Betacellulin UBCUBCEGFp-EGFRp-ERBB2PLCG1ATPADPUBCUBCADPUBCNRG1/2p-ERBB3p-ERBB2PI3KATPPIK3CAATPGAB1 ADPGRB2SOS1p-Y349,350-SHC1Phosphorylated ERBB2 heterodimersPIP3 activates AKT signalingCUL5Phosphorylated ERBB2 heterodimersMATKUBBp-Y349,Y350-SHC1 p-4Y-PLCG1ERBB2IP GRB2-1 p-10Y-ERBB3-1 UBCUBCERBB2IP GRB7p-Y349,Y350-SHC1 HSP90AA1 NRG1/2p-10Y-ERBB3p-ERBB2GRB7PIK3R1 GRB2-1 UBCNRG1/2p-ERBB3p-ERBB2PIK3R1UBCUBCEGFp-EGFRp-ERBB2GRB2GAB1NRG1-10 UBCp-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform HSP90AA1 GRB2SOS1p-Y877-ERBB2 heterodimersRPS27AUBCSOS1 CDC37UBA52UBCUBCUBCUBCKRASCDC37p21 RASGTPUBCUBBGRB2-1 HRASPIK3CAp-6Y-EGFR PIK3R1 ADPHSP90AA1 PIK3CA Phosphorylated ERBB2 heterodimersUBA52DAG and IP3 signalingSHC1 ERBB3-1 UBA52UBCUBCp-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform UBCGDPUBC22, 341218


Description

ERBB2, also known as HER2 or NEU, is a receptor tyrosine kinase (RTK) belonging to the EGFR family. ERBB2 possesses an extracellular domain that does not bind any known ligand, contrary to other EGFR family members, a single transmembrane domain, and an intracellular domain consisting of an active kinase and a C-tail with multiple tyrosine phosphorylation sites. Inactive ERBB2 is associated with a chaperone heat shock protein 90 (HSP90) and its co-chaperone CDC37 (Xu et al. 2001, Citri et al. 2004, Xu et al. 2005). In addition, ERBB2 is associated with ERBB2IP (also known as ERBIN or LAP2), a protein responsible for proper localization of ERBB2. In epithelial cells, ERBB2IP restricts expression of ERBB2 to basolateral plasma membrane regions (Borg et al. 2000).

ERBB2 becomes activated by forming a heterodimer with another ligand-activated EGFR family member, either EGFR, ERBB3 or ERBB4, which is accompanied by dissociation of chaperoning proteins HSP90 and CDC37 (Citri et al. 2004), as well as ERBB2IP (Borg et al. 2000) from ERBB2. ERBB2 heterodimers function to promote cell proliferation, cell survival and differentiation, depending on the cellular context. ERBB2 can also be activated by homodimerization when it is overexpressed, in cancer for example.

In cells expressing both ERBB2 and EGFR, EGF stimulation of EGFR leads to formation of both ERBB2:EGFR heterodimers (Wada et al. 1990, Karunagaran et al. 1996) and EGFR homodimers. Heterodimers of ERBB2 and EGFR trans-autophosphorylate on twelve tyrosine residues, six in the C-tail of EGFR and six in the C-tail of ERBB2 - Y1023, Y1139, Y1196, Y1221, Y1222 and Y1248 (Margolis et al. 1989, Hazan et al. 1990,Walton et al. 1990, Helin et al. 1991, Ricci et al. 1995, Pinkas-Kramarski 1996). Phosphorylated tyrosine residues in the C-tail of EGFR and ERBB2 serve as docking sites for downstream signaling molecules. Three key signaling pathways activated by ERBB2:EGFR heterodimers are RAF/MAP kinase cascade, PI3K-induced AKT signaling, and signaling by phospholipase C gamma (PLCG1). Downregulation of EGFR signaling is mediated by ubiquitin ligase CBL, and is shown under Signaling by EGFR.

In cells expressing ERBB2 and ERBB3, ERBB3 activated by neuregulin NRG1 or NRG2 binding (Tzahar et al. 1994) forms a heterodimer with ERBB2 (Pinkas-Kramarski et al. 1996, Citri et al. 2004). ERBB3 is the only EGFR family member with no kinase activity, and can only function in heterodimers, with ERBB2 being its preferred heterodimerization partner. After heterodimerization, ERBB2 phosphorylates ten tyrosine residues in the C-tail of ERBB3, Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 (Prigent et al. 1994, Pinkas-Kramarski et al. 1996, Vijapurkar et al. 2003, Li et al. 2007) that subsequently serve as docking sites for downstream signaling molecules, resulting in activation of PI3K-induced AKT signaling and RAF/MAP kinase cascade. Signaling by ERBB3 is downregulated by the action of RNF41 ubiquitin ligase, also known as NRDP1.

In cells expressing ERBB2 and ERBB4, ligand stimulated ERBB4 can either homodimerize or form heterodimers with ERBB2 (Li et al. 2007), resulting in trans-autophosphorylation of ERBB2 and ERBB4 on C-tail tyrosine residues that will subsequently serve as docking sites for downstream signaling molecules, leading to activation of RAF/MAP kinase cascade and, in the case of ERBB4 CYT1 isoforms, PI3K-induced AKT signaling (Hazan et al. 1990, Cohen et al. 1996, Li et al. 2007, Kaushansky et al. 2008). Signaling by ERBB4 is downregulated by the action of WWP1 and ITCH ubiquitin ligases, and is shown under Signaling by ERBB4.

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  76. Cao Z, Wu X, Yen L, Sweeney C, Carraway KL.; ''Neuregulin-induced ErbB3 downregulation is mediated by a protein stability cascade involving the E3 ubiquitin ligase Nrdp1.''; PubMed Europe PMC Scholia
  77. Gao GX, Dong HJ, Gu HT, Gao Y, Pan YZ, Yang Y, Chen XQ.; ''[PI3-kinase mediates activity of RhoA and interaction of RhoA with mDia1 in thrombin-induced platelet aggregation].''; PubMed Europe PMC Scholia
  78. Qiu XB, Goldberg AL.; ''Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3.''; PubMed Europe PMC Scholia
  79. Lukong KE, Larocque D, Tyner AL, Richard S.; ''Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression.''; PubMed Europe PMC Scholia
  80. Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE, Yarden Y.; ''ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer.''; PubMed Europe PMC Scholia
  81. Lukong KE, Huot ME, Richard S.; ''BRK phosphorylates PSF promoting its cytoplasmic localization and cell cycle arrest.''; PubMed Europe PMC Scholia
  82. Fan G, Aleem S, Yang M, Miller WT, Tonks NK.; ''Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase.''; PubMed Europe PMC Scholia
  83. Ostrander JH, Daniel AR, Lofgren K, Kleer CG, Lange CA.; ''Breast tumor kinase (protein tyrosine kinase 6) regulates heregulin-induced activation of ERK5 and p38 MAP kinases in breast cancer cells.''; PubMed Europe PMC Scholia
  84. Seth A, Otomo C, Rosen MK.; ''Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1.''; PubMed Europe PMC Scholia
  85. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  86. Peng M, Ball-Kell SM, Tyner AL.; ''Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse.''; PubMed Europe PMC Scholia
  87. Habas R, Kato Y, He X.; ''Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1.''; PubMed Europe PMC Scholia
  88. Sepp-Lorenzino L, Eberhard I, Ma Z, Cho C, Serve H, Liu F, Rosen N, Lupu R.; ''Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells.''; PubMed Europe PMC Scholia
  89. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMed Europe PMC Scholia
  90. Zaoui K, Honoré S, Isnardon D, Braguer D, Badache A.; ''Memo-RhoA-mDia1 signaling controls microtubules, the actin network, and adhesion site formation in migrating cells.''; PubMed Europe PMC Scholia
  91. Li D, Sewer MB.; ''RhoA and DIAPH1 mediate adrenocorticotropin-stimulated cortisol biosynthesis by regulating mitochondrial trafficking.''; PubMed Europe PMC Scholia
  92. Kang SA, Lee ES, Yoon HY, Randazzo PA, Lee ST.; ''PTK6 inhibits down-regulation of EGF receptor through phosphorylation of ARAP1.''; PubMed Europe PMC Scholia
  93. Nezami AG, Poy F, Eck MJ.; ''Structure of the autoinhibitory switch in formin mDia1.''; PubMed Europe PMC Scholia
  94. Ricci A, Lanfrancone L, Chiari R, Belardo G, Pertica C, Natali PG, Pelicci PG, Segatto O.; ''Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase.''; PubMed Europe PMC Scholia
  95. Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M, Yarden Y.; ''Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions.''; PubMed Europe PMC Scholia
  96. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  97. Chen HY, Shen CH, Tsai YT, Lin FC, Huang YP, Chen RH.; ''Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin.''; PubMed Europe PMC Scholia
  98. Jackson JG, St Clair P, Sliwkowski MX, Brattain MG.; ''Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects.''; PubMed Europe PMC Scholia
  99. Ehrlich ES, Wang T, Luo K, Xiao Z, Niewiadomska AM, Martinez T, Xu W, Neckers L, Yu XF.; ''Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase.''; PubMed Europe PMC Scholia
  100. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
  101. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  102. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  103. Cohen BD, Green JM, Foy L, Fell HP.; ''HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers.''; PubMed Europe PMC Scholia
  104. Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMed Europe PMC Scholia
  105. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  106. Goel RK, Lukong KE.; ''Tracing the footprints of the breast cancer oncogene BRK - Past till present.''; PubMed Europe PMC Scholia
  107. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  108. Wang HM, Xu YF, Ning SL, Yang DX, Li Y, Du YJ, Yang F, Zhang Y, Liang N, Yao W, Zhang LL, Gu LC, Gao CJ, Pang Q, Chen YX, Xiao KH, Ma R, Yu X, Sun JP.; ''The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes.''; PubMed Europe PMC Scholia
  109. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  110. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  111. Vega FM, Fruhwirth G, Ng T, Ridley AJ.; ''RhoA and RhoC have distinct roles in migration and invasion by acting through different targets.''; PubMed Europe PMC Scholia
  112. Kühn S, Geyer M.; ''Formins as effector proteins of Rho GTPases.''; PubMed Europe PMC Scholia
  113. Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W, Ullrich A.; ''Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3.''; PubMed Europe PMC Scholia
  114. Xu Y, Moseley JB, Sagot I, Poy F, Pellman D, Goode BL, Eck MJ.; ''Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture.''; PubMed Europe PMC Scholia
  115. Gensler M, Buschbeck M, Ullrich A.; ''Negative regulation of HER2 signaling by the PEST-type protein-tyrosine phosphatase BDP1.''; PubMed Europe PMC Scholia
  116. Cheng L, Zhang J, Ahmad S, Rozier L, Yu H, Deng H, Mao Y.; ''Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment.''; PubMed Europe PMC Scholia
  117. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX.; ''Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.''; PubMed Europe PMC Scholia
  118. Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMed Europe PMC Scholia
  119. Xie Y, Pendergast AM, Hung MC.; ''Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu.''; PubMed Europe PMC Scholia
  120. Batzer AG, Blaikie P, Nelson K, Schlessinger J, Margolis B.; ''The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor.''; PubMed Europe PMC Scholia
  121. Qiu C, Lienhard S, Hynes NE, Badache A, Leahy DJ.; ''Memo is homologous to nonheme iron dioxygenases and binds an ErbB2-derived phosphopeptide in its vestigial active site.''; PubMed Europe PMC Scholia
  122. Citri A, Gan J, Mosesson Y, Vereb G, Szollosi J, Yarden Y.; ''Hsp90 restrains ErbB-2/HER2 signalling by limiting heterodimer formation.''; PubMed Europe PMC Scholia
  123. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  124. Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L.; ''Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90.''; PubMed Europe PMC Scholia
  125. Castro NE, Lange CA.; ''Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells.''; PubMed Europe PMC Scholia
  126. Fazioli F, Kim UH, Rhee SG, Molloy CJ, Segatto O, Di Fiore PP.; ''The erbB-2 mitogenic signaling pathway: tyrosine phosphorylation of phospholipase C-gamma and GTPase-activating protein does not correlate with erbB-2 mitogenic potency.''; PubMed Europe PMC Scholia
  127. Fan L, Pellegrin S, Scott A, Mellor H.; ''The small GTPase Rif is an alternative trigger for the formation of actin stress fibers in epithelial cells.''; PubMed Europe PMC Scholia
  128. Ikeda O, Miyasaka Y, Sekine Y, Mizushima A, Muromoto R, Nanbo A, Yoshimura A, Matsuda T.; ''STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation.''; PubMed Europe PMC Scholia
  129. Zrihan-Licht S, Deng B, Yarden Y, McShan G, Keydar I, Avraham H.; ''Csk homologous kinase, a novel signaling molecule, directly associates with the activated ErbB-2 receptor in breast cancer cells and inhibits their proliferation.''; PubMed Europe PMC Scholia
  130. Kamalati T, Jolin HE, Fry MJ, Crompton MR.; ''Expression of the BRK tyrosine kinase in mammary epithelial cells enhances the coupling of EGF signalling to PI 3-kinase and Akt, via erbB3 phosphorylation.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
101567view11:43, 1 November 2018ReactomeTeamreactome version 66
101103view21:27, 31 October 2018ReactomeTeamreactome version 65
100632view20:01, 31 October 2018ReactomeTeamreactome version 64
100182view16:46, 31 October 2018ReactomeTeamreactome version 63
99732view15:12, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94020view13:52, 16 August 2017ReactomeTeamreactome version 61
93639view11:29, 9 August 2017ReactomeTeamreactome version 61
87120view18:38, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86754view09:25, 11 July 2016ReactomeTeamreactome version 56
83403view11:08, 18 November 2015ReactomeTeamVersion54
81604view13:08, 21 August 2015ReactomeTeamVersion53
77062view08:36, 17 July 2014ReactomeTeamFixed remaining interactions
76767view12:13, 16 July 2014ReactomeTeamFixed remaining interactions
76090view10:15, 11 June 2014ReactomeTeamRe-fixing comment source
75801view11:33, 10 June 2014ReactomeTeamReactome 48 Update
75152view14:10, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74799view08:53, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active AKTProteinREACT_13319 (Reactome)
Betacellulin ProteinP35070 (Uniprot-TrEMBL)
CDC37ProteinQ16543 (Uniprot-TrEMBL)
CDC37ComplexREACT_117086 (Reactome)
CUL5ProteinQ93034 (Uniprot-TrEMBL)
DAG and IP3 signalingPathwayREACT_111064 (Reactome) This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
EGF

p-EGFR p-ERBB2 GRB2 GAB1

PI3K		ComplexREACT_116434 (Reactome)
EGF

p-EGFR p-ERBB2 GRB2 GAB1

PIK3R1		ComplexREACT_116584 (Reactome)
EGF

p-EGFR p-ERBB2 GRB2

GAB1		ComplexREACT_117153 (Reactome)
EGF

p-EGFR p-ERBB2 GRB2

SOS1		ComplexREACT_116273 (Reactome)
EGF

p-EGFR p-ERBB2

PLCG1		ComplexREACT_116869 (Reactome)
EGFProteinP01133 (Uniprot-TrEMBL)
ERBB2

ERBB2IP HSP90

CDC37		ComplexREACT_117260 (Reactome)
ERBB2 ProteinP04626 (Uniprot-TrEMBL)
ERBB2 heterodimersComplexREACT_116379 (Reactome)
ERBB2IP ProteinQ96RT1 (Uniprot-TrEMBL)
ERBB2IPProteinQ96RT1 (Uniprot-TrEMBL)
ERBB3 RNF41ComplexREACT_116975 (Reactome)
ERBB3-1 ProteinP21860-1 (Uniprot-TrEMBL)
ERBB3-1ProteinP21860-1 (Uniprot-TrEMBL)
Epiregulin ProteinO14944 (Uniprot-TrEMBL)
GAB1 ProteinQ13480 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2 GAB1ComplexREACT_12705 (Reactome)
GRB2

SOS1 p-Y349,350-SHC1

Phosphorylated ERBB2 heterodimers		ComplexREACT_116174 (Reactome)
GRB2 SOS1ComplexREACT_4435 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB7 ProteinQ14451 (Uniprot-TrEMBL)
GRB7ProteinQ14451 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HBEGFProteinQ99075 (Uniprot-TrEMBL)
HRASProteinP01112 (Uniprot-TrEMBL)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90ComplexREACT_117107 (Reactome)
KRASProteinP01116 (Uniprot-TrEMBL)
Ligand-Activated EGFR/ERBB3/ERBB4ComplexREACT_116645 (Reactome)
MATK ProteinP42679 (Uniprot-TrEMBL)
MATKProteinP42679 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
NRG1 ProteinQ02297 (Uniprot-TrEMBL)
NRG1-10 ProteinQ02297-10 (Uniprot-TrEMBL)
NRG1/2 ERBB3ComplexREACT_117375 (Reactome)
NRG1/2

Ub-p-10Y-ERBB3

p-ERBB2		ComplexREACT_117753 (Reactome)
NRG1/2

p-10Y-ERBB3 p-ERBB2

GRB7		ComplexREACT_116889 (Reactome)
NRG1/2

p-10Y-ERBB3 p-ERBB2

RNF41		ComplexREACT_116551 (Reactome)
NRG1/2

p-ERBB3 p-ERBB2

PI3K		ComplexREACT_116598 (Reactome)
NRG1/2

p-ERBB3 p-ERBB2

PIK3R1		ComplexREACT_117674 (Reactome)
NRG1/2ProteinREACT_117513 (Reactome)
NRG2 ProteinO14511 (Uniprot-TrEMBL)
NRGs/EGFLs

p-ERBB4 p-ERBB2 GRB2

SOS1		ComplexREACT_116478 (Reactome)
NRGs/EGFLs

p-ERBB4cyt1 p-ERBB2

PI3K		ComplexREACT_117020 (Reactome)
NRGs/EGFLs

p-ERBB4cyt1 p-ERBB2

PIK3R1		ComplexREACT_116930 (Reactome)
PIMetaboliteCHEBI:16618 (ChEBI)
PIMetaboliteCHEBI:18348 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CAProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R1ProteinP27986 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayREACT_75829 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PLCG1ProteinP19174 (Uniprot-TrEMBL)
Phosphorylated ERBB2 EGFR heterodimersComplexREACT_117507 (Reactome)
Phosphorylated ERBB2 ERBB3 heterodimersComplexREACT_116858 (Reactome)
Phosphorylated ERBB2 ERBB4 heterodimersComplexREACT_117434 (Reactome)
Phosphorylated ERBB2 ERBB4cyt1 heterodimersComplexREACT_117511 (Reactome)
Phosphorylated ERBB2 heterodimers MATKComplexREACT_117768 (Reactome)
Phosphorylated ERBB2 heterodimersComplexREACT_116377 (Reactome)
Phosphorylated p-6Y-ERBB2 heterodimersComplexREACT_116794 (Reactome)
Phosphorylated p-Y877-ERBB2 heterodimersComplexREACT_116234 (Reactome)
RAF/MAP kinase cascadePathwayREACT_634 (Reactome) The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.
RNF41 ProteinQ9H4P4 (Uniprot-TrEMBL)
RNF41ProteinQ9H4P4 (Uniprot-TrEMBL)
RPS27AProteinP62979 (Uniprot-TrEMBL)
SHC1 Phosphorylated ERBB2 heterodimersComplexREACT_116413 (Reactome)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
STUB1ProteinQ9UNE7 (Uniprot-TrEMBL)
UBA52ProteinP62987 (Uniprot-TrEMBL)
UBBProteinP0CG47 (Uniprot-TrEMBL)
UBCProteinP0CG48 (Uniprot-TrEMBL)
USP8ProteinP40818 (Uniprot-TrEMBL)
Ub-ERBB2

ERBB2IP HSP90

CDC37		ComplexREACT_116340 (Reactome)
Ub-ERBB2

ERBB2IP Ub-HSP90

CDC37		ComplexREACT_116767 (Reactome)
Ub-ERBB3ComplexREACT_117196 (Reactome)
Ub-RNF41 p-USP8ComplexREACT_117304 (Reactome)
Ub-RNF41ComplexREACT_117273 (Reactome)
UbProteinREACT_3316 (Reactome)
p-10Y-ERBB3-1 ProteinP21860-1 (Uniprot-TrEMBL)
p-4Y-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-6Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-7Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-T945-USP8 ProteinP40818 (Uniprot-TrEMBL)
p-T945-USP8ProteinP40818 (Uniprot-TrEMBL)
p-Y,Y877-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-Y-ERBB2 ProteinP04626 (Uniprot-TrEMBL)
p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform ProteinQ15303-2 (Uniprot-TrEMBL)
p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform ProteinQ15303-1 (Uniprot-TrEMBL)
p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform ProteinQ15303-3 (Uniprot-TrEMBL)
p-Y349,350-SHC1 Phosphorylated ERBB2 heterodimersComplexREACT_117006 (Reactome)
p-Y349,Y350-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y419/420/426-N-myristoyl-SRC/FYN/YES1ProteinREACT_116628 (Reactome)
p-Y877-ERBB2 heterodimersComplexREACT_117823 (Reactome)
p21 RAS GDPComplexREACT_2657 (Reactome)
p21 RAS GTPComplexREACT_4782 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_115659 (Reactome)
ADPArrowREACT_115673 (Reactome)
ADPArrowREACT_115797 (Reactome)
ADPArrowREACT_115850 (Reactome)
ADPArrowREACT_115882 (Reactome)
ADPArrowREACT_116044 (Reactome)
ADPArrowREACT_116057 (Reactome)
ADPArrowREACT_116065 (Reactome)
ADPArrowREACT_116116 (Reactome)
ATPREACT_115659 (Reactome)
ATPREACT_115673 (Reactome)
ATPREACT_115797 (Reactome)
ATPREACT_115850 (Reactome)
ATPREACT_115882 (Reactome)
ATPREACT_116044 (Reactome)
ATPREACT_116057 (Reactome)
ATPREACT_116065 (Reactome)
ATPREACT_116116 (Reactome)
Active AKTmim-catalysisREACT_116065 (Reactome)
CDC37ArrowREACT_115761 (Reactome)
CUL5mim-catalysisREACT_115557 (Reactome)
EGF

p-EGFR p-ERBB2 GRB2 GAB1

PI3K		mim-catalysisREACT_115673 (Reactome)
EGF

p-EGFR p-ERBB2 GRB2 GAB1

PIK3R1		REACT_115734 (Reactome)
EGF

p-EGFR p-ERBB2 GRB2

GAB1		REACT_115532 (Reactome)
EGF

p-EGFR p-ERBB2 GRB2

SOS1		mim-catalysisREACT_115771 (Reactome)
EGF

p-EGFR p-ERBB2

PLCG1		REACT_115882 (Reactome)
EGF

p-EGFR p-ERBB2

PLCG1		mim-catalysisREACT_115882 (Reactome)
ERBB2

ERBB2IP HSP90

CDC37		REACT_115557 (Reactome)
ERBB2

ERBB2IP HSP90

CDC37		REACT_115761 (Reactome)
ERBB2

ERBB2IP HSP90

CDC37		REACT_116015 (Reactome)
ERBB2 heterodimersArrowREACT_115761 (Reactome)
ERBB2 heterodimersREACT_115797 (Reactome)
ERBB2 heterodimersREACT_116044 (Reactome)
ERBB2 heterodimersmim-catalysisREACT_116044 (Reactome)
ERBB2IPArrowREACT_115761 (Reactome)
ERBB3 RNF41REACT_115952 (Reactome)
ERBB3 RNF41mim-catalysisREACT_115952 (Reactome)
ERBB3-1REACT_115637 (Reactome)
ERBB3-1REACT_115643 (Reactome)
GDPArrowREACT_115675 (Reactome)
GDPArrowREACT_115771 (Reactome)
GDPArrowREACT_116041 (Reactome)
GRB2 GAB1REACT_116087 (Reactome)
GRB2

SOS1 p-Y349,350-SHC1

Phosphorylated ERBB2 heterodimers		mim-catalysisREACT_116041 (Reactome)
GRB2 SOS1REACT_116115 (Reactome)
GRB2 SOS1REACT_116127 (Reactome)
GRB2 SOS1REACT_116140 (Reactome)
GRB7REACT_115703 (Reactome)
GTPREACT_115675 (Reactome)
GTPREACT_115771 (Reactome)
GTPREACT_116041 (Reactome)
HSP90ArrowREACT_115761 (Reactome)
Ligand-Activated EGFR/ERBB3/ERBB4REACT_115761 (Reactome)
MATKREACT_115602 (Reactome)
NRG1/2

Ub-p-10Y-ERBB3

p-ERBB2		ArrowREACT_115599 (Reactome)
NRG1/2

p-10Y-ERBB3 p-ERBB2

RNF41		REACT_115599 (Reactome)
NRG1/2

p-10Y-ERBB3 p-ERBB2

RNF41		mim-catalysisREACT_115599 (Reactome)
NRG1/2

p-ERBB3 p-ERBB2

PI3K		mim-catalysisREACT_116116 (Reactome)
NRG1/2

p-ERBB3 p-ERBB2

PIK3R1		REACT_116108 (Reactome)
NRG1/2REACT_115637 (Reactome)
NRGs/EGFLs

p-ERBB4 p-ERBB2 GRB2

SOS1		mim-catalysisREACT_115675 (Reactome)
NRGs/EGFLs

p-ERBB4cyt1 p-ERBB2

PI3K		mim-catalysisREACT_116057 (Reactome)
NRGs/EGFLs

p-ERBB4cyt1 p-ERBB2

PIK3R1		REACT_115622 (Reactome)
PIArrowREACT_115673 (Reactome)
PIArrowREACT_116057 (Reactome)
PIArrowREACT_116116 (Reactome)
PIK3CAREACT_115622 (Reactome)
PIK3CAREACT_115734 (Reactome)
PIK3CAREACT_116108 (Reactome)
PIK3R1REACT_115532 (Reactome)
PIK3R1REACT_115880 (Reactome)
PIK3R1REACT_115895 (Reactome)
PIREACT_115673 (Reactome)
PIREACT_116057 (Reactome)
PIREACT_116116 (Reactome)
PLCG1REACT_115579 (Reactome)
Phosphorylated ERBB2 EGFR heterodimersArrowREACT_115882 (Reactome)
Phosphorylated ERBB2 EGFR heterodimersREACT_115579 (Reactome)
Phosphorylated ERBB2 EGFR heterodimersREACT_116087 (Reactome)
Phosphorylated ERBB2 EGFR heterodimersREACT_116115 (Reactome)
Phosphorylated ERBB2 ERBB3 heterodimersREACT_115703 (Reactome)
Phosphorylated ERBB2 ERBB3 heterodimersREACT_115880 (Reactome)
Phosphorylated ERBB2 ERBB3 heterodimersREACT_116128 (Reactome)
Phosphorylated ERBB2 ERBB4 heterodimersREACT_116140 (Reactome)
Phosphorylated ERBB2 ERBB4cyt1 heterodimersREACT_115895 (Reactome)
Phosphorylated ERBB2 heterodimersREACT_115602 (Reactome)
Phosphorylated ERBB2 heterodimersREACT_116025 (Reactome)
Phosphorylated p-6Y-ERBB2 heterodimersArrowREACT_116044 (Reactome)
Phosphorylated p-Y877-ERBB2 heterodimersArrowREACT_115659 (Reactome)
REACT_115532 (Reactome) Regulatory subunit p85 of PI3K (PIK3R1) binds GAB1 in complex with GRB2 and phosphorylated ERBB2:EGFR heterodimer.
REACT_115557 (Reactome) E3 ubiquitin ligase Cullin-5 (CUL5) is recruited to the ERBB2 site at the plasma membrane and ubiquitinates ERBB2 in an HSP90-dependent way, targeting it for degradation. Ubiquitination of ERBB2 by CUL5 appears to be independent of CUL5 adaptor proteins ElonginB and ElonginC.
REACT_115579 (Reactome) Phospholipase C gamma 1 (PLCG1) binds to phosphorylated tyrosine Y1023 of ERBB2 or phosphorylated tyrosines Y992 and Y1173 of EGFR.
REACT_115599 (Reactome) RNF41 ubiquitinates activated ERBB3, thereby downregulating ERBB3-mediated signaling. This reaction is part of a negative feedback loop in ERBB2:ERBB3 signaling.
REACT_115602 (Reactome) MATK (also known as CHK or CSK homologous kinase) binds to ERBB2 through phosphorylated tyrosine residue Y1253 in the C-tail of ERBB2 and, through an unknown mechanism, inhibits ERBB2 downstream signaling.
REACT_115622 (Reactome) Catalytic subunit p110 of PI3K (PIK3CA) is recruited by the regulatory p85 subunit of PI3K (PIK3R1) directly bound to phosphorylated ERBB2:ERBB4cyt1 heterodimer, resulting in the assembly of an active PI3K complex.
REACT_115637 (Reactome) ERBB3 becomes activated by binding either neuregulin 1 (NRG1) or neuregulin 2 (NRG2).
REACT_115643 (Reactome) RNF41 ubiquitin ligase is able to bind unstimulated ERBB3.
REACT_115659 (Reactome) Phosphorylation of ERBB2 on tyrosine residue Y877 by SRC family kinases significantly increases trans-autophosphorylation rate of ERBB2 heterodimers, presumably by enabling the kinase domain of ERBB2 to achieve a conformation that positively affects ERBB2 kinase activity. The downstream signaling of phosphorylated ERBB2 heterodimers that are phosphorylated on Y877 of ERBB2, in addition to the known trans-autophosphorylation sites, has not been studied extensively; it is assumed that the behavior of Y877-phosphorylated ERBB2 heterodimers is qualitatively similar to the behavior of trans-autophosphorylated ERBB2 heterodimers which do not harbor this modification.
REACT_115673 (Reactome) Active PI3K in complex with p-EGFR:p-ERBB2:GRB2:GAB1 phosphorylates PIP2 into PIP3, leading to activation of AKT signaling.
REACT_115675 (Reactome) SOS1 bound to GRB2 in complex with any of the phosphorylated ERBB2:ERBB4 heterodimers catalyzes guanyl-nucleotide exchange on RAS, leading to the activation of the MAP kinase cascade.
REACT_115703 (Reactome) Phosphorylated tyrosine residues Y1199 and Y1262 of ERBB3 in complex with ERBB2 are docking sites for GRB7 binding.
REACT_115734 (Reactome) Catalytic subunit p110 of PI3K (PIK3CA) is recruited by the regulatory p85 subunit of PI3K (PIK3R1) bound to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR.
REACT_115761 (Reactome) ERBB2, which does not bind any known ligand, is activated through formation of a heterodimer with another ligand-activated ERBB family member. ERBB2 heterodimerization partners are EGF-stimulated EGFR (Wada et al. 1990, Karunagaran et al. 1996), ERBB3 stimulated by neuregulins NRG1 or NRG2 (Pinkas-Kramarski et al. 1996), and ERBB4 stimulated by neuregulins or EGF-like ligands (Li et al. 2007). In the process of dimerization, ERBB2 dissociates from chaperone proteins HSP90 and CDC37 (Xu et al 2001, Citri et al. 2004). Activated ERBB2 also dissociates from ERBB2IP, the protein reponsible for proper localization of ERBB2 to basolateral membranes of epithelial cells (Borg et al. 2000).
REACT_115763 (Reactome) Phosphorylated USP8 deubiquitinates RNF41 and increases RNF41 level in the cell.
REACT_115771 (Reactome) SOS1 bound to GRB2 in complex with phosphorylated ERBB2:EGFR heterodimer catalyzes guanyl-nucleotide exchange on RAS, leading to activation of the MAP kinase cascade.
REACT_115797 (Reactome) Dissociation of HSP90 from ERBB2 upon formation of ERBB2 heterodimers (with either EGFR, ERBB3 or ERBB4) enables phosphorylation of ERBB2 on the tyrosine residue Y877, mediated by one of SRC family kinases - SRC, FYN or YES1. Although not a mandatory prerequisite of ERBB2 catalytic activity, the phosphorylation at Y877 significantly increases the kinase activity of ERBB2.
REACT_115850 (Reactome) Once bound to ERBB2 heterodimers, SHC1 is phosphorylated on tyrosine residues by the tyrosine kinase activity of either ERBB2 or its heterodimerization partners EGFR and ERBB4.
REACT_115880 (Reactome) Membrane associated p85 subunit of PI3K (PIK3R1) binds to phosphorylated tyrosine residues of ERBB3 (Y1054, Y1197, Y1222, Y1224, Y1276 and Y1289) in complex with ERBB2.
REACT_115882 (Reactome) Phospholipase C gamma 1 (PLCG1) is phosphorylated by phosphorylated EGFR:ERBB2 heterodimer.
REACT_115895 (Reactome) p85 subunit of PI3K (PIK3R1) directly binds to any of the two phosphorylated ERBB4 CYT1 isoforms in complex with ERBB2 through interaction with a phosphorylated tyrosine residue in the C-tail of ERBB4 CYT1 (Y1056 in ERBB4 JM-A CYT1; Y1046 in ERBB4 JM-B CYT1).
REACT_115952 (Reactome) RNF41 ubiquitinates unstimulated ERBB3, targeting it for degradation and regulating ERBB3 level in the cell.
REACT_115963 (Reactome) RNF41 is able to self-ubiquitinate, which keeps its levels low when ERBB3 is unstimulated.
REACT_116015 (Reactome) E3 ubiquitin ligase CHIP (STUB1) mediates ERBB2 ubiquitination by associating with the ERBB2 indirectly, through the chaperone protein HSP90. CHIP (STUB1) ubiquitinates both ERBB2 and HSP90, leading to their proteasome-dependent degradation. Ubiquitination of ERBB2 by CHIP (STUB1) is independent of ERBB2 activation.
REACT_116025 (Reactome) SHC1 binds phosphorylated ERBB2:EGFR heterodimers through phosphorylated tyrosine residues on either ERBB2 (Y1196, Y1221, Y1222 and Y1248) or EGFR (Y1148 and Y1173). Heterodimers of ERBB2 and ERBB3 recruit SHC1 through a phosphorylated tyrosine residue Y1328 in the C-tail of ERBB3. Heterodimers of ERBB2 and ERBB4 isoforms recruit SHC1 through phosphorylated tyrosines in the C-tail of etiher ERBB2 (Y1196, Y1221, Y1222 and Y1248) or ERBB4 (Y1188 and Y1242 in ERBB4 JM-A CYT1 isoform; Y1178 and Y1232 in ERBB4 JM-B CYT1 isoform; Y1172 and Y1226 in ERBB4 JM-A CYT2 isoform). Association of SHC1 with ERBB2:EGFR and ERBB2:ERBB3 heterodimers was demonstrated in engineered mouse 32D cells in which human ERBB2, EGFR and ERBB3 were expressed. Therefore, these experiments showed association of human ERBB receptor dimers and mouse Shc1. In the case of ERBB2:ERBB4 heterodimers, direct evidence, involving human proteins only, is available.
REACT_116041 (Reactome) SOS1, bound to GRB2 in complex with phosphorylated SHC1 and phosphorylated ERBB2 dimers, catalyzes guanyl-nucleotide exchange on RAS.
REACT_116044 (Reactome) Dimers of ERBB2 and EGF-bound EGFR trans-autophosphorylate on six EGFR tyrosine residues and six ERBB2 tyrosine residues to form phosphorylated heterodimers that activate downstream signaling cascades (Ricci et al. 1995, Pinkas-Kramarski et al. 1996, Walton et al. 1990, Margolis et al. 1989, Hazan et al. 1990, Helin et al. 1991).

In heterodimers of ERBB2 and neuregulin-stimulated ERBB3, ERBB2 phosphorylates ERBB3 on tyrosine residues that serve as docking sites for p85 subunit of PI3K (Y1054, Y1197, Y1222, Y1224, Y1260, Y1276 and Y1289), as well as SHC1 (Y1328) and GRB7 (Y1199 and Y1262). Since ERBB3 lacks catalytic activity, it cannot phosphorylate ERBB2. Hovewer, since ERBB2:ERBB3 heterodimers usually oligomerize on the cell surface, ERBB2 can become trans-autophosphorylated by and adjacent ERBB2 protein. It is not known if ERBB2 in the ERBB2:ERBB3 hetero-oligomer is phosphorylated on all conserved tyrosine residues and if the phosphorylation status of ERBB2 in the ERBB2:ERBB3 hetero-oligoimer significantly affects signaling (Li et al. 2007, Pinkas-Kramarski et al. 1996, Prigent et al. 1994, Vijapurkar et al. 2003, Wallasch et al. 1995).

Heterodimers of ERBB2 and ERBB4 trans-autophosphorylate on tyrosine residues that serve as docking sites for PLC-gamma, GRB2 and SHC1, as well as p85 subunit of PI3K (PIK3R1) in the case of ERBB2 heterodimers with ERBB4 CYT1 isoforms (ERBB4cyt1) - ERBB4 JM-A CYT1 and ERBB4 JM-B-CYT1 (Li et al. 2007, Kaushansky et al. 2008, Hazan et al. 1990, Cohen et al. 1996).
REACT_116057 (Reactome) Active PI3K in complex with phosphorylated ERBB2:ERBB4cyt1 heterodimer phosphorylates PIP2 into PIP3, leading to activation of AKT signaling.
REACT_116065 (Reactome) Activated AKT phosphorylates USP8, thereby stabilizing it and allowing it to deubiquitinate NRDP1, which results in increased NRDP1 level and downregulation of ERBB3. This represents a negative feedback loop in ERBB3-mediated signaling.
REACT_116087 (Reactome) GAB1 in complex with GRB2 is recruited to activated ERBB2:EGFR heterodimer through phosphorylated tyrosine residues that serve as docking sites for GRB2.
REACT_116108 (Reactome) PI3K subunit p85 (PIK3R1) bound to ERBB2:p-ERBB3 recruits PI3K subunit p110 (PIK3CA) to form an active PI3K complex.
REACT_116115 (Reactome) Phosphorylated ERBB2:EGFR heterodimer recruits GRB2:SOS1 complex through phosphorylated tyrosine residues on either ERBB2 or EGFR that serve as direct docking sites for GRB2.
REACT_116116 (Reactome) Activated PI3K complex directly bound to phosphorylated heterodimer of ERBB2 and ERBB3 phosphorylates PIP2 and converts it into PIP3, leading to activation of AKT signaling.
REACT_116127 (Reactome) Phosphorylated SHC1 bound to phosphorylated ERBB2 dimers recruits GRB2:SOS1 complex.
REACT_116128 (Reactome) In addition to regulating the level of unstimulated ERBB3, ubiquitin ligase RNF41 is able to interact with neuregulin-activated ERBB3.
REACT_116140 (Reactome) GRB2:SOS1 complex binds to phosphorylated tyrosine residue Y1139 of ERBB2 in complex with ERBB4.
REACT_116151 (Reactome) Ubiquitinated RNF41 binds deubiquitinating enzyme USP8, previously activated by phosphorylation on threonine residue T945.
RNF41ArrowREACT_115599 (Reactome)
RNF41ArrowREACT_115763 (Reactome)
RNF41ArrowREACT_115952 (Reactome)
RNF41REACT_115643 (Reactome)
RNF41REACT_115963 (Reactome)
RNF41REACT_116128 (Reactome)
RNF41mim-catalysisREACT_115963 (Reactome)
SHC1 Phosphorylated ERBB2 heterodimersREACT_115850 (Reactome)
SHC1 Phosphorylated ERBB2 heterodimersmim-catalysisREACT_115850 (Reactome)
SHC1REACT_116025 (Reactome)
STUB1mim-catalysisREACT_116015 (Reactome)
USP8REACT_116065 (Reactome)
Ub-ERBB3ArrowREACT_115952 (Reactome)
Ub-RNF41 p-USP8mim-catalysisREACT_115763 (Reactome)
Ub-RNF41REACT_116151 (Reactome)
UbArrowREACT_115763 (Reactome)
UbREACT_115557 (Reactome)
UbREACT_115599 (Reactome)
UbREACT_115952 (Reactome)
UbREACT_115963 (Reactome)
UbREACT_116015 (Reactome)
p-4Y-PLCG1ArrowREACT_115882 (Reactome)
p-T945-USP8ArrowREACT_115763 (Reactome)
p-T945-USP8ArrowREACT_116065 (Reactome)
p-T945-USP8REACT_116151 (Reactome)
p-Y349,350-SHC1 Phosphorylated ERBB2 heterodimersArrowREACT_115850 (Reactome)
p-Y349,350-SHC1 Phosphorylated ERBB2 heterodimersREACT_116127 (Reactome)
p-Y419/420/426-N-myristoyl-SRC/FYN/YES1mim-catalysisREACT_115797 (Reactome)
p-Y877-ERBB2 heterodimersArrowREACT_115797 (Reactome)
p-Y877-ERBB2 heterodimersREACT_115659 (Reactome)
p-Y877-ERBB2 heterodimersmim-catalysisREACT_115659 (Reactome)
p21 RAS GDPREACT_115675 (Reactome)
p21 RAS GDPREACT_115771 (Reactome)
p21 RAS GDPREACT_116041 (Reactome)
p21 RAS GTPArrowREACT_115675 (Reactome)
p21 RAS GTPArrowREACT_115771 (Reactome)
p21 RAS GTPArrowREACT_116041 (Reactome)
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