Signaling by EGFR (Homo sapiens)

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1, 15, 26, 586830, 39221310, 523, 5, 8, 19822150, 6380675, 8640, 5617, 36, 705412, 6013, 1468822, 42, 851845, 77114611, 378112, 6010, 252728, 615975, 86791823733, 5, 8, 198, 4171163165574424, 32, 5329471866556830, 393363138, 74cytosolEPS15 ClathrinGTP HSP90:BenzoquinoidansamycinsGAB1 UBC(305-380) GRB2-1 Ligand-responsiveEGFR mutantsUBC(77-152) Benzoquinoidansamycinsp-6Y-EGFR HSP90AA1 UBC(229-304) EGF:p-6Y-EGFR:CBL:GRB2PLCG1HKI-272 EGFR UBC(533-608) Ub-SH3KBP1 UBC(153-228) GRB2-1 H2OEGF:p-6Y-EGFR:p-Y371-CBL:GRB2EGF UBC(381-456) RPS27A(1-76) EGF EPN1UBC(153-228) STAM2 p-6Y-EGFR EGFR SHC1STAM p-6Y-EGFR UBA52(1-76) KRAS EGF:p-6Y-EGFR:PLCG1GRB2-1 ADPUBB(153-228) ATPCBL:GRB2CBL:Beta-PixHerbimycin A GRB2-1 SOS1 Ligand-responsiveEGFRmutants:HSP90:CDC37EGFR:CetuximabBeta-Pix:CDC42:GTPAP2A2(1-939) PIK3R1 p-6Y-EGFR GAB1 p-Y349,Y350-SHC1 ADPEGF EGF:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1EGF UBC(533-608) SH3GL2 UBA52(1-76) STAM PiSTAM2 EGFRvIII GAB1 CDC37 ADPH2OEGF:Ub-p-6Y-EGFR:p-Y371-CBLHSP90AA1 EPN1 ADPPXN:CSK:SRCGTPUBC(609-684) PIP3 activates AKTsignalingPTPN11 UBC(77-152) Resistantligand-responsiveEGFRmutants:CovalentEGFR TKIsEGF EGFRvIIIp-6Y-EGFR UBC(77-152) PIK3R1 Afatinib EGF:p-5Y-EGFR:GRB2:p-5Y-GAB1:SHP2CLTA UbEGF SPRY2 SH3GL2 PI(4,5)P2EGFRvIII UBC(229-304) CBL:SPRY1/2SPRY1/2AP2B1 CBLATPEGF EPS15 SRC-1PIK3R1 p-6Y-EGFR EPS15 p-6Y-EGFR HGS PI(3,4,5)P3 GRB2:GAB1UBC(229-304) SH3GL2 SH3KBP1 UBC(381-456) EGFRvIII mutantdimerPIK3CA SH3KBP1 UBC(381-456) CDC42 CBL:SPRY1/2KRAS EGFRvIIImutant:HSP90:CDC37CLTA EGF:Ligand-responsive EGFR mutants dimerp-4Y-PLCG1GDP EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15EGF:p-6Y-EGFR:p-Y371-CBL:Ub-CIN85:Endophilin:Epsin:Eps15R:Eps15GAB1 H2OEPS15L1CDC37 EGF:p-6Y-EGFRSRC-1 CBL EGF CSKAP2M1 EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1SH3GL2 p-6Y-EGFR LRIG1GTP GRB2-1:SOS1p-6Y-EGFR p-Y55-SPRY2EGF EGF:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2AP2A1 UBB(153-228) GRB2-1 p-6Y-EGFR PXN UbVandetanib p-Y371-CBL EGF Lapatinib EGF:p-6Y-EGFR:CBL:CIN85UBB(1-76) Non-covalent EGFRtyrosine kinaseinhibitorsPI(3,4,5)P3p-6Y-EGFR CetuximabUBC(609-684) UbAP2M1 UBB(77-152) CDC37 ATPResistantligand-responsiveEGFR mutantsRAF/MAP kinasecascadeUb-Beta-Pix:CDC42:GTPSH3KBP1 NRAS HGS GRB2-1 EPS15 p-6Y-EGFR p-6Y-EGFR UBC(1-76) Erlotinib p-Y627,Y659-GAB1 ATPHSP90AA1 p-6Y-EGFR CDC37 SH3GL2 EGF:EGFR dimerADPEGF AP2S1 EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTPADPEGF:p-6Y-EGFR:GRB2:SOS1PXN Ligand-responsiveEGFR mutants dimerEGF:EGFRDimer:Covalent EGFRTKIsEGF:p-6Y-EGFR:GRB2:GAB1:PIK3R1CSK CBL EGF GRB2-1 p-Y317-PAG1CDC37 UBC(229-304) Gefitinib UBC(381-456) EGF EGF CDC37 PI(4,5)P2EGF:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2EGF:p-6Y-EGFR:GRB2:GAB1:PIK3GRB2:GAB1PTPN11 GRB2-1 p-Y371-CBL EGF Pelitinib CBL:Beta-Pix:CDC42:GTPSensitiveligand-responsiveEGFRmutants:Non-covalent EGFR TKIsCDC42 EGFRGRB2:GAB1:PIK3R1DAG and IP3signalingEGF ADAM10(215-824) SPRY1 HSP90AA1 SPRY2 EPS15L1 GTP PIK3R1p-5Y-GAB1 CBL HKI-272 p-Y55-SPRY2 EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2ARHGEF7 GTP p-6Y-EGFR UBC(305-380) SH3KBP1 EGF UBC(305-380) p-Y371-CBL UBB(1-76) EGF GRB2-1 GAB1 GRB2-1 H2Op-6Y-EGFR CBL UBB(153-228) GRB2-1 EGF UBA52(1-76) ARHGEF7 GRB2:GAB1:PIP3EGF:Ligand-responsive EGFR mutants:HSP90:CDC37CBL SH3KBP1 EPS15L1 UBC(1-76) RPS27A(1-76) ATPPip-6Y-EGFR UBC(609-684) GTP EGF:Ub-p-6Y-EGFR:p-Y371-CBL:GRB2Pelitinib CDC42:GTPp-6Y-EGFR RPS27A(1-76) HGS GDPUBB(1-76) SHC1 UBC(153-228) EGFUbCBL CBL EPN1 UBC(77-152) EGF UBB(77-152) EPS15L1 STAM2 AP-2 complexp-Y53-SPRY1 GRB2-1UbEGF GRB2-1 CBL SOS1 CDC37 p21 RAS:GTPp-6Y-EGFR UBC(457-532) SOS1 STAM p-Y55-SPRY2 17-AAG EGF EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:Epsin:Eps15R:Eps15:ClathrinHRAS ADAM12 GAB1ADPNRAS EGF STAM2 PTPN11 EGFR p-Y371-CBL p-5Y-GAB1 UBC(457-532) PTPN11AP2B1 SPRY1/2HGS EGFR EGF:p-6Y-EGFR:CBLGRB2-1 UBB(77-152) ADAM:Zn2+STAM2 Zn2+ EGF SH3KBP1UBB(77-152) CDC42 WZ4002 p-6Y-EGFR AP2A1 ADPPiEPN1 SH3GL2 CBL SPRY1 p-Y371-CBL STAM GRB2-1 CBL p-6Y-EGFR RPS27A(1-76) UBC(457-532) GRB2-117-DMAG p-Y371-CBL EPS15L1 HGS EPN1 p-4Y-EGFR EPS15 UBC(457-532) CDC42 ATPp-5Y-GAB1 UBA52(1-76) p-6Y-EGFR GAB1 PIK3CAEGF EGF:p-6Y-EGFR:p-Y349,350-SHC1AP2S1 STAM EGF:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1p21 RAS:GDPCanertinib ADAM17 Pro-EGFSRC-1 CIN85:EndophilinPAG1GRB2-1 EGF:p-6Y-EGFR:GRB2:GAB1CDC42 HSP90AA1 EGF Canertinib EGF:p-6Y-EGFR:p-Y371-CBLSPRY2 GRB2-1 Eps15:HGS:STAMSOS1HSP90AA1 EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:SPRY1/2:Endophilin:Epsin:Eps15R:Eps15p-6Y-EGFR UBC(305-380) EGF PLCG1 EGF UbCBLGRB2-1 GRB2-1 p-Y55-SPRY2UBC(533-608) Active dimers ofligand-responsiveEGFR mutantsGTP Afatinib UBB(1-76) EGF:EGFRARHGEF7 GRB2-1 p-6Y-EGFR EGF GAB1 EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilinp-Y371-CBL UBB(153-228) p-6Y-EGFR EGF EGF p-6Y-EGFR SPRY1 ARHGEF7 UBC(1-76) UBC(153-228) IPI-504 EGF:p-6Y-EGFR:GRB2:p-Y627,659-GAB1:SHP2CDC37p-Y349,Y350-SHC1 WZ4002 p-6Y-EGFR PXN:SRCHSP90EGF p-Y371-CBL EGF p-4Y-PLCG1 Geldanamycin Covalent EGFRtyrosine kinaseinhibitorsUBC(1-76) HSP90AA1 p-6Y-EGFR CBL ATPp-Y53-SPRY1 UBC(533-608) p-Y371-CBL EGF:p-6Y-EGFR:SHC1HRAS ARHGEF7 PiEGF UBC(609-684) SH3KBP1 AP2A2(1-939) EGF GRB2-1 HSP90AA1 ATP8, 48701772, 84354, 7, 9, 20, 34...78


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. Source:Reactome.

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  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
  98. Ren Y, Meng S, Mei L, Zhao ZJ, Jove R, Wu J.; ''Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor.''; PubMed Europe PMC Scholia
  99. Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, Yoshimoto K, King JC, Nghiemphu P, Yuza Y, Xu Q, Greulich H, Thomas RK, Paez JG, Peck TC, Linhart DJ, Glatt KA, Getz G, Onofrio R, Ziaugra L, Levine RL, Gabriel S, Kawaguchi T, O'Neill K, Khan H, Liau LM, Nelson SF, Rao PN, Mischel P, Pieper RO, Cloughesy T, Leahy DJ, Sellers WR, Sawyers CL, Meyerson M, Mellinghoff IK.; ''Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.''; PubMed Europe PMC Scholia
  100. Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM.; ''Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis.''; PubMed Europe PMC Scholia

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)
ADAM10(215-824) ProteinO14672 (Uniprot-TrEMBL)
ADAM12 ProteinO43184 (Uniprot-TrEMBL)
ADAM17 ProteinP78536 (Uniprot-TrEMBL)
ADAM:Zn2+ComplexR-HSA-179842 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AP-2 complexComplexR-HSA-177480 (Reactome)
AP2A1 ProteinO95782 (Uniprot-TrEMBL)
AP2A2(1-939) ProteinO94973 (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 mutants		R-HSA-1220582 (Reactome)
Afatinib MetaboliteCHEBI:61390 (ChEBI)
Benzoquinoid ansamycinsR-ALL-1217511 (Reactome)
Beta-Pix:CDC42:GTPComplexR-HSA-182917 (Reactome)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBL:Beta-Pix:CDC42:GTPComplexR-HSA-182956 (Reactome)
CBL:Beta-PixComplexR-HSA-182942 (Reactome)
CBL:GRB2ComplexR-HSA-182910 (Reactome)
CBL:SPRY1/2ComplexR-HSA-182914 (Reactome)
CBL:SPRY1/2ComplexR-HSA-182938 (Reactome)
CBLProteinP22681 (Uniprot-TrEMBL)
CDC37 ProteinQ16543 (Uniprot-TrEMBL)
CDC37ComplexR-HSA-1225828 (Reactome)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GTPComplexR-HSA-182921 (Reactome)
CIN85:EndophilinComplexR-HSA-182934 (Reactome)
CLTA ProteinP09496 (Uniprot-TrEMBL)
CSK ProteinP41240 (Uniprot-TrEMBL)
CSKProteinP41240 (Uniprot-TrEMBL)
Canertinib MetaboliteCHEBI:61399 (ChEBI)
CetuximabR-NUL-1248673 (Reactome)
ClathrinComplexR-HSA-177482 (Reactome)
Covalent EGFR

tyrosine kinase

inhibitors		R-ALL-1216522 (Reactome)
DAG and IP3 signalingPathwayR-HSA-1489509 (Reactome) This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
EGF ProteinP01133 (Uniprot-TrEMBL)
EGF:EGFR

Dimer:Covalent EGFR

TKIs		ComplexR-HSA-1225979 (Reactome)
EGF:EGFR dimerComplexR-HSA-179845 (Reactome)
EGF:EGFRComplexR-HSA-179847 (Reactome)
EGF:Ligand-responsive EGFR mutants dimerComplexR-HSA-1500847 (Reactome)
EGF:Ligand-responsive EGFR mutants:HSP90:CDC37R-HSA-1220578 (Reactome)
EGF:Ub-p-6Y-EGFR:p-Y371-CBL:GRB2ComplexR-HSA-182945 (Reactome)
EGF:Ub-p-6Y-EGFR:p-Y371-CBLComplexR-HSA-182930 (Reactome)
EGF:p-5Y-EGFR:GRB2:p-5Y-GAB1:SHP2ComplexR-HSA-180326 (Reactome)
EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTPComplexR-HSA-182932 (Reactome)
EGF:p-6Y-EGFR:CBL:CIN85ComplexR-HSA-182943 (Reactome)
EGF:p-6Y-EGFR:CBL:GRB2ComplexR-HSA-182928 (Reactome)
EGF:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2ComplexR-HSA-182939 (Reactome)
EGF:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2ComplexR-HSA-182935 (Reactome)
EGF:p-6Y-EGFR:CBLComplexR-HSA-182960 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3ComplexR-HSA-179791 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3R1ComplexR-HSA-179867 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1ComplexR-HSA-180348 (Reactome)
EGF:p-6Y-EGFR:GRB2:SOS1ComplexR-HSA-179820 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2ComplexR-HSA-180269 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1ComplexR-HSA-180286 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-Y627,659-GAB1:SHP2ComplexR-HSA-180503 (Reactome)
EGF:p-6Y-EGFR:PLCG1ComplexR-HSA-212717 (Reactome)
EGF:p-6Y-EGFR:SHC1ComplexR-HSA-180301 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1ComplexR-HSA-180331 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1ComplexR-HSA-180337 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15ComplexR-HSA-182961 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:SPRY1/2:Endophilin:Epsin:Eps15R:Eps15ComplexR-HSA-182931 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:Epsin:Eps15R:Eps15:ClathrinComplexR-HSA-182941 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:EndophilinComplexR-HSA-182946 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2ComplexR-HSA-182948 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:Ub-CIN85:Endophilin:Epsin:Eps15R:Eps15ComplexR-HSA-182936 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBLComplexR-HSA-182953 (Reactome)
EGF:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1ComplexR-HSA-212703 (Reactome)
EGF:p-6Y-EGFRComplexR-HSA-179882 (Reactome)
EGFProteinP01133 (Uniprot-TrEMBL)
EGFR ProteinP00533 (Uniprot-TrEMBL)
EGFR:CetuximabComplexR-HSA-1248675 (Reactome)
EGFRProteinP00533 (Uniprot-TrEMBL)
EGFRvIII mutant:HSP90:CDC37ComplexR-HSA-1248004 (Reactome)
EGFRvIII 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 dimerComplexR-HSA-1248010 (Reactome)
EGFRvIIIProteinP00533 (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)
EPS15L1 ProteinQ9UBC2 (Uniprot-TrEMBL)
EPS15L1ProteinQ9UBC2 (Uniprot-TrEMBL)
Eps15:HGS:STAMComplexR-HSA-182947 (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)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB2:GAB1:PIK3R1ComplexR-HSA-179864 (Reactome)
GRB2:GAB1:PIP3ComplexR-HSA-180282 (Reactome)
GRB2:GAB1ComplexR-HSA-179849 (Reactome)
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)
HRAS ProteinP01112 (Uniprot-TrEMBL)
HSP90:Benzoquinoid ansamycinsComplexR-HSA-1218829 (Reactome)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90ComplexR-HSA-1221657 (Reactome)
Herbimycin A MetaboliteCHEBI:5674 (ChEBI)
IPI-504 MetaboliteCHEBI:71956 (ChEBI)
KRAS ProteinP01116 (Uniprot-TrEMBL)
LRIG1ProteinQ96JA1 (Uniprot-TrEMBL)
Lapatinib MetaboliteCHEBI:49603 (ChEBI)
Ligand-responsive

EGFR

mutants:HSP90:CDC37		R-HSA-1218825 (Reactome)
Ligand-responsive EGFR mutants dimerComplexR-HSA-1500849 (Reactome)
Ligand-responsive EGFR mutantsR-HSA-1182966 (Reactome)
NRAS ProteinP01111 (Uniprot-TrEMBL)
Non-covalent EGFR

tyrosine kinase

inhibitors		R-ALL-1216523 (Reactome)
PAG1ProteinQ9NWQ8 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CAProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R1ProteinP27986 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (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.
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PXN ProteinP49023 (Uniprot-TrEMBL)
PXN:CSK:SRCComplexR-HSA-180522 (Reactome)
PXN:SRCComplexR-HSA-180523 (Reactome)
Pelitinib MetaboliteCHEBI:38927 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
Pro-EGFProteinP01133 (Uniprot-TrEMBL)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Resistant

ligand-responsive EGFR mutants:Covalent

EGFR TKIs		ComplexR-HSA-1220579 (Reactome)
Resistant

ligand-responsive

EGFR mutants		R-HSA-1220585 (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 ProteinO43609 (Uniprot-TrEMBL)
SPRY1/2R-HSA-182909 (Reactome)
SPRY1/2R-HSA-182912 (Reactome)
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 TKIs		ComplexR-HSA-1220587 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-Beta-Pix:CDC42:GTPComplexR-HSA-182915 (Reactome)
Ub-SH3KBP1 ProteinQ96B97 (Uniprot-TrEMBL)
UbR-HSA-113595 (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-GAB1 ProteinQ13480 (Uniprot-TrEMBL)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-Y317-PAG1ProteinQ9NWQ8 (Uniprot-TrEMBL)
p-Y349,Y350-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y371-CBL ProteinP22681 (Uniprot-TrEMBL)
p-Y53-SPRY1 ProteinO43609 (Uniprot-TrEMBL)
p-Y55-SPRY2 ProteinO43597 (Uniprot-TrEMBL)
p-Y55-SPRY2ProteinO43597 (Uniprot-TrEMBL)
p-Y627,Y659-GAB1 ProteinQ13480 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADAM:Zn2+mim-catalysisR-HSA-177946 (Reactome)
ADPArrowR-HSA-177930 (Reactome)
ADPArrowR-HSA-177933 (Reactome)
ADPArrowR-HSA-177934 (Reactome)
ADPArrowR-HSA-177937 (Reactome)
ADPArrowR-HSA-177939 (Reactome)
ADPArrowR-HSA-182969 (Reactome)
ADPArrowR-HSA-183058 (Reactome)
ADPArrowR-HSA-212710 (Reactome)
AP-2 complexR-HSA-183077 (Reactome)
ATPR-HSA-177930 (Reactome)
ATPR-HSA-177933 (Reactome)
ATPR-HSA-177934 (Reactome)
ATPR-HSA-177937 (Reactome)
ATPR-HSA-177939 (Reactome)
ATPR-HSA-182969 (Reactome)
ATPR-HSA-183058 (Reactome)
ATPR-HSA-212710 (Reactome)
Active dimers of

ligand-responsive

EGFR mutants		R-HSA-1220610 (Reactome)
Benzoquinoid ansamycinsR-HSA-1218824 (Reactome)
Beta-Pix:CDC42:GTPR-HSA-183002 (Reactome)
CBL:Beta-Pix:CDC42:GTPArrowR-HSA-183094 (Reactome)
CBL:Beta-PixR-HSA-183094 (Reactome)
CBL:GRB2ArrowR-HSA-183052 (Reactome)
CBL:GRB2R-HSA-183067 (Reactome)
CBL:SPRY1/2ArrowR-HSA-182988 (Reactome)
CBL:SPRY1/2ArrowR-HSA-183035 (Reactome)
CBLR-HSA-182988 (Reactome)
CBLR-HSA-183035 (Reactome)
CBLR-HSA-183052 (Reactome)
CBLR-HSA-183055 (Reactome)
CDC37R-HSA-1218833 (Reactome)
CDC37R-HSA-1247999 (Reactome)
CDC42:GTPR-HSA-183094 (Reactome)
CIN85:EndophilinR-HSA-182994 (Reactome)
CIN85:EndophilinR-HSA-183072 (Reactome)
CSKArrowR-HSA-177923 (Reactome)
CetuximabR-HSA-1248677 (Reactome)
ClathrinR-HSA-183077 (Reactome)
Covalent EGFR

tyrosine kinase

inhibitors		R-HSA-1220611 (Reactome)
Covalent EGFR

tyrosine kinase

inhibitors		R-HSA-1225978 (Reactome)
EGF:EGFR

Dimer:Covalent EGFR

TKIs		ArrowR-HSA-1225978 (Reactome)
EGF:EGFR dimerArrowR-HSA-177922 (Reactome)
EGF:EGFR dimerR-HSA-1225978 (Reactome)
EGF:EGFR dimerR-HSA-177934 (Reactome)
EGF:EGFR dimerR-HSA-177937 (Reactome)
EGF:EGFR dimermim-catalysisR-HSA-177934 (Reactome)
EGF:EGFRArrowR-HSA-177942 (Reactome)
EGF:EGFRR-HSA-177922 (Reactome)
EGF:Ligand-responsive EGFR mutants dimerArrowR-HSA-1220613 (Reactome)
EGF:Ligand-responsive EGFR mutants:HSP90:CDC37R-HSA-1220613 (Reactome)
EGF:Ub-p-6Y-EGFR:p-Y371-CBL:GRB2ArrowR-HSA-183036 (Reactome)
EGF:Ub-p-6Y-EGFR:p-Y371-CBLArrowR-HSA-182993 (Reactome)
EGF:p-5Y-EGFR:GRB2:p-5Y-GAB1:SHP2ArrowR-HSA-177935 (Reactome)
EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTPArrowR-HSA-183002 (Reactome)
EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTPR-HSA-183084 (Reactome)
EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTPmim-catalysisR-HSA-183084 (Reactome)
EGF:p-6Y-EGFR:CBL:CIN85R-HSA-183002 (Reactome)
EGF:p-6Y-EGFR:CBL:GRB2ArrowR-HSA-183067 (Reactome)
EGF:p-6Y-EGFR:CBL:GRB2R-HSA-183058 (Reactome)
EGF:p-6Y-EGFR:CBL:GRB2mim-catalysisR-HSA-183058 (Reactome)
EGF:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2ArrowR-HSA-183051 (Reactome)
EGF:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2ArrowR-HSA-183089 (Reactome)
EGF:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2R-HSA-183051 (Reactome)
EGF:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2mim-catalysisR-HSA-183051 (Reactome)
EGF:p-6Y-EGFR:CBLArrowR-HSA-183055 (Reactome)
EGF:p-6Y-EGFR:CBLArrowR-HSA-183084 (Reactome)
EGF:p-6Y-EGFR:CBLR-HSA-182969 (Reactome)
EGF:p-6Y-EGFR:CBLmim-catalysisR-HSA-182969 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3ArrowR-HSA-177927 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3R1ArrowR-HSA-177941 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3R1R-HSA-177927 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3mim-catalysisR-HSA-177939 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1ArrowR-HSA-177940 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1R-HSA-177930 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1mim-catalysisR-HSA-177930 (Reactome)
EGF:p-6Y-EGFR:GRB2:SOS1ArrowR-HSA-177943 (Reactome)
EGF:p-6Y-EGFR:GRB2:SOS1mim-catalysisR-HSA-177938 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2ArrowR-HSA-177944 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2R-HSA-177924 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2R-HSA-177935 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2mim-catalysisR-HSA-177923 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2mim-catalysisR-HSA-177924 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2mim-catalysisR-HSA-177926 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2mim-catalysisR-HSA-177935 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1ArrowR-HSA-177930 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1R-HSA-177944 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-Y627,659-GAB1:SHP2ArrowR-HSA-177924 (Reactome)
EGF:p-6Y-EGFR:PLCG1ArrowR-HSA-212706 (Reactome)
EGF:p-6Y-EGFR:PLCG1R-HSA-212710 (Reactome)
EGF:p-6Y-EGFR:PLCG1mim-catalysisR-HSA-212710 (Reactome)
EGF:p-6Y-EGFR:SHC1ArrowR-HSA-177925 (Reactome)
EGF:p-6Y-EGFR:SHC1R-HSA-177933 (Reactome)
EGF:p-6Y-EGFR:SHC1mim-catalysisR-HSA-177933 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1ArrowR-HSA-177936 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1mim-catalysisR-HSA-177945 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1ArrowR-HSA-177933 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1R-HSA-177936 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15ArrowR-HSA-183072 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15R-HSA-182986 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15R-HSA-182990 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15mim-catalysisR-HSA-182986 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:SPRY1/2:Endophilin:Epsin:Eps15R:Eps15ArrowR-HSA-182990 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:Epsin:Eps15R:Eps15:ClathrinArrowR-HSA-183077 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:EndophilinArrowR-HSA-182994 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:EndophilinR-HSA-183077 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2ArrowR-HSA-183058 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2R-HSA-182994 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2R-HSA-183036 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2mim-catalysisR-HSA-183036 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:Ub-CIN85:Endophilin:Epsin:Eps15R:Eps15ArrowR-HSA-182986 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBLArrowR-HSA-182969 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBLR-HSA-182993 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBLR-HSA-183072 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBLR-HSA-183089 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBLmim-catalysisR-HSA-182993 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBLmim-catalysisR-HSA-183089 (Reactome)
EGF:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1ArrowR-HSA-212710 (Reactome)
EGF:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1R-HSA-212713 (Reactome)
EGF:p-6Y-EGFRArrowR-HSA-177934 (Reactome)
EGF:p-6Y-EGFRArrowR-HSA-177937 (Reactome)
EGF:p-6Y-EGFRArrowR-HSA-212713 (Reactome)
EGF:p-6Y-EGFRR-HSA-177925 (Reactome)
EGF:p-6Y-EGFRR-HSA-177940 (Reactome)
EGF:p-6Y-EGFRR-HSA-177941 (Reactome)
EGF:p-6Y-EGFRR-HSA-177943 (Reactome)
EGF:p-6Y-EGFRR-HSA-183055 (Reactome)
EGF:p-6Y-EGFRR-HSA-183067 (Reactome)
EGF:p-6Y-EGFRR-HSA-212706 (Reactome)
EGFArrowR-HSA-177946 (Reactome)
EGFR-HSA-177942 (Reactome)
EGFR:CetuximabArrowR-HSA-1248677 (Reactome)
EGFRR-HSA-1248677 (Reactome)
EGFRR-HSA-177942 (Reactome)
EGFRvIII mutant:HSP90:CDC37ArrowR-HSA-1247999 (Reactome)
EGFRvIII mutant:HSP90:CDC37R-HSA-1248002 (Reactome)
EGFRvIII mutant dimerArrowR-HSA-1248002 (Reactome)
EGFRvIIIR-HSA-1247999 (Reactome)
EPN1R-HSA-183072 (Reactome)
EPN1R-HSA-183077 (Reactome)
EPS15L1R-HSA-183072 (Reactome)
EPS15L1R-HSA-183077 (Reactome)
Eps15:HGS:STAMR-HSA-183072 (Reactome)
Eps15:HGS:STAMR-HSA-183077 (Reactome)
GAB1R-HSA-177920 (Reactome)
GDPArrowR-HSA-177938 (Reactome)
GDPArrowR-HSA-177945 (Reactome)
GRB2-1:SOS1ArrowR-HSA-109813 (Reactome)
GRB2-1:SOS1R-HSA-177936 (Reactome)
GRB2-1:SOS1R-HSA-177943 (Reactome)
GRB2-1R-HSA-109813 (Reactome)
GRB2-1R-HSA-177920 (Reactome)
GRB2-1R-HSA-183052 (Reactome)
GRB2:GAB1:PIK3R1ArrowR-HSA-177931 (Reactome)
GRB2:GAB1:PIK3R1R-HSA-177941 (Reactome)
GRB2:GAB1:PIP3ArrowR-HSA-179467 (Reactome)
GRB2:GAB1:PIP3R-HSA-177940 (Reactome)
GRB2:GAB1ArrowR-HSA-177920 (Reactome)
GRB2:GAB1R-HSA-177931 (Reactome)
GRB2:GAB1R-HSA-179467 (Reactome)
GTPR-HSA-177938 (Reactome)
GTPR-HSA-177945 (Reactome)
H2OR-HSA-177923 (Reactome)
H2OR-HSA-177924 (Reactome)
H2OR-HSA-177926 (Reactome)
H2OR-HSA-177935 (Reactome)
HSP90:Benzoquinoid ansamycinsArrowR-HSA-1218824 (Reactome)
HSP90R-HSA-1218824 (Reactome)
HSP90R-HSA-1218833 (Reactome)
HSP90R-HSA-1247999 (Reactome)
LRIG1TBarR-HSA-177942 (Reactome)
Ligand-responsive

EGFR

mutants:HSP90:CDC37		ArrowR-HSA-1218833 (Reactome)
Ligand-responsive

EGFR

mutants:HSP90:CDC37		R-HSA-1220614 (Reactome)
Ligand-responsive EGFR mutants dimerArrowR-HSA-1220614 (Reactome)
Ligand-responsive EGFR mutantsR-HSA-1218833 (Reactome)
Non-covalent EGFR

tyrosine kinase

inhibitors		R-HSA-1220610 (Reactome)
PAG1ArrowR-HSA-177926 (Reactome)
PI(3,4,5)P3ArrowR-HSA-177939 (Reactome)
PI(3,4,5)P3ArrowR-HSA-177940 (Reactome)
PI(3,4,5)P3R-HSA-179467 (Reactome)
PI(4,5)P2R-HSA-177939 (Reactome)
PI(4,5)P2R-HSA-183077 (Reactome)
PIK3CAR-HSA-177927 (Reactome)
PIK3R1R-HSA-177931 (Reactome)
PLCG1R-HSA-212706 (Reactome)
PTPN11R-HSA-177944 (Reactome)
PXN:CSK:SRCR-HSA-177923 (Reactome)
PXN:SRCArrowR-HSA-177923 (Reactome)
PiArrowR-HSA-177923 (Reactome)
PiArrowR-HSA-177924 (Reactome)
PiArrowR-HSA-177926 (Reactome)
PiArrowR-HSA-177935 (Reactome)
Pro-EGFR-HSA-177946 (Reactome)
R-HSA-109813 (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.
R-HSA-1218824 (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.
R-HSA-1218833 (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.
R-HSA-1220610 (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).
R-HSA-1220611 (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.
R-HSA-1220613 (Reactome) Although ligand-responsive EGFR mutants dimerize spontaneously, dimerization is increased in the presence of EGF.
R-HSA-1220614 (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.
R-HSA-1225978 (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.
R-HSA-1247999 (Reactome) Association of EGFRvIII mutant with HSP90 chaperone protein and its co-chaperone CDC37 is necessary for the proper functioning of mutant EGFR.
R-HSA-1248002 (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.
R-HSA-1248677 (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.
R-HSA-177920 (Reactome) GRB2 (Growth factor receptor-bound protein 2) binds to GAB1 (GRB2-associated binding protein 1).
R-HSA-177922 (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.
R-HSA-177923 (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.
R-HSA-177924 (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.
R-HSA-177925 (Reactome) SHC1 (Src homology 2 domain-containing) transforming protein can bind to either tyrosine 1148 and/or tyrosine 1173 sites on the EGF receptor.
R-HSA-177926 (Reactome) Dephosphorylation of CBP/PAG negatively regulates the recruitment of the Src inhibiting kinase, Csk. Src is not negatively regulated by phosphorylation by Csk.
R-HSA-177927 (Reactome) The 110 kDa catalytic subunit (PIK3CA) binds to the 85 kDa regulatory subunit (PIK3R1) to create the active PIK3.
R-HSA-177930 (Reactome) EGFR kinase phosphorylates the phosphorylation sites tyrosine 627 and 659 on GAB1
R-HSA-177931 (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.
R-HSA-177933 (Reactome) Once bound to EGFR, SHC1 is phosphorylated on two tyrosines (Y349, Y350).
R-HSA-177934 (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.
R-HSA-177935 (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.
R-HSA-177936 (Reactome) The tyrosine sites on SHC1 become possible binding sites for the GRB2:SOS1 complex.
R-HSA-177937 (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.
R-HSA-177938 (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.
R-HSA-177939 (Reactome) The kinase activity of PIK3 mediates the phosphorylation of PIP2 to form PIP3
R-HSA-177940 (Reactome) GAB1 binds to EGF receptors via tyrosine autophosphorylation sites on the receptor.
R-HSA-177941 (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.
R-HSA-177942 (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.
R-HSA-177943 (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.
R-HSA-177944 (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.
R-HSA-177945 (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).
R-HSA-177946 (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.
R-HSA-179467 (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.
R-HSA-182969 (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.
R-HSA-182986 (Reactome) The adaptor protein CIN85 is monoubiquitinated by CBL after EGF stimulation. Monoubiquitination is thought to regulate receptor internalization and endosomal sorting.
R-HSA-182988 (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.
R-HSA-182990 (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.
R-HSA-182993 (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.
R-HSA-182994 (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.
R-HSA-183002 (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.
R-HSA-183035 (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.
R-HSA-183036 (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.
R-HSA-183051 (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.
R-HSA-183052 (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.
R-HSA-183055 (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.
R-HSA-183058 (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.
R-HSA-183067 (Reactome) Upon EGF stimulation and consequent EGFR phosphorylation, GRB2 binds phosphorylated tyrosines
R-HSA-183072 (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.
R-HSA-183077 (Reactome) Epsin directly modifies membrane curvature on binding to PIP2 in conjunction with clathrin polymerization.
R-HSA-183084 (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.
R-HSA-183089 (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.
R-HSA-183094 (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.
R-HSA-212706 (Reactome) Inactive phospholipase C-gamma1 (PLCG1) binds to activated epidermal growth factor receptor (EGFR).
R-HSA-212710 (Reactome) EGFR phosphorylates PLC-gamma1, thus activating it.
R-HSA-212713 (Reactome) Once activated PLC-gamma1 dissociates from EGFR, it can hydrolyze PIP2.
Resistant

ligand-responsive EGFR mutants:Covalent

EGFR TKIs		ArrowR-HSA-1220611 (Reactome)
Resistant

ligand-responsive

EGFR mutants		ArrowR-HSA-1220610 (Reactome)
Resistant

ligand-responsive

EGFR mutants		R-HSA-1220611 (Reactome)
SH3KBP1ArrowR-HSA-183002 (Reactome)
SHC1R-HSA-177925 (Reactome)
SOS1R-HSA-109813 (Reactome)
SPRY1/2R-HSA-182990 (Reactome)
SPRY1/2R-HSA-183089 (Reactome)
SRC-1mim-catalysisR-HSA-177937 (Reactome)
Sensitive

ligand-responsive EGFR

mutants:Non-covalent EGFR TKIs		ArrowR-HSA-1220610 (Reactome)
Ub-Beta-Pix:CDC42:GTPArrowR-HSA-183084 (Reactome)
UbR-HSA-182986 (Reactome)
UbR-HSA-182993 (Reactome)
UbR-HSA-183036 (Reactome)
UbR-HSA-183051 (Reactome)
UbR-HSA-183084 (Reactome)
UbR-HSA-183089 (Reactome)
p-4Y-PLCG1ArrowR-HSA-212713 (Reactome)
p-Y317-PAG1R-HSA-177926 (Reactome)
p-Y55-SPRY2R-HSA-182988 (Reactome)
p-Y55-SPRY2R-HSA-183035 (Reactome)
p21 RAS:GDPR-HSA-177938 (Reactome)
p21 RAS:GDPR-HSA-177945 (Reactome)
p21 RAS:GTPArrowR-HSA-177938 (Reactome)
p21 RAS:GTPArrowR-HSA-177945 (Reactome)
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