Signaling by EGFR (Homo sapiens)

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32, 50, 63, 72364060, 62, 71532, 6, 467, 1418693, 5, 10, 12, 19...5, 9, 12, 19, 39...135, 6, 12, 19, 41...1928, 78121, 4539, 4612, 20, 27, 5258, 763748678229, 77825, 12, 19, 64, 737552, 6422, 654411, 7038, 79593, 5, 10, 12, 19...33, 47152531, 404, 51, 55167, 8112, 644348746, 19, 4157546134, 80835, 9, 12, 19, 23...4682826828, 78497, 8183522, 6548183319, 20, 52, 6423, 42196, 19, 4112, 20, 27, 5229, 77305969EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 SPRY1/2 CBLSPRY1/2 HSP90 p-5Y-EGFRvIII mutant dimer EGFLigand-responsive EGFR mutants resistant to non-covalent TKIsHSP90CDC37 p-5Y-EGFRvIII mutant dimer p-EGFR mutantsGRB2GAB1PIK3R1 HSP90 EGFp-6Y-EGFRGRB2p-Y627,659-GAB1SHP2 CDC37 p-EGFR mutantsGRB2GAB1PIK3R1 p21 RASGTP Active dimers of ligand-responsive EGFR mutants sensitive to non-covalent TKIs Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 Eps15HGSSTAM STAM EGFPhospho-EGFR EGFLigand-responsive EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 p21 RASGDP EGFp-6Y-EGFRCBLCIN85 Dimers of EGFLigand-responsive p-6Y-EGFR mutants EGFp-6Y-EGFRp-Y371-CBLGRB2CIN85Endophilin Ligand-responsive p-6Y-EGFR mutant dimers EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 CDC37 p21 RAS Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Dimers of EGFLigand-responsive p-6Y-EGFR mutants Eps15HGSSTAM Ligand-responsive p-6Y-EGFR mutant dimers GRB2Phospho-GAB1 EGFPhospho-EGFR Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 p-EGFR mutantsp-Y472,771,783,1254-PLCG1 CDC37 STAM CDC37 Dimers of ligand-responsive p-6Y-EGFR mutants Ligand-responsive EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 HSP90 Ligand-responsive p-6Y-EGFR mutant dimers Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 CBLGRB2 CBLBeta-PixCDC42GTP EGFp-6Y-EGFR Reversible EGFR-specific TKIs EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFRvIII mutantHSP90CDC37 GRB2GAB1 EGFPhospho-EGFR CDC37 Benzoquinoid ansamycins EGFp-6Y-EGFR EGFRCetuximab EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 Dimers of EGFLigand-responsive p-6Y-EGFR mutants STAM Phospho-EGFRvIIImutHSP90CDC37 Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 Phospho-EGFRvIIImutHSP90CDC37 Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 EGFPhospho-EGFR Non-covalent EGFR tyrosine kinase inhibitors CDC42GTP Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 HSP90 EGFPhospho-EGFR EGFEGFR p-EGFR mutants dimer p-EGFR mutants dimer EGFRvIII mutant dimer Ligand-responsive EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Clathrin Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFp-6Y-EGFRPLCG1 Ligand-responsive p-6Y-EGFR mutant dimers Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFPhospho-EGFR Sensitive ligand-responsive EGFR mutantsNon-covalent EGFR TKIs EGFp-6Y-EGFRCBLp-Y53/55-SPRY1/2 Phospho-EGFRvIIImutHSP90CDC37 EGFp-6Y-EGFRCBLUb-p-Y53/55-SPRY1/2 Eps15HGSSTAM EGFp-6Y-EGFRp-Y371-CBLGRB2 EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFp-6Y-EGFRGRB2GAB1 p-EGFR mutants dimer Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 EGFp-6Y-EGFRp-Y371-CBLGRB2CIN85EndophilinEpsinEps15REps15Clathrin CDC37 Ligand-responsive EGFR mutants resistant to non-covalent TKIsHSP90CDC37 EGFp-6Y-EGFRGRB2GAB1PIK3 EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 EGFp-6Y-EGFRp-Y349,350-SHC1GRB2SOS1 p-EGFR mutantsp-Y349,350-SHC1GRB2SOS1 Phospho-EGFRvIIImutHSP90CDC37 CDC37 EGFp-5Y-EGFRGRB2p-5Y-GAB1SHP2 CDC42GTP Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 Dimers of ligand-responsive p-6Y-EGFR mutants Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 HSP90 Dimers of ligand-responsive p-6Y-EGFR mutants Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 Ligand-responsive p-6Y-EGFR mutant dimers EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 EGFPhospho-EGFR Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 EGFPhospho-EGFR CDC37 Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFLigand-responsive EGFR mutantsHSP90CDC37 Dimers of EGFLigand-responsive p-6Y-EGFR mutants CBLBeta-Pix Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 CDC37 EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 Dimers of EGFLigand-responsive p-6Y-EGFR mutants Ub-p-Y53/55-SPRY1/2 EGFp-6Y-EGFRp-Y371-CBL EGFp-6Y-EGFRSHC1 Ligand-responsive p-6Y-EGFR mutant dimers Dimers of EGFLigand-responsive p-6Y-EGFR mutants GRB2SOS1 EGFp-6Y-EGFRp-Y472,771,783,1254-PLCG1 Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 Covalent EGFR tyrosine kinase inhibitors EGFPhospho-EGFR ADAMZn2+ Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFp-6Y-EGFR CBLBeta-Pix EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 GRB2Phospho-GAB1CDC42GTP EGFLigand-responsive EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 HSP90Benzoquinoid ansamycins EGFPhospho-EGFR EGFp-6Y-EGFRCBLBeta-PixCDC42GTP EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 p-EGFR mutantsp-Y349,350-SHC1 GRB2SOS1 Ub HSP90 Reversible anti-EGFRplus TKIs p-5Y-EGFRvIII mutant dimer p-5Y-EGFRvIII mutant dimer EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 p-5Y-EGFRvIII mutant dimer Adaptor protein complex 2 EGFp-6Y-EGFR HSP90 GRB2GAB1 Irreversible EGFR-specific TKIs HSP90 p-EGFR mutants dimer EGFp-6Y-EGFR EGFPhospho-EGFR EGFPhospho-EGFR EGFPhospho-EGFR p-EGFR mutantsGRB2SOS1 AP-2 complex Phospho-EGFRvIIImutHSP90CDC37 CDC37 HSP90 GRB2GAB1PIK3R1 CDC42GTP GRB2GAB1 CDC37 GRB2Phospho-GAB1 EGFEGFR dimer Eps15HGSSTAM EGFp-6Y-EGFRp-Y349,350-SHC1 Ligand-responsive p-6Y-EGFR mutantsp-Y371-CBL Ub EGFPhospho-EGFR Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Resistant ligand-responsive EGFR mutantsCovalent EGFR TKIs EGFLigand-responsive EGFR mutants dimer EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Irreversible EGFR-specific TKIs CIN85Endophilin CBLGRB2 Ligand-responsive EGFR mutants dimer EGFp-6Y-EGFRGRB2GAB1PIK3R1 Ligand-responsive Ub-p-6Y-EGFR mutantsp-Y371-CBL EGFp-6Y-EGFR EGFp-6Y-EGFRp-Y349,350-SHC1 Dimers of EGFLigand-responsive p-6Y-EGFR mutants Ub EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Dimers of EGFLigand-responsive p-6Y-EGFR mutants EGFp-6Y-EGFRGRB2p-5Y-GAB1 EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 SPRY1/2 EGFEGFR p-Y53/55-SPRY1/2 Resistant ligand-responsive EGFR mutants Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 p-5Y-EGFRvIII mutant dimer Dimers of ligand-responsive p-6Y-EGFR mutants CBLSPRY1/2 Dimers of ligand-responsive EGFR mutants sensitive to non-covalent TKIs ADAM metalloprotease CIN85Endophilin Dimers of ligand-responsive p-6Y-EGFR mutants EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 Phospho-EGFRvIIImutHSP90CDC37 p-EGFR mutants dimer Irreversible anti-EGFRplus TKIs GRB2GAB1PIP3 Adaptor protein complex 2 EGFUb-p-6Y-EGFRp-Y371-CBLGRB2 CDC37 EGFp-6Y-EGFR EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 p21 RAS CDC37 CDC37 GRB2GAB1 PXNCSKSRC Irreversible anti-EGFRplus TKIs p-5Y-EGFRvIII mutant dimer Ligand-responsive p-6Y-EGFR mutant dimers Ligand-responsive p-6Y-EGFR mutant dimers EGFp-6Y-EGFR Ligand-responsive EGFR mutantsHSP90CDC37 EGFEGFR DimerCovalent EGFR TKIs Dimers of ligand-responsive p-6Y-EGFR mutants Dimers of EGFLigand-responsive p-6Y-EGFR mutants p-EGFR mutants dimer HSP90 CIN85Endophilin GRB2SOS1 Dimers of EGFLigand-responsive EGFR mutants sensitive to non-covalent TKIs Dimers of ligand-responsive p-6Y-EGFR mutants Clathrin-coated vesicle EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 Dimers of EGFLigand-responsive p-6Y-EGFR mutants EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 HSP90 p-EGFR mutantsSHC1 Ligand-responsive p-6Y-EGFR mutant dimers Ligand-responsive p-6Y-EGFR mutant dimers HSP90 Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 cytosolp-EGFR mutants dimer Phospho-EGFRvIIImutHSP90CDC37 Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 Dimers of ligand-responsive p-6Y-EGFR mutants Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 EGFp-6Y-EGFRCBLGRB2 Dimers of EGFLigand-responsive EGFR mutants resistant to non-covalent TKIs HSP90 Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 HSP90 EGFp-6Y-EGFRp-Y371-CBLCIN85SPRY1/2EndophilinEpsinEps15REps15 EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFp-6Y-EGFRp-Y371-CBLUb-CIN85EndophilinEpsinEps15REps15 EGFLigand-responsive EGFR mutants resistant to non-covalent TKIsHSP90CDC37 GRB2GAB1PIK3R1 GRB2GAB1PIK3R1 Beta-PixCDC42GTP HSP90 HSP90 EGFp-6Y-EGFRCBL Beta-PixCDC42GTP Phospho-EGFRvIIImutHSP90CDC37 p-Y53/55-SPRY1/2 Ligand-responsive p-6Y-EGFR mutantsHSP90CDC37 STAM Ub-Beta-PixCDC42GTP Ub GRB2SOS1 HSP90 EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 EGFUb-p-6Y-EGFRp-Y371-CBL AP-2 complex EGFp-6Y-EGFR EGFp-6Y-EGFR EGFp-6Y-EGFRCBL EGFp-6Y-EGFR CDC37 EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 CIN85 ubiquitinatedEndophilin Phospho-EGFRvIIImutHSP90CDC37 SPRY1/2 EGFp-6Y-EGFRp-Y371-CBLCIN85EndophilinEpsinEps15REps15 GRB2SOS1 Covalent EGFR tyrosine kinase inhibitors EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 CDC37 EGFEGFR GRB2GAB1 Ligand-responsive p-6Y-EGFR mutant dimers PXNSRC Phospho-CBLGRB2 EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 Dimers of ligand-responsive p-6Y-EGFR mutants EGFPhospho-EGFR EGFp-6Y-EGFRGRB2SOS1 Clathrin Dimers of EGFLigand-responsive p-6Y-EGFR mutants p-EGFR mutantsGRB2GAB1PI3K Eps15HGSSTAM EGFp-6Y-EGFR p-EGFR mutantsPLCG1 EGFp-6Y-EGFRCBL p-EGFR mutantsp-Y349,350-SHC1 Ub p-EGFR mutants dimer Ligand-responsive EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 CDC37 Ligand-responsive p-6Y-EGFR mutantsCBL HSP90 CDC42GTP p-5Y-EGFRvIII mutant dimer Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 GRB2Phospho-GAB1 Dimers of ligand-responsive p-6Y-EGFR mutants STAM CDC37 Ligand-responsive p-6Y-EGFR mutantsp-Y371-CBL CDC37 EGFRvIII mutantHSP90CDC37 Dimers of ligand-responsive EGFR mutants resistant to non-covalent TKIs EGFLigand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 EGFLigand-responsive p-6Y-EGFR mutantsHSP90CDC37 EGFp-6Y-EGFR EGFEGFR dimer p-5Y-EGFRvIII mutant dimer CIN85Endophilin EGFp-6Y-EGFRGRB2p-5Y-GAB1SHP2 EGFLigand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIsHSP90CDC37 HSP90 Dimers of ligand-responsive p-6Y-EGFR mutants HSP90 CIN85Endophilin Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIsHSP90CDC37 SH3GL2 EGFUBCCBLGRB2EPS15 ATPEGFR HSP90AA1 CBLBeta-PixCDC42GTPUBBSPRY2 EPN1 UBCPXNSRCPIK3R1GTP EGFEGFR DimerCovalent EGFR TKIsHKI-272 p-6Y-EGFR GRB2-1 EGFp-6Y-EGFRCBLp-Y53/55-SPRY1/2UBBPIK3R1 p-6Y-EGFR p-EGFR mutantsp-Y349,350-SHC1GRB2SOS1p-EGFRvIII mutant EGFUbGRB2-1 Eps15HGSSTAMEGFp-6Y-EGFRp-Y371-CBLGRB2CIN85EndophilinADAM17 EGFGRB2-1 EGFHSP90AA1 p-4Y-PLCG1 UBCH2OGTP EGFR SRC-1UBCEGFp-6Y-EGFRSHC1CLTA p-Y349,Y350-SHC1 p-EGFRvIII mutant Lapatinib Resistant ligand-responsive EGFR mutantsEPS15L1p-6Y-EGFR p-6Y-EGFR ARHGEF7 WZ4002 p-6Y-EGFR Ub-SH3KBP1 Non-covalent EGFR tyrosine kinase inhibitorsHGS PXN p-EGFRvIII mutant AP-2 complexEPS15L1Pip-EGFR mutantsPLCG1ADPCanertinib UBCGRB2GAB1PIK3R1EPN1 GDP Ligand-responsive EGFR mutantsp-EGFR mutantsSHC1UBCEGFUBCGAB1 CBL EGFp-6Y-EGFRPLCG1ClathrinEGFUBCATPEPS15 SHC1 STAM SH3KBP1 STAM CDC37STAM2 EGFLigand-responsive p-6Y-EGFR mutantsp-Y371-CBLGRB2-1 EGFp-6Y-EGFR HSP90AA1 HSP90AA1 p-EGFRvIII mutant GTP Beta-PixCDC42GTPARHGEF7 CDC42 CDC37ATPPTPN11 EGFp-6Y-EGFRCBLp-EGFR mutantsGRB2SOS1EPS15 EGFp-6Y-EGFRGRB2GAB1PIK3R1AP2A1 ATPHKI-272 ADAM12 UBCEGFCBLSPRY1/2UBBCBL EGFp-6Y-EGFRGRB2SOS1EGFRvIII mutantHSP90CDC37EGFGRB2-1 UBCCSKSOS1 EGFEGFp-6Y-EGFR p-Y371-CBL Active dimers of ligand-responsive EGFR mutantsEGFRvIII mutantUbp-Y371-CBL EGFp-6Y-EGFR GRB2-1 SPRY1/2UBCUBBp-EGFR mutants dimerSOS1 UBCARHGEF7 HSP90AA1 CetuximabUBBEGFUBCp-6Y-EGFR AP2A2UBCGRB2-1 GRB2-1 PiCDC37HSP90AA1 Pro-EGFHGS UBBH2OEGFGRB2SOS1ATPSOS1 PIGRB2-1 UBCGRB2-1 CDC37p-Y55-SPRY2UBBEGFp-5Y-EGFRGRB2p-5Y-GAB1SHP2Ligand-responsive p-6Y-EGFR mutantsCBLEGFp-6Y-EGFRp-Y371-CBLGRB2CIN85EndophilinEpsinEps15REps15ClathrinPiPIK3R1 AP2B1 EGFRvIII mutant PIAP2A1 PIK3R1 GRB2-1 STAM2 SH3GL2 EGFLigand-responsive EGFR mutantsHSP90CDC37UBCEPS15L1CDC42 CBL p-EGFR mutantsp-Y349,350-SHC1EGFUb-p-6Y-EGFRp-Y371-CBLAP2M1 Geldanamycin UBA52EGFRPS27Ap-Y349,Y350-SHC1 EGFp-6Y-EGFRp-Y371-CBLGRB2p-Y371-CBL CDC42 p-5Y-GAB1 GAB1EGFp-6Y-EGFRGRB2p-5Y-GAB1SHP2EGFp-6Y-EGFRGRB2p-5Y-GAB1AP2S1 UBCNRAS Gefitinib EGFCDC37CDC42 SH3GL2 ATPSTAM2 SPRY1p-6Y-EGFR p-Y53-SPRY1Canertinib PIK3CA EPN1SH3KBP117-AAG CDC37Ligand-responsive EGFR mutants dimerUBCp-EGFRvIII mutant GRB2-1 p-5Y-GAB1 SRC-1 p-6Y-EGFR p-6Y-EGFR p-6Y-EGFR EGFPIUbHSP90DAG and IP3 signalingUBCSPRY2 EGFp-6Y-EGFRRPS27Ap-Y371-CBL Pelitinib GAB1 HRASADPCBL p-EGFRvIII mutant PLCG1CDC37PXN UBCCDC37CDC37p-Y317-PAG1GRB2GAB1PIP3CDC37p-Y371-CBL GRB2-1 GTP 17-DMAG EGFUBA52EGFSH3GL2 EGFRvIII mutant dimerADPHSP90AA1 GRB2-1 UBA52AP2S1 EGFEGFRp-6Y-EGFR UBCCSK UBA52GAB1 ATPp-EGFRvIII mutant ADPp-6Y-EGFR EGFRCetuximabSRC-1 p-6Y-EGFR EGFIPI-504 CIN85EndophilinKRASEGFEGFUb-p-6Y-EGFRp-Y371-CBLGRB2CBLBeta-PixSH3KBP1 HSP90Benzoquinoid ansamycinsEGFBenzoquinoid ansamycinsPIK3CA ADPPIK3CAEGFZn2+ UBBUBCHSP90AA1 HSP90AA1 UBCUBBEGFARHGEF7 ADPPLCG1ADPHSP90AA1 PTPN11UBBSPRY2 ADPEGFp-6Y-EGFRp-Y371-CBLGRB2-1EGFREGFGRB2GAB1p-4Y-EGFR AP2A2p-Y371-CBL HSP90AA1 UBBCBL Pelitinib UBCSH3KBP1 EGFp-6Y-EGFRp-Y371-CBLUb-CIN85EndophilinEpsinEps15REps15Sensitive ligand-responsive EGFR mutantsNon-covalent EGFR TKIsGRB2-1 HGS EGFLigand-responsive EGFR mutants dimerp-4Y-PLCG1 p21 RASGDPGAB1 UBCHSP90AA1 HGS EGFUBCGRB2GAB1STAM2 UBCp-Y371-CBL KRASEGFCBL EGFp-6Y-EGFRp-Y349,350-SHC1GRB2SOS1AP2B1 CBL HSP90AA1 UBCGRB2-1 EGFp-6Y-EGFRCBLGRB2PTPN11 UBA52UBBUb-Beta-PixCDC42GTPATPGTP p-Y349,Y350-SHC1 HSP90AA1 ADPLigand-responsive p-6Y-EGFR mutant dimersEGFp-6Y-EGFRCBLCIN85GRB2-1 p-EGFR mutantsp-Y472,771,783,1254-PLCG1HSP90AA1 UBCEGFPTPN11 GAB1 GAB1 p-4Y-PLCG1EGFHGS p-5Y-EGFRvIII mutant dimerErlotinib GRB2-1 EGFAfatinib ADPEGFp-6Y-EGFRGRB2GAB1CDC37EGFp-EGFR mutantsGRB2GAB1PIK3R1EGFUBCp-Y55-SPRY2 PLCG1PIP3 activates AKT signalingPiPIp-6Y-EGFR UBCp-6Y-EGFR GAB1 EGFHSP90AA1 GTP SH3KBP1 Vandetanib UBCSPRY1HSP90AA1 p-6Y-EGFR EPS15 p-Y55-SPRY2p-EGFR mutantsGRB2GAB1PI3KGAB1 UbUBCp21 RASGTPUbUBCp-6Y-EGFR EPN1 p-6Y-EGFR EGFUbGRB2-1 EGFLRIG1GRB2-1 PXNCSKSRCATPp-Y53-SPRY1CDC37GDPSPRY1/2GAB1 ATPHSP90AA1 p-6Y-EGFR STAM UBCp-Y55-SPRY2 CBL Herbimycin A RPS27AEGFp-6Y-EGFRCBLUb-p-Y53/55-SPRY1/2p-6Y-EGFR EGFR Ligand-responsive EGFR mutantsHSP90CDC37CDC42 PIK3R1 SOS1PAG1SH3GL2 EGFp-6Y-EGFRp-Y349,350-SHC1NRAS GRB2-1 EPN1 EGFp-Y349,Y350-SHC1 EGFp-Y627,Y659-GAB1 RPS27ASH3KBP1 EGFp-6Y-EGFRGRB2GAB1PIK3CDC37SHC1RPS27Ap-EGFRvIII mutant p-EGFRvIII mutant p-6Y-EGFR GRB2-1 ADAM10HSP90AA1 ADPUBCSOS1 ADPCDC37CBL UBCEGFEPS15L1GTPATPUBCp-6Y-EGFR STAM CDC37CBLWZ4002 UBCp-6Y-EGFR CBLEPS15 CBL p-Y371-CBL ATPEGFRvIII mutant EGFp-6Y-EGFRp-Y371-CBLCIN85SPRY1/2EndophilinEpsinEps15REps15UBCATPCBL EGFEGFR dimerUBBUBCEGFUBCARHGEF7 GRB2-1 CDC37UBCp-5Y-GAB1 UBCp-Y371-CBL Covalent EGFR tyrosine kinase inhibitorsCDC42GTPRAF/MAP kinase cascadeSH3KBP1 EGFR ADPSH3GL2 EGFp-6Y-EGFRp-Y472,771,783,1254-PLCG1GRB2-1 ADAMZn2+EGFEGFEGFp-6Y-EGFRp-Y371-CBLCIN85EndophilinEpsinEps15REps15EGFCBL SHC1 GRB2-1STAM SOS1 HSP90AA1 CBLSPRY1/2CDC37STAM2 H2OEGFp-6Y-EGFRGRB2p-Y627,659-GAB1SHP2CDC37EGFUbp-6Y-EGFR EGFLigand-responsive Ub-p-6Y-EGFR mutantsp-Y371-CBLp-6Y-EGFR EGFATPUBBPIK3R1 HRASEGFAP2M1 Afatinib EGFp-6Y-EGFRCBLBeta-PixCDC42GTPUBCCLTA p-Y371-CBL ADPCDC37UBBH2OEPS15L1Resistant ligand-responsive EGFR mutantsCovalent EGFR TKIsSPRY1CDC37p-Y371-CBL 25624, 6617, 842126, 52676


Description

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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=177929

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  10. Panchamoorthy G, Fukazawa T, Miyake S, Soltoff S, Reedquist K, Druker B, Shoelson S, Cantley L, Band H.; ''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.''; PubMed Europe PMC Scholia
  11. Kassenbrock CK, Anderson SM.; ''Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations.''; PubMed Europe PMC Scholia
  12. Schmidt MHH, Husnjak K, Szymkiewicz I, Haglund K, Dikic I.; ''Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule betaPix.''; PubMed Europe PMC Scholia
  13. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  14. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  15. Helin K, Beguinot L.; ''Internalization and down-regulation of the human epidermal growth factor receptor are regulated by the carboxyl-terminal tyrosines.''; PubMed Europe PMC Scholia
  16. Red Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, Carpenter G.; ''The juxtamembrane region of the EGF receptor functions as an activation domain.''; PubMed Europe PMC Scholia
  17. Sakaguchi K, Okabayashi Y, Kido Y, Kimura S, Matsumura Y, Inushima K, Kasuga M.; ''Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells.''; PubMed Europe PMC Scholia
  18. Wells A.; ''EGF receptor.''; PubMed Europe PMC Scholia
  19. de Melker AA, van der Horst G, Borst J.; ''Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment.''; PubMed Europe PMC Scholia
  20. Pao W, Chmielecki J.; ''Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.''; PubMed Europe PMC Scholia
  21. Kapoor GS, Zhan Y, Johnson GR, O'Rourke DM.; ''Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB activation through Gab1 in glioblastoma cells.''; PubMed Europe PMC Scholia
  22. 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
  23. Sherrill JM, Kyte J.; ''Activation of epidermal growth factor receptor by epidermal growth factor.''; PubMed Europe PMC Scholia
  24. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  25. Rodrigues GA, Falasca M, Zhang Z, Ong SH, Schlessinger J.; ''A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling.''; PubMed Europe PMC Scholia
  26. Wahl MI, Nishibe S, Kim JW, Kim H, Rhee SG, Carpenter G.; ''Identification of two epidermal growth factor-sensitive tyrosine phosphorylation sites of phospholipase C-gamma in intact HSC-1 cells.''; PubMed Europe PMC Scholia
  27. 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
  28. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA, Eastern Cooperative Oncology Group.; ''Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.''; PubMed Europe PMC Scholia
  29. Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH.; ''The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37).''; PubMed Europe PMC Scholia
  30. Grøvdal LM, Stang E, Sorkin A, Madshus IH.; ''Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation.''; PubMed Europe PMC Scholia
  31. Lock LS, Royal I, Naujokas MA, Park M.; ''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.''; PubMed Europe PMC Scholia
  32. Fan YX, Wong L, Deb TB, Johnson GR.; ''Ligand regulates epidermal growth factor receptor kinase specificity: activation increases preference for GAB1 and SHC versus autophosphorylation sites.''; PubMed Europe PMC Scholia
  33. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  34. 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
  35. Carpenter G, Ji Q.; ''Phospholipase C-gamma as a signal-transducing element.''; PubMed Europe PMC Scholia
  36. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  37. Li MY, Lai PL, Chou YT, Chi AP, Mi YZ, Khoo KH, Chang GD, Wu CW, Meng TC, Chen GC.; ''Protein tyrosine phosphatase PTPN3 inhibits lung cancer cell proliferation and migration by promoting EGFR endocytic degradation.''; PubMed Europe PMC Scholia
  38. 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
  39. Sun T, Aceto N, Meerbrey KL, Kessler JD, Zhou C, Migliaccio I, Nguyen DX, Pavlova NN, Botero M, Huang J, Bernardi RJ, Schmitt E, Hu G, Li MZ, Dephoure N, Gygi SP, Rao M, Creighton CJ, Hilsenbeck SG, Shaw CA, Muzny D, Gibbs RA, Wheeler DA, Osborne CK, Schiff R, Bentires-Alj M, Elledge SJ, Westbrook TF.; ''Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.''; PubMed Europe PMC Scholia
  40. Montagner A, Yart A, Dance M, Perret B, Salles JP, Raynal P.; ''A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation.''; PubMed Europe PMC Scholia
  41. Huang F, Khvorova A, Marshall W, Sorkin A.; ''Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference.''; PubMed Europe PMC Scholia
  42. Lavictoire SJ, Parolin DA, Klimowicz AC, Kelly JF, Lorimer IA.; ''Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII.''; PubMed Europe PMC Scholia
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  50. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  51. Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY, Guy GR.; ''Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling.''; PubMed Europe PMC Scholia
  52. Lehr S, Kotzka J, Herkner A, Klein E, Siethoff C, Knebel B, Noelle V, Brüning JC, Klein HW, Meyer HE, Krone W, Müller-Wieland D.; ''Identification of tyrosine phosphorylation sites in human Gab-1 protein by EGF receptor kinase in vitro.''; PubMed Europe PMC Scholia
  53. Cunnick JM, Mei L, Doupnik CA, Wu J.; ''Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2.''; PubMed Europe PMC Scholia
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  59. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
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  61. Patterson J, Palombella VJ, Fritz C, Normant E.; ''IPI-504, a novel and soluble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells.''; PubMed Europe PMC Scholia
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  63. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP.; ''Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent.''; PubMed Europe PMC Scholia
  64. Margolis B, Bellot F, Honegger AM, Ullrich A, Schlessinger J, Zilberstein A.; ''Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor.''; PubMed Europe PMC Scholia
  65. Margolis BL, Lax I, Kris R, Dombalagian M, Honegger AM, Howk R, Givol D, Ullrich A, Schlessinger J.; ''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.''; PubMed Europe PMC Scholia
  66. Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J.; ''Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling.''; PubMed Europe PMC Scholia
  67. Batzer AG, Rotin D, Ureña JM, Skolnik EY, Schlessinger J.; ''Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor.''; PubMed Europe PMC Scholia
  68. Rubin C, Litvak V, Medvedovsky H, Zwang Y, Lev S, Yarden Y.; ''Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops.''; PubMed Europe PMC Scholia
  69. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E.; ''Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.''; PubMed Europe PMC Scholia
  70. Galisteo ML, Dikic I, Batzer AG, Langdon WY, Schlessinger J.; ''Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation.''; PubMed Europe PMC Scholia
  71. Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM.; ''Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.''; PubMed Europe PMC Scholia
  72. Marmor MD, Yarden Y.; ''Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases.''; PubMed Europe PMC Scholia
  73. 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.; ''Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein.''; PubMed Europe PMC Scholia
  74. Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ, Gray NS, Jänne PA.; ''Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.''; PubMed Europe PMC Scholia
  75. Fernandes H, Cohen S, Bishayee S.; ''Glycosylation-induced conformational modification positively regulates receptor-receptor association: a study with an aberrant epidermal growth factor receptor (EGFRvIII/DeltaEGFR) expressed in cancer cells.''; PubMed Europe PMC Scholia
  76. Holgado-Madruga M, Moscatello DK, Emlet DR, Dieterich R, Wong AJ.; ''Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor.''; PubMed Europe PMC Scholia
  77. Klapisz E, Sorokina I, Lemeer S, Pijnenburg M, Verkleij AJ, van Bergen en Henegouwen PM.; ''A ubiquitin-interacting motif (UIM) is essential for Eps15 and Eps15R ubiquitination.''; PubMed Europe PMC Scholia
  78. VanderKuur J, Allevato G, Billestrup N, Norstedt G, Carter-Su C.; ''Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2.''; PubMed Europe PMC Scholia
  79. Okutani T, Okabayashi Y, Kido Y, Sugimoto Y, Sakaguchi K, Matuoka K, Takenawa T, Kasuga M.; ''Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells.''; PubMed Europe PMC Scholia
  80. Soler C, Alvarez CV, Beguinot L, Carpenter G.; ''Potent SHC tyrosine phosphorylation by epidermal growth factor at low receptor density or in the absence of receptor autophosphorylation sites.''; PubMed Europe PMC Scholia
  81. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H.; ''EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.''; PubMed Europe PMC Scholia
  82. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W.; ''Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors.''; PubMed Europe PMC Scholia
  83. Haglund K, Shimokawa N, Szymkiewicz I, Dikic I.; ''Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors.''; PubMed Europe PMC Scholia
  84. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ.; ''The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.''; PubMed Europe PMC Scholia
  85. Bache KG, Raiborg C, Mehlum A, Stenmark H.; ''STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes.''; PubMed Europe PMC Scholia
  86. 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
  87. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  88. Kazazic M, Bertelsen V, Pedersen KW, Vuong TT, Grandal MV, Rødland MS, Traub LM, Stang E, Madshus IH.; ''Epsin 1 is involved in recruitment of ubiquitinated EGF receptors into clathrin-coated pits.''; PubMed Europe PMC Scholia
  89. Songyang Z, Margolis B, Chaudhuri M, Shoelson SE, Cantley LC.; ''The phosphotyrosine interaction domain of SHC recognizes tyrosine-phosphorylated NPXY motif.''; PubMed Europe PMC Scholia
  90. Lombardo CR, Consler TG, Kassel DB.; ''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.''; PubMed Europe PMC Scholia
  91. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  92. Meisenhelder J, Suh PG, Rhee SG, Hunter T.; ''Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro.''; PubMed Europe PMC Scholia
  93. Wu WJ, Tu S, Cerione RA.; ''Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation.''; PubMed Europe PMC Scholia
  94. Herbst RS.; ''Review of epidermal growth factor receptor biology.''; PubMed Europe PMC Scholia
  95. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  96. Lock LS, Frigault MM, Saucier C, Park M.; ''Grb2-independent recruitment of Gab1 requires the C-terminal lobe and structural integrity of the Met receptor kinase domain.''; PubMed Europe PMC Scholia
  97. Schlessinger J.; ''Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.''; PubMed Europe PMC Scholia
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History

View all...
CompareRevisionActionTimeUserComment
123308view06:57, 15 July 2022EgonwMarked from chemical compounds as Type="Metabolite"
101353view11:23, 1 November 2018ReactomeTeamreactome version 66
100891view20:57, 31 October 2018ReactomeTeamreactome version 65
100432view19:32, 31 October 2018ReactomeTeamreactome version 64
99981view16:16, 31 October 2018ReactomeTeamreactome version 63
99535view14:52, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93859view13:41, 16 August 2017ReactomeTeamreactome version 61
93424view11:23, 9 August 2017ReactomeTeamreactome version 61
86511view09:19, 11 July 2016ReactomeTeamreactome version 56
83196view10:21, 18 November 2015ReactomeTeamVersion54
81574view13:06, 21 August 2015ReactomeTeamVersion53
77036view08:33, 17 July 2014ReactomeTeamFixed remaining interactions
76741view12:10, 16 July 2014ReactomeTeamFixed remaining interactions
76066view10:12, 11 June 2014ReactomeTeamRe-fixing comment source
75776view11:29, 10 June 2014ReactomeTeamReactome 48 Update
75126view14:07, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74773view08:51, 30 April 2014ReactomeTeamReactome46
45218view17:28, 7 October 2011KhanspersOntology Term : 'epidermal growth factor/neuregulin signaling pathway' added !
42126view21:59, 4 March 2011MaintBotAutomatic update
39936view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
17-AAG MetaboliteCHEBI:64153 (ChEBI)
17-DMAG MetaboliteCHEBI:65324 (ChEBI)
ADAM Zn2+ComplexREACT_9655 (Reactome)
ADAM10ProteinO14672 (Uniprot-TrEMBL)
ADAM12 ProteinO43184 (Uniprot-TrEMBL)
ADAM17 ProteinP78536 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AP-2 complexComplexREACT_13288 (Reactome)
AP2A1 ProteinO95782 (Uniprot-TrEMBL)
AP2A2ProteinO94973 (Uniprot-TrEMBL)
AP2B1 ProteinP63010 (Uniprot-TrEMBL)
AP2M1 ProteinQ96CW1 (Uniprot-TrEMBL)
AP2S1 ProteinP53680 (Uniprot-TrEMBL)
ARHGEF7 ProteinQ14155 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active dimers of ligand-responsive EGFR mutantsComplexREACT_116938 (Reactome)
Afatinib MetaboliteCHEBI:61390 (ChEBI)
Benzoquinoid ansamycinsMetaboliteREACT_117275 (Reactome)
Beta-Pix

CDC42

GTP		ComplexREACT_12882 (Reactome)
CBL

Beta-Pix CDC42

GTP		ComplexREACT_13219 (Reactome)
CBL Beta-PixComplexREACT_13162 (Reactome)
CBL GRB2ComplexREACT_13333 (Reactome)
CBL SPRY1/2ComplexREACT_12947 (Reactome)
CBL SPRY1/2ComplexREACT_13051 (Reactome)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBLProteinP22681 (Uniprot-TrEMBL)
CDC37ProteinQ16543 (Uniprot-TrEMBL)
CDC37ComplexREACT_117086 (Reactome)
CDC42 GTPComplexREACT_12889 (Reactome)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CIN85 EndophilinComplexREACT_12741 (Reactome)
CLTA ProteinP09496 (Uniprot-TrEMBL)
CSK ProteinP41240 (Uniprot-TrEMBL)
CSKProteinP41240 (Uniprot-TrEMBL)
Canertinib MetaboliteCHEBI:61399 (ChEBI)
CetuximabREACT_116480 (Reactome)
ClathrinComplexREACT_9338 (Reactome)
Covalent EGFR tyrosine kinase inhibitorsMetaboliteREACT_116254 (Reactome)
DAG and IP3 signalingPathwayWP2688 (WikiPathways) This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
EGF

EGFR Dimer

Covalent EGFR TKIs		ComplexREACT_117215 (Reactome)
EGF EGFR dimerComplexREACT_9820 (Reactome)
EGF EGFRComplexREACT_9893 (Reactome)
EGF

Ligand-responsive EGFR mutants HSP90

CDC37		ComplexREACT_116916 (Reactome)
EGF Ligand-responsive EGFR mutants dimerComplexREACT_116688 (Reactome)
EGF

Ub-p-6Y-EGFR p-Y371-CBL

GRB2		ComplexREACT_12838 (Reactome)
EGF

Ub-p-6Y-EGFR

p-Y371-CBL		ComplexREACT_12986 (Reactome)
EGF

p-5Y-EGFR GRB2 p-5Y-GAB1

SHP2		ComplexREACT_13205 (Reactome)
EGF

p-6Y-EGFR CBL Beta-Pix CDC42

GTP		ComplexREACT_12733 (Reactome)
EGF

p-6Y-EGFR CBL

CIN85		ComplexREACT_13382 (Reactome)
EGF

p-6Y-EGFR CBL

GRB2		ComplexREACT_13163 (Reactome)
EGF

p-6Y-EGFR CBL

Ub-p-Y53/55-SPRY1/2		ComplexREACT_12687 (Reactome)
EGF

p-6Y-EGFR CBL

p-Y53/55-SPRY1/2		ComplexREACT_13028 (Reactome)
EGF

p-6Y-EGFR

CBL		ComplexREACT_12959 (Reactome)
EGF

p-6Y-EGFR GRB2 GAB1

PIK3R1		ComplexREACT_13343 (Reactome)
EGF

p-6Y-EGFR GRB2 GAB1

PIK3		ComplexREACT_12738 (Reactome)
EGF

p-6Y-EGFR GRB2

GAB1		ComplexREACT_13196 (Reactome)
EGF

p-6Y-EGFR GRB2

SOS1		ComplexREACT_12657 (Reactome)
EGF

p-6Y-EGFR GRB2 p-5Y-GAB1

SHP2		ComplexREACT_12771 (Reactome)
EGF

p-6Y-EGFR GRB2

p-5Y-GAB1		ComplexREACT_12983 (Reactome)
EGF

p-6Y-EGFR GRB2 p-Y627,659-GAB1

SHP2		ComplexREACT_12652 (Reactome)
EGF

p-6Y-EGFR

PLCG1		ComplexREACT_13280 (Reactome)
EGF

p-6Y-EGFR

SHC1		ComplexREACT_12643 (Reactome)
EGF

p-6Y-EGFR p-Y349,350-SHC1 GRB2

SOS1		ComplexREACT_13054 (Reactome)
EGF

p-6Y-EGFR

p-Y349,350-SHC1		ComplexREACT_12720 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL CIN85 Endophilin Epsin Eps15R

Eps15		ComplexREACT_13366 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL CIN85 SPRY1/2 Endophilin Epsin Eps15R

Eps15		ComplexREACT_12661 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL GRB2 CIN85 Endophilin Epsin Eps15R Eps15

Clathrin		ComplexREACT_13237 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL GRB2 CIN85

Endophilin		ComplexREACT_12726 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL

GRB2		ComplexREACT_13256 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL Ub-CIN85 Endophilin Epsin Eps15R

Eps15		ComplexREACT_13370 (Reactome)
EGF

p-6Y-EGFR

p-Y371-CBL		ComplexREACT_13081 (Reactome)
EGF

p-6Y-EGFR

p-Y472,771,783,1254-PLCG1		ComplexREACT_13347 (Reactome)
EGF p-6Y-EGFRComplexREACT_9673 (Reactome)
EGFProteinP01133 (Uniprot-TrEMBL)
EGFR CetuximabComplexREACT_117571 (Reactome)
EGFR ProteinP00533 (Uniprot-TrEMBL)
EGFRProteinP00533 (Uniprot-TrEMBL)
EGFRvIII mutant

HSP90

CDC37		ComplexREACT_117752 (Reactome)
EGFRvIII mutant ProteinP00533 (Uniprot-TrEMBL) EGFR V30_R297delinsG mutant of EGFR, commonly known as EGFRvIII, is found in ~25% high-grade glioblastomas and can also be found in squamous cell carcinoma of the lung. EGFRvIII lacks the ligand biding domain and is constitutively active.
EGFRvIII mutant dimerComplexREACT_117412 (Reactome)
EGFRvIII mutantProteinP00533 (Uniprot-TrEMBL) EGFR V30_R297delinsG mutant of EGFR, commonly known as EGFRvIII, is found in ~25% high-grade glioblastomas and can also be found in squamous cell carcinoma of the lung. EGFRvIII lacks the ligand biding domain and is constitutively active.
EPN1 ProteinQ9Y6I3 (Uniprot-TrEMBL)
EPN1ProteinQ9Y6I3 (Uniprot-TrEMBL)
EPS15 ProteinP42566 (Uniprot-TrEMBL)
EPS15L1ProteinQ9UBC2 (Uniprot-TrEMBL)
Eps15

HGS

STAM		ComplexREACT_12763 (Reactome)
Erlotinib MetaboliteCHEBI:114785 (ChEBI) Erlotinib (OSI-774, Tarceva) is an EGFR-specific tyrosine kinase inhibitor (TKI) from the anilinoquinazoline class of TKIs, developed by OSI/Genentech. Erlotinib competitively inhibits binding of ATP to kinase domain of EGFR, thereby preventing EGFR autophosphorylation and downstream signaling, which halts proliferation of EGFR-dependent tumor cells (Moyer et al. 1997 , Stamos et al. 2002).
GAB1 ProteinQ13480 (Uniprot-TrEMBL)
GAB1ProteinQ13480 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2

GAB1

PIK3R1		ComplexREACT_12870 (Reactome)
GRB2

GAB1

PIP3		ComplexREACT_13218 (Reactome)
GRB2 GAB1ComplexREACT_12705 (Reactome)
GRB2 SOS1ComplexREACT_4435 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Gefitinib MetaboliteCHEBI:49668 (ChEBI) Gefitinib (ZD1839, Iressa) is a low-molecular-weight EGFR tyrosine kinase inhibitor (TKI) from the anilinoquinazoline class of TKIs, developed by AstraZeneca Pharmaceuticals. Gefitinib selectively inhibits EGFR-stimulated tumor cell growth and blocks EGFR autophosphorylation in tumor cells by competitive inhibition of ATP binding to kinase domain of EGFR (Wakeling et al. 2002, Yun et al. 2007).
Geldanamycin MetaboliteCHEBI:5292 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HGS ProteinO14964 (Uniprot-TrEMBL)
HKI-272 MetaboliteCHEBI:61390 (ChEBI)
HRASProteinP01112 (Uniprot-TrEMBL)
HSP90 Benzoquinoid ansamycinsComplexREACT_116873 (Reactome)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90ComplexREACT_117107 (Reactome)
Herbimycin A MetaboliteCHEBI:5674 (ChEBI)
IPI-504 MetaboliteCHEBI:71956 (ChEBI)
KRASProteinP01116 (Uniprot-TrEMBL)
LRIG1ProteinQ96JA1 (Uniprot-TrEMBL)
Lapatinib MetaboliteCHEBI:49603 (ChEBI)
Ligand-responsive EGFR mutants

HSP90

CDC37		ComplexREACT_116857 (Reactome)
Ligand-responsive EGFR mutants dimerComplexREACT_117130 (Reactome)
Ligand-responsive EGFR mutantsProteinREACT_117041 (Reactome)
Ligand-responsive Ub-p-6Y-EGFR mutants p-Y371-CBLComplexREACT_116599 (Reactome)
Ligand-responsive p-6Y-EGFR mutant dimersComplexREACT_117728 (Reactome)
Ligand-responsive p-6Y-EGFR mutants CBLComplexREACT_116570 (Reactome)
Ligand-responsive p-6Y-EGFR mutants p-Y371-CBLComplexREACT_117735 (Reactome)
NRAS ProteinP01111 (Uniprot-TrEMBL)
Non-covalent EGFR tyrosine kinase inhibitorsMetaboliteREACT_117456 (Reactome)
PAG1ProteinQ9NWQ8 (Uniprot-TrEMBL)
PIMetaboliteCHEBI:16618 (ChEBI)
PIMetaboliteCHEBI:18348 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CAProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R1ProteinP27986 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayWP2653 (WikiPathways) 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)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PXN

CSK

SRC		ComplexREACT_12813 (Reactome)
PXN SRCComplexREACT_13128 (Reactome)
PXN ProteinP49023 (Uniprot-TrEMBL)
Pelitinib MetaboliteCHEBI:38927 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
Pro-EGFProteinP01133 (Uniprot-TrEMBL)
RAF/MAP kinase cascadePathwayWP2735 (WikiPathways) 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.
RPS27AProteinP62979 (Uniprot-TrEMBL)
Resistant ligand-responsive EGFR mutants Covalent EGFR TKIsComplexREACT_117723 (Reactome)
Resistant ligand-responsive EGFR mutantsComplexREACT_117827 (Reactome)
SH3GL2 ProteinQ99962 (Uniprot-TrEMBL)
SH3KBP1 ProteinQ96B97 (Uniprot-TrEMBL)
SH3KBP1ProteinQ96B97 (Uniprot-TrEMBL)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS1ProteinQ07889 (Uniprot-TrEMBL)
SPRY1/2REACT_13097 (Reactome)
SPRY1/2REACT_13348 (Reactome)
SPRY1ProteinO43609 (Uniprot-TrEMBL)
SPRY2 ProteinO43597 (Uniprot-TrEMBL)
SRC-1 ProteinP12931-1 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
STAM ProteinQ92783 (Uniprot-TrEMBL)
STAM2 ProteinO75886 (Uniprot-TrEMBL)
Sensitive ligand-responsive EGFR mutants Non-covalent EGFR TKIsComplexREACT_117305 (Reactome)
UBA52ProteinP62987 (Uniprot-TrEMBL)
UBBProteinP0CG47 (Uniprot-TrEMBL)
UBCProteinP0CG48 (Uniprot-TrEMBL)
Ub-Beta-Pix

CDC42

GTP		ComplexREACT_13061 (Reactome)
Ub-SH3KBP1 ProteinQ96B97 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
Vandetanib MetaboliteCHEBI:49960 (ChEBI)
WZ4002 MetaboliteCHEBI:61400 (ChEBI)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
p-4Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-4Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-4Y-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-5Y-EGFRvIII mutant dimerComplexREACT_116729 (Reactome)
p-5Y-GAB1 ProteinQ13480 (Uniprot-TrEMBL)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-EGFR mutants

GRB2 GAB1

PI3K		ComplexREACT_116903 (Reactome)
p-EGFR mutants

GRB2 GAB1

PIK3R1		ComplexREACT_117295 (Reactome)
p-EGFR mutants

GRB2

SOS1		ComplexREACT_116562 (Reactome)
p-EGFR mutants PLCG1ComplexREACT_117319 (Reactome)
p-EGFR mutants SHC1ComplexREACT_116600 (Reactome)
p-EGFR mutants

p-Y349,350-SHC1 GRB2

SOS1		ComplexREACT_116797 (Reactome)
p-EGFR mutants p-Y349,350-SHC1ComplexREACT_117226 (Reactome)
p-EGFR mutants p-Y472,771,783,1254-PLCG1ComplexREACT_116620 (Reactome)
p-EGFR mutants dimerComplexREACT_117763 (Reactome)
p-EGFRvIII mutant ProteinP00533 (Uniprot-TrEMBL) EGFR V30_R297delinsG mutant of EGFR, commonly known as EGFRvIII, is found in ~25% high-grade glioblastomas and can also be found in squamous cell carcinoma of the lung. EGFRvIII lacks the ligand biding domain and is constitutively active.
p-Y317-PAG1ProteinQ9NWQ8 (Uniprot-TrEMBL)
p-Y349,Y350-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y371-CBL ProteinP22681 (Uniprot-TrEMBL)
p-Y53-SPRY1ProteinO43609 (Uniprot-TrEMBL)
p-Y55-SPRY2 ProteinO43597 (Uniprot-TrEMBL)
p-Y55-SPRY2ProteinO43597 (Uniprot-TrEMBL)
p-Y627,Y659-GAB1 ProteinQ13480 (Uniprot-TrEMBL)
p21 RAS GDPComplexREACT_2657 (Reactome)
p21 RAS GTPComplexREACT_4782 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADAM Zn2+REACT_9423 (Reactome)
ADPArrowREACT_115610 (Reactome)
ADPArrowREACT_115627 (Reactome)
ADPArrowREACT_115772 (Reactome)
ADPArrowREACT_115796 (Reactome)
ADPArrowREACT_115841 (Reactome)
ADPArrowREACT_115884 (Reactome)
ADPArrowREACT_12424 (Reactome)
ADPArrowREACT_12490 (Reactome)
ADPArrowREACT_12491 (Reactome)
ADPArrowREACT_12569 (Reactome)
ADPArrowREACT_12592 (Reactome)
ADPArrowREACT_12636 (Reactome)
ADPArrowREACT_9388 (Reactome)
ADPArrowREACT_9401 (Reactome)
AP-2 complexREACT_12495 (Reactome)
ATPREACT_115610 (Reactome)
ATPREACT_115627 (Reactome)
ATPREACT_115772 (Reactome)
ATPREACT_115796 (Reactome)
ATPREACT_115841 (Reactome)
ATPREACT_115884 (Reactome)
ATPREACT_12424 (Reactome)
ATPREACT_12490 (Reactome)
ATPREACT_12491 (Reactome)
ATPREACT_12569 (Reactome)
ATPREACT_12592 (Reactome)
ATPREACT_12636 (Reactome)
ATPREACT_9388 (Reactome)
ATPREACT_9401 (Reactome)
Active dimers of ligand-responsive EGFR mutantsREACT_115609 (Reactome)
Active dimers of ligand-responsive EGFR mutantsREACT_115772 (Reactome)
Benzoquinoid ansamycinsREACT_115865 (Reactome)
Beta-Pix

CDC42

GTP		REACT_12412 (Reactome)
CBL Beta-PixREACT_12465 (Reactome)
CBL GRB2REACT_12626 (Reactome)
CBLREACT_115614 (Reactome)
CBLREACT_12441 (Reactome)
CBLREACT_12500 (Reactome)
CBLREACT_12632 (Reactome)
CBLREACT_12635 (Reactome)
CDC37REACT_115549 (Reactome)
CDC37REACT_115768 (Reactome)
CDC42 GTPREACT_12465 (Reactome)
CIN85 EndophilinREACT_12521 (Reactome)
CIN85 EndophilinREACT_12527 (Reactome)
CSKArrowREACT_12601 (Reactome)
CetuximabREACT_115741 (Reactome)
ClathrinREACT_12495 (Reactome)
Covalent EGFR tyrosine kinase inhibitorsREACT_115744 (Reactome)
Covalent EGFR tyrosine kinase inhibitorsREACT_116096 (Reactome)
EGF EGFR dimerREACT_116096 (Reactome)
EGF EGFR dimerREACT_9388 (Reactome)
EGF EGFR dimerREACT_9401 (Reactome)
EGF

p-5Y-EGFR GRB2 p-5Y-GAB1

SHP2		ArrowREACT_12629 (Reactome)
EGF

p-6Y-EGFR CBL Beta-Pix CDC42

GTP		ArrowREACT_12412 (Reactome)
EGF

p-6Y-EGFR CBL Beta-Pix CDC42

GTP		REACT_12451 (Reactome)
EGF

p-6Y-EGFR CBL

CIN85		REACT_12412 (Reactome)
EGF

p-6Y-EGFR CBL

GRB2		REACT_12491 (Reactome)
EGF

p-6Y-EGFR CBL

p-Y53/55-SPRY1/2		REACT_12381 (Reactome)
EGF

p-6Y-EGFR

CBL		ArrowREACT_12451 (Reactome)
EGF

p-6Y-EGFR

CBL		REACT_12424 (Reactome)
EGF

p-6Y-EGFR GRB2 GAB1

PIK3R1		REACT_12501 (Reactome)
EGF

p-6Y-EGFR GRB2 GAB1

PIK3		REACT_12636 (Reactome)
EGF

p-6Y-EGFR GRB2

GAB1		ArrowREACT_12423 (Reactome)
EGF

p-6Y-EGFR GRB2

GAB1		REACT_12490 (Reactome)
EGF

p-6Y-EGFR GRB2

SOS1		REACT_12386 (Reactome)
EGF

p-6Y-EGFR GRB2 p-5Y-GAB1

SHP2		REACT_12390 (Reactome)
EGF

p-6Y-EGFR GRB2 p-5Y-GAB1

SHP2		REACT_12601 (Reactome)
EGF

p-6Y-EGFR GRB2 p-5Y-GAB1

SHP2		REACT_12605 (Reactome)
EGF

p-6Y-EGFR GRB2 p-5Y-GAB1

SHP2		REACT_12629 (Reactome)
EGF

p-6Y-EGFR GRB2

p-5Y-GAB1		ArrowREACT_12490 (Reactome)
EGF

p-6Y-EGFR GRB2

p-5Y-GAB1		REACT_12466 (Reactome)
EGF

p-6Y-EGFR GRB2 p-Y627,659-GAB1

SHP2		ArrowREACT_12605 (Reactome)
EGF

p-6Y-EGFR

PLCG1		REACT_12569 (Reactome)
EGF

p-6Y-EGFR

SHC1		REACT_12592 (Reactome)
EGF

p-6Y-EGFR p-Y349,350-SHC1 GRB2

SOS1		REACT_12402 (Reactome)
EGF

p-6Y-EGFR

p-Y349,350-SHC1		ArrowREACT_12592 (Reactome)
EGF

p-6Y-EGFR

p-Y349,350-SHC1		REACT_12514 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL CIN85 Endophilin Epsin Eps15R

Eps15		REACT_12387 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL CIN85 Endophilin Epsin Eps15R

Eps15		REACT_12520 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL GRB2 CIN85

Endophilin		REACT_12495 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL

GRB2		ArrowREACT_12491 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL

GRB2		REACT_12521 (Reactome)
EGF

p-6Y-EGFR p-Y371-CBL

GRB2		REACT_12562 (Reactome)
EGF

p-6Y-EGFR

p-Y371-CBL		ArrowREACT_12424 (Reactome)
EGF

p-6Y-EGFR

p-Y371-CBL		REACT_12432 (Reactome)
EGF

p-6Y-EGFR

p-Y371-CBL		REACT_12515 (Reactome)
EGF

p-6Y-EGFR

p-Y371-CBL		REACT_12527 (Reactome)
EGF

p-6Y-EGFR

p-Y472,771,783,1254-PLCG1		ArrowREACT_12569 (Reactome)
EGF p-6Y-EGFRArrowREACT_12407 (Reactome)
EGF p-6Y-EGFRArrowREACT_9388 (Reactome)
EGF p-6Y-EGFRArrowREACT_9401 (Reactome)
EGF p-6Y-EGFRREACT_12392 (Reactome)
EGF p-6Y-EGFRREACT_12401 (Reactome)
EGF p-6Y-EGFRREACT_12423 (Reactome)
EGF p-6Y-EGFRREACT_12425 (Reactome)
EGF p-6Y-EGFRREACT_12580 (Reactome)
EGF p-6Y-EGFRREACT_12626 (Reactome)
EGF p-6Y-EGFRREACT_12632 (Reactome)
EGFREACT_115811 (Reactome)
EGFREACT_9481 (Reactome)
EGFRREACT_115741 (Reactome)
EGFRREACT_9481 (Reactome)
EGFRvIII mutant dimerREACT_115610 (Reactome)
EGFRvIII mutantREACT_115549 (Reactome)
EPN1REACT_12495 (Reactome)
EPN1REACT_12527 (Reactome)
EPS15L1REACT_12495 (Reactome)
EPS15L1REACT_12527 (Reactome)
Eps15

HGS

STAM		REACT_12495 (Reactome)
Eps15

HGS

STAM		REACT_12527 (Reactome)
GAB1REACT_12535 (Reactome)
GDPArrowREACT_115809 (Reactome)
GDPArrowREACT_116154 (Reactome)
GDPArrowREACT_12386 (Reactome)
GDPArrowREACT_12402 (Reactome)
GRB2

GAB1

PIK3R1		REACT_115604 (Reactome)
GRB2

GAB1

PIK3R1		REACT_12425 (Reactome)
GRB2

GAB1

PIP3		REACT_12423 (Reactome)
GRB2 GAB1REACT_12534 (Reactome)
GRB2 GAB1REACT_12616 (Reactome)
GRB2 SOS1REACT_115562 (Reactome)
GRB2 SOS1REACT_116141 (Reactome)
GRB2 SOS1REACT_12392 (Reactome)
GRB2 SOS1REACT_12514 (Reactome)
GRB2-1REACT_12535 (Reactome)
GRB2-1REACT_12635 (Reactome)
GRB2-1REACT_2257 (Reactome)
GTPREACT_115809 (Reactome)
GTPREACT_116154 (Reactome)
GTPREACT_12386 (Reactome)
GTPREACT_12402 (Reactome)
H2OREACT_12390 (Reactome)
H2OREACT_12601 (Reactome)
H2OREACT_12605 (Reactome)
H2OREACT_12629 (Reactome)
HSP90REACT_115549 (Reactome)
HSP90REACT_115768 (Reactome)
HSP90REACT_115865 (Reactome)
LRIG1TBarREACT_9481 (Reactome)
Ligand-responsive EGFR mutants

HSP90

CDC37		REACT_115811 (Reactome)
Ligand-responsive EGFR mutantsREACT_115768 (Reactome)
Ligand-responsive p-6Y-EGFR mutant dimersArrowREACT_115772 (Reactome)
Ligand-responsive p-6Y-EGFR mutant dimersREACT_115614 (Reactome)
Ligand-responsive p-6Y-EGFR mutants CBLREACT_115796 (Reactome)
Ligand-responsive p-6Y-EGFR mutants CBLTBarREACT_115732 (Reactome)
Ligand-responsive p-6Y-EGFR mutants p-Y371-CBLArrowREACT_115796 (Reactome)
Ligand-responsive p-6Y-EGFR mutants p-Y371-CBLREACT_115732 (Reactome)
Non-covalent EGFR tyrosine kinase inhibitorsREACT_115609 (Reactome)
PAG1ArrowREACT_12390 (Reactome)
PIArrowREACT_115884 (Reactome)
PIArrowREACT_12423 (Reactome)
PIArrowREACT_12636 (Reactome)
PIK3CAREACT_116004 (Reactome)
PIK3CAREACT_12501 (Reactome)
PIK3R1REACT_12616 (Reactome)
PIREACT_115884 (Reactome)
PIREACT_12495 (Reactome)
PIREACT_12534 (Reactome)
PIREACT_12636 (Reactome)
PLCG1REACT_115745 (Reactome)
PLCG1REACT_12401 (Reactome)
PTPN11REACT_12466 (Reactome)
PXN

CSK

SRC		REACT_12601 (Reactome)
PXN SRCArrowREACT_12601 (Reactome)
PiArrowREACT_12390 (Reactome)
PiArrowREACT_12601 (Reactome)
PiArrowREACT_12605 (Reactome)
PiArrowREACT_12629 (Reactome)
REACT_115549 (Reactome) Association of EGFRvIII mutant with HSP90 chaperone protein and its co-chaperone CDC37 is necessary for the proper functioning of mutant EGFR.
REACT_115562 (Reactome) Recruitment of GRB2:SOS1 complex by SHC1 bound to phosphorylated dimers of EGFR cancer mutants has not been directly tested, but is assumed to happen in the same way it happens with the SHC1 bound to the phosphorylated homodimer of wild-type EGFR.
REACT_115604 (Reactome) Direct binding of GRB2:GAB1:PIK3R1 complex to phosphorylated homodimers of EGFR cancer mutants has not been tested. This complex is recruted to EGFR via GRB2 binding to phosphorylated tyrosine residues Y1068 and Y1086 (corresponding to Y1092 and Y1110, respectively, when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus). Phosphorylation of Y1068 (i.e. Y1092) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Lynch et al. 2004, Greulich et al. 2005, Yang et al. 2006, Choi et al. 2007); EGFR G719S mutant (Greulich et al. 2005, Choi et al. 2007); EGFR L747_P753insS mutant (Sordella et al. 2004, Lynch et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP (Greulich et al. 2005); EGFR L747_S752del mutant (Pao et al. 2004); EGFR L861Q mutant (Lee et al. 2006, Yang et al. 2006); EGFRvIII mutant (Huang et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR T263P mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007).
REACT_115609 (Reactome) Non-covalent (reversible) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, lapatinib and vandetanib, selectively inhibit EGFR-stimulated tumor cell growth by blocking EGFR mutant autophosphorylation through competitive inhibition of ATP binding to the kinase domain. A number of EGFR kinase domain mutants and extracellular domain point mutants show increased senistivity to non-covalent TKIs compared with the wild-type EGFR. EGFR kinase domain mutants may be resistant to non-covalent TKIs due to primary or secondary mutations in the kinase domain that increase the affinity of the kinase domain for ATP, such as small insertions within exon 20, and substituion of threonine 790 with methionine (T790M).
REACT_115610 (Reactome) Upon dimerization, EGFRvIII mutants trans-autophosphorylate on tyrosine residues Y992, Y1068, Y0186, Y1143 and Y1173 while the tyrosine residue Y1045, a docking site for CBL, remains either unphosphorylated or hypophosphorylated, allowing EGFRvIII to activate downstream signaling cascades while escaping downregulation.
REACT_115614 (Reactome) CBL binds to phosphorylated tyrosine Y1045 residue of EGFR cancer mutants. Phosphorylation of Y1045 (corresponding to Y1069 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Greulich et al. 2005, Choi et al. 2007); EGFR G719S mutant (Sordella et al. 2004, Greulich et al. 1005, Choi et al. 2007); EGFR L747_P753delinsS mutant (Sordella et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP mutant (Greulich et al. 2005); EGFR L861Q mutant (Choi et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005; Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). Very little if any phosphorylation of Y1045 was shown in EGFR T263P mutant (Lee et al. 2006) and EGFR D770_N771insNPH mutant (Xu et al. 2007). Direct binding of CBL was demonstrated for the EGFR L858R mutant (Yang et al. 2006, Padron et al. 2007) and EGFR E746_A750del mutant (Padron et al. 2007). In EGFRvIII mutant, Y1045 (Y1069) is not phosphorylated (Han et al. 2006, Grandal et al. 2007). Han et al. detected no CBL binding to EGFRvIII mutant (Han et al. 2006), while Grandal et al. detected very little binding, which they explained by indirect recruitment of CBL to EGFRvIII through GRB2 (Grandal et al. 2007).
REACT_115623 (Reactome) Although ligand-responsive EGFR mutants dimerize spontaneously, dimerization is increased in the presence of EGF.
REACT_115627 (Reactome) Once recruited, PLC-gamma 1 is assumed to be phosphorylated by EGFR cancer mutants in the same way it is phosphorylated by the wild-type EGFR.
REACT_115732 (Reactome) Phosphorylated CBL does not ubiquitinate EGFR kinase domain mutants efficiently, which enables mutant proteins to escape degradation. There are indications that phosphorylated CBL shows decreased affinity for EGFR kinase domain mutants compared to wild-type EGFR proteins, and quickly dissociates, before ubiquitination is completed. This decreased affinity may be due to altered structure of EGFR kinase domain mutants or to the presence of the chaperone protein HSP90 in complex with the mutant protein. Weaker afinity for phosphorylated CBL was directly demonstrated for EGFR L858R mutant (Yang et al. 2006), and poor ubiquitination inspite of CBL binding was shown for EGFR L858R and EGFR E746_A750del mutants (Yang et al. 2006, Padron et al. 2007).
REACT_115741 (Reactome) Cetuximab binds to the extracellular domain of EGFR and blocks ligand binding, leading to receptor inactivation, internalization and degradation. Cetuximab is approved for combination therapy and monotherapy of metastatic colorectal cancer and advanced squamous cell carcinoma of head and neck in patients whose tumors over-express wild-type EGFR protein, usually due to amplification of EGFR gene.
REACT_115744 (Reactome) Covalent (irreversible) tyrosine kinase inhibitors (TKIs), pelitinib, WZ4002, HKI-272, canertinib and afatinib, form a covalent bond with the EGFR cysteine residue C397 and inhibit trans-autophosphorylation of mutants resistant to non-covalent TKIs. However, effective concentrations of covalent TKIs also inhibit wild type EGFR, resulting in severe side effects. Hence, covalent TKIs have not shown much promise as therapeutics.
REACT_115745 (Reactome) Tyrosine residue Y992, a docking site for PLC-gamma 1 (PLCG1), is phosphorylated in EGFR cancer mutants and expected to recruit PLC-gamma 1 in the same way as the wild-type EGFR receptor. Phosphorylation of Y992 (corresponding to Y1016 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus) has been directly demonstrated for the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Choi et al. 2007); EGFR G719S mutant (Choi et al. 2007); EGFR L747_P753delinsS mutant (Sordella et al. 2004, Choi et ak, 2007); EGFR L861Q mutant (Choi et al. 2007); EGFRvIII mutant (Grandal et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007).
REACT_115768 (Reactome) EGFR kinase domain mutants need continuous association with HSP90 chaperone protein for proper functioning. CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 binds a protein kinase through its N-terminal domain and HSP90 through its C-terminal domain, arresting ATP-ase activity of HSP90 and enabling the loading of a client kinase. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (reviewed by Gray Jr. et al. 2008). Association of EGFR extracellular domain point mutants with HSP90 chaperone has not been tested.
REACT_115772 (Reactome) The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Activation of ligand-responsive EGFR mutants through spontaneous or EGF-induced dimerization results in trans-autophosphorylation of 5 tyrosine residues (Y992, Y1068, Y1086, Y1148 and Y1173), which enables constitutive receptor signaling as it provides specific binding sites for cytosolic target proteins involved in signal transduction (Zhang et al. 2006, Yun et al. 2007, Sordella et al. 2004, Lee et al. 2006). Tyrosine residue Y1045, involved in EGFR down-regulation, is usually phosphorylated in ligand-responsive EGFR mutants (Sordella et al. 2004, Lee et al. 2006). The exact phosphorylation pattern has not been examined for each mutant, but is assumed to closely follow, based on existing experimental evidence, the trans-autophosphorylation pattern of the wild-type EGFR.
REACT_115796 (Reactome) EGFR L858R mutant was shown to directly phosphorylate CBL on tyrosine residue Y371. Other EGFR cancer mutants with phosphorylation of tyrosine Y1045 (Y1069) are assumed to bind and phosphorylate CBL in a manner similar to the wild-type EGFR.
REACT_115809 (Reactome) SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1, recruited by GRB2 bound to p-SHC1:p-EGFR mutants, is assumed to activate RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP). Although this reaction has not been shown to occur directly for EGFR cancer mutants, activation of RAF/MAP kinase cascade, through detection of phosphorylated ERK1/2, has been demonstrated in cells expressing EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Shimamura et al. 2005), EGFR E746_A750 mutant (Sordella et al. 2004, Shimamura et al. 2005), EGFR L747_P753delinS mutant (Sordella et al. 2004), and EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005).
REACT_115811 (Reactome) Ligand-responsive EGFR mutants are able to bind EGF and exhibit increased activity in the presence of EGF.
REACT_115841 (Reactome) Constitutive phosphorylation of SHC1 was directly demonstrated in cells expressing EGFR L858R mutant (Greulich et al. 2005). Other EGFR cancer mutants were not directly tested for their ability to phosphorylate SHC1, but are assumed to interact with SHC1 in the same way as the wild-type EGFR protein.
REACT_115865 (Reactome) Benzoquinoid ansamycins (geldanamycin, herbimycin, and geldanamycin derivatives 17-AAG, 17-DMAG and IPI-504) are antitumor antibiotics that inactivate HSP90 by binding to its substrate-binding pocket.
REACT_115884 (Reactome) The kinase activity of PI3K mediates the phosphorylation of PIP2 to form PIP3. It is assumed that EGFR cancer mutants induce PI3K/AKT signaling in a manner similar to wild-type EGFR. Phosphorylation of AKT on serine residue S473, and therby activation of PI3K/AKT signaling cascade, has been directly demonstrated in cells expressing the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Greulich et al. 2005, Shimamura et al. 2005); EGFR G719S mutant (Greulich et al. 2005); EGFR E746_A750del mutant (Sordella et al. 2004, Shimamura et al. 2005); EGFR L747_P753insS mutant (Sordella et al. 2004); EGFR L747_A750delinsP mutant (Greulich et al. 2005); EGFR L861Q mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007); EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005).
REACT_115887 (Reactome) EGFRvIII mutant lacks the ligand binding domain and is therefore unable to bind EGFR ligands, but is able to dimerize spontaneously. Self-dimerization may be dependent on N-linked glycosylation.
REACT_115903 (Reactome) Once phosphorylated, PLC-gamma 1 is expected to dissociate from phosphorylated EGFR cancer mutants and induce downstream signaling in the same way it does when activated by the wild-type EGFR. However, except for the phosphorylation of PLCG1 binding site in EGFR cancer mutants, other events involved in activation of PLCG1 signaling have not been studied in cells expressing EGFR cancer mutants.
REACT_115980 (Reactome) EGFR ligand-responsive mutants dimerize spontaneously, without ligand binding, although ligand binding ability is preserved. This was experimentally demonstrated for EFGR L858R mutant and is presumed to happen in other constitutively active EGFR kinase domain mutants and EGFR extracellular domain point mutants.
REACT_116004 (Reactome) The 110 kDa catalytic subunit of PI3K (PIK3CA) binds to the 85 kDa regulatory subunit of PI3K (PIK3R1) to create the active PI3K. EGFR cancer mutants are assumed to mediate the assembly of active PI3K in a manner similar to wild-type EGFR.
REACT_116063 (Reactome) SHC1 (Src homology 2 domain-containing transforming protein) is known to bind two phosphorylated tyrosine docking sites of EGFR: Y1148 and Y1173 (corresponding to Y1172 and Y1197 when counting from the first amino acid of EGFR precursor, before the cleavage of the 24-amino acid signal peptide at the N-terminus takes place). Phosphorylation of Y1173 tyrosine residue was directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Greulich et al. 2005); EGFR G719S mutant (Greulich et al. 2005); EGFR L747_P753delinsS mutant (Sordella et al. 2004); EGFR L747_A750delinsP (Greulich et al. 2005); EGFRvIII mutant (Han et al. 2006, Grandal et al. 2007); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). Phosphorylation of Y1148 was shown in EGFRvIII mutant (Huang et al. 2007).
Besides EGFR L858R mutant, which was directly shown to bind SHC1 (Greulich et al. 2005), binding of SHC1 was not tested in other EGFR cancer mutants. Nonetheless, it is assumed that SHC1 binds EGFR cancer mutants in the same way it binds wild-type EGFR.
REACT_116096 (Reactome) Covalent (irreversible) TKIs, pelitinib, WZ4002, HKI-272, canertinib and afatinib, inhibit the wild-type EGFR through formation of the covalent bond with the cysteine residue C397.
REACT_116141 (Reactome) Direct binding of GRB2:SOS1 complex to phosphorylated homodimers of EGFR cancer mutants has not been tested. GRB2 binds to phosphorylated tyrosine residues Y1068 and Y1086 (corresponding to Y1092 and Y1110, respectively, when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus). Phosphorylation of Y1068 (i.e. Y1092) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Lynch et al. 2004, Greulich et al. 2005, Yang et al. 2006, Choi et al. 2007); EGFR G719S mutant (Greulich et al. 2005, Choi et al. 2007); EGFR L747_P753insS mutant (Sordella et al. 2004, Lynch et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP (Greulich et al. 2005); EGFR L747_S752del mutant (Pao et al. 2004); EGFR L861Q mutant (Lee et al. 2006, Yang et al. 2006); EGFRvIII mutant (Huang et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR T263P mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007).
REACT_116154 (Reactome) Based on the wild-type EGFR signaling, it is assumed that the guanine nucleotide exchange factor SOS1 interacts with phosphorylated EGFR mutants through the adaptor protein, GRB2. Upon formation of this complex, SOS1 activates RAS by promoting GDP release and GTP binding. Although this reaction has not been directly confirmed for EGFR cancer mutants, activation of RAF/MAP kinase cascade has been demonstrated, through detection of phosphorylated ERK1/2, in cells expressing EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Shimamura et al. 2005), EGFR E746_A750del mutant (Sordella et al. 2004, Shimamura et al. 2005), EGFR L747_P753delinsS mutant (Sordella et al. 2004) and EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005).
REACT_12381 (Reactome) 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.
REACT_12386 (Reactome) 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.
REACT_12387 (Reactome) 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.
REACT_12390 (Reactome) Dephosphorylation of CBP/PAG negatively regulates the recruitment of the Src inhibiting kinase, Csk. Src is not negatively regulated by phosphorylation by Csk.
REACT_12392 (Reactome) 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.
REACT_12401 (Reactome) Inactive phospholipase C-gamma1 (PLCG1) binds to activated epidermal growth factor receptor (EGFR).
REACT_12402 (Reactome) SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP).
REACT_12407 (Reactome) Once activated PLC-gamma1 dissociates from EGFR, it can hydrolyze PIP2.
REACT_12412 (Reactome) High concentrations of active CDC42 and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 from the CBL complex. This competitive mechanism could block the CIN85-imposed clustering phenomenon on CBL that is required for tighter binding.
REACT_12423 (Reactome) GAB1 binds to EGF receptors via tyrosine autophosphorylation sites on the receptor.
REACT_12424 (Reactome) 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.
REACT_12425 (Reactome) 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.
REACT_12432 (Reactome) 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.
REACT_12441 (Reactome) 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.
REACT_12451 (Reactome) 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.
REACT_12465 (Reactome) 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.
REACT_12466 (Reactome) 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.
REACT_12490 (Reactome) EGFR kinase phosphorylates the phosphorylation sites tyrosine 627 and 659 on GAB1
REACT_12491 (Reactome) 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.
REACT_12495 (Reactome) Epsin directly modifies membrane curvature on binding to PIP2 in conjunction with clathrin polymerization.
REACT_12500 (Reactome) 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.
REACT_12501 (Reactome) The 110 kDa catalytic subunit (PIK3CA) binds to the 85 kDa regulatory subunit (PIK3R1) to create the active PIK3.
REACT_12514 (Reactome) The tyrosine sites on SHC1 become possible binding sites for the GRB2:SOS1 complex.
REACT_12515 (Reactome) 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.
REACT_12520 (Reactome) The adaptor protein CIN85 is monoubiquitinated by CBL after EGF stimulation. Monoubiquitination is thought to regulate receptor internalization and endosomal sorting.
REACT_12521 (Reactome) 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.
REACT_12527 (Reactome) 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.
REACT_12534 (Reactome) 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.
REACT_12535 (Reactome) GRB2 (Growth factor receptor-bound protein 2) binds to GAB1 (GRB2-associated binding protein 1).
REACT_12562 (Reactome) 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.
REACT_12569 (Reactome) EGFR phosphorylates PLC-gamma1, thus activating it.
REACT_12580 (Reactome) SHC1 (Src homology 2 domain-containing) transforming protein can bind to either tyrosine 1148 and/or tyrosine 1173 sites on the EGF receptor.
REACT_12592 (Reactome) Once bound to EGFR, SHC1 is phosphorylated on two tyrosines (Y349, Y350).
REACT_12601 (Reactome) 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.
REACT_12605 (Reactome) 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.
REACT_12616 (Reactome) 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.
REACT_12626 (Reactome) Upon EGF stimulation and consequent EGFR phosphorylation, GRB2 binds phosphorylated tyrosines
REACT_12629 (Reactome) 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.
REACT_12632 (Reactome) 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.
REACT_12635 (Reactome) 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.
REACT_12636 (Reactome) The kinase activity of PIK3 mediates the phosphorylation of PIP2 to form PIP3
REACT_2257 (Reactome) 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.
REACT_9388 (Reactome) 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.
REACT_9397 (Reactome) 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.
REACT_9401 (Reactome) 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.
REACT_9423 (Reactome) 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.
REACT_9481 (Reactome) 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.
Resistant ligand-responsive EGFR mutantsArrowREACT_115609 (Reactome)
Resistant ligand-responsive EGFR mutantsREACT_115744 (Reactome)
SH3KBP1ArrowREACT_12412 (Reactome)
SHC1REACT_116063 (Reactome)
SHC1REACT_12580 (Reactome)
SOS1REACT_2257 (Reactome)
SPRY1/2REACT_12387 (Reactome)
SPRY1/2REACT_12432 (Reactome)
SRC-1REACT_9401 (Reactome)
Sensitive ligand-responsive EGFR mutants Non-covalent EGFR TKIsArrowREACT_115609 (Reactome)
Ub-Beta-Pix

CDC42

GTP		ArrowREACT_12451 (Reactome)
UbREACT_115732 (Reactome)
UbREACT_12381 (Reactome)
UbREACT_12432 (Reactome)
UbREACT_12451 (Reactome)
UbREACT_12515 (Reactome)
UbREACT_12520 (Reactome)
UbREACT_12562 (Reactome)
p-4Y-PLCG1ArrowREACT_115903 (Reactome)
p-4Y-PLCG1ArrowREACT_12407 (Reactome)
p-5Y-EGFRvIII mutant dimerArrowREACT_115610 (Reactome)
p-EGFR mutants

GRB2 GAB1

PI3K		REACT_115884 (Reactome)
p-EGFR mutants

GRB2 GAB1

PIK3R1		REACT_116004 (Reactome)
p-EGFR mutants

GRB2

SOS1		REACT_116154 (Reactome)
p-EGFR mutants PLCG1REACT_115627 (Reactome)
p-EGFR mutants SHC1REACT_115841 (Reactome)
p-EGFR mutants

p-Y349,350-SHC1 GRB2

SOS1		REACT_115809 (Reactome)
p-EGFR mutants p-Y349,350-SHC1ArrowREACT_115841 (Reactome)
p-EGFR mutants p-Y349,350-SHC1REACT_115562 (Reactome)
p-EGFR mutants p-Y472,771,783,1254-PLCG1ArrowREACT_115627 (Reactome)
p-EGFR mutants dimerArrowREACT_115903 (Reactome)
p-EGFR mutants dimerREACT_115604 (Reactome)
p-EGFR mutants dimerREACT_115745 (Reactome)
p-EGFR mutants dimerREACT_116063 (Reactome)
p-EGFR mutants dimerREACT_116141 (Reactome)
p-Y317-PAG1REACT_12390 (Reactome)
p-Y55-SPRY2REACT_12441 (Reactome)
p-Y55-SPRY2REACT_12500 (Reactome)
p21 RAS GDPREACT_115809 (Reactome)
p21 RAS GDPREACT_116154 (Reactome)
p21 RAS GDPREACT_12386 (Reactome)
p21 RAS GDPREACT_12402 (Reactome)
p21 RAS GTPArrowREACT_115809 (Reactome)
p21 RAS GTPArrowREACT_116154 (Reactome)
p21 RAS GTPArrowREACT_12386 (Reactome)
p21 RAS GTPArrowREACT_12402 (Reactome)
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