Signaling by EGFR (Homo sapiens)

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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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History

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Revision	Action	Time	User	Comment
123308	view	06:57, 15 July 2022	Egonw	Marked from chemical compounds as Type="Metabolite"
101353	view	11:23, 1 November 2018	ReactomeTeam	reactome version 66
100891	view	20:57, 31 October 2018	ReactomeTeam	reactome version 65
100432	view	19:32, 31 October 2018	ReactomeTeam	reactome version 64
99981	view	16:16, 31 October 2018	ReactomeTeam	reactome version 63
99535	view	14:52, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
93859	view	13:41, 16 August 2017	ReactomeTeam	reactome version 61
93424	view	11:23, 9 August 2017	ReactomeTeam	reactome version 61
86511	view	09:19, 11 July 2016	ReactomeTeam	reactome version 56
83196	view	10:21, 18 November 2015	ReactomeTeam	Version54
81574	view	13:06, 21 August 2015	ReactomeTeam	Version53
77036	view	08:33, 17 July 2014	ReactomeTeam	Fixed remaining interactions
76741	view	12:10, 16 July 2014	ReactomeTeam	Fixed remaining interactions
76066	view	10:12, 11 June 2014	ReactomeTeam	Re-fixing comment source
75776	view	11:29, 10 June 2014	ReactomeTeam	Reactome 48 Update
75126	view	14:07, 8 May 2014	Anwesha	Fixing comment source for displaying WikiPathways description
74773	view	08:51, 30 April 2014	ReactomeTeam	Reactome46
45218	view	17:28, 7 October 2011	Khanspers	Ontology Term : 'epidermal growth factor/neuregulin signaling pathway' added !
42126	view	21:59, 4 March 2011	MaintBot	Automatic update
39936	view	05:57, 21 January 2011	MaintBot	New pathway

External references

DataNodes

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Name	Type	Database reference	Comment
17-AAG [cytosol]	Metabolite	CHEBI:64153 (ChEBI)
17-DMAG [cytosol]	Metabolite	CHEBI:65324 (ChEBI)
ADAM10(215-824) [plasma membrane]	Protein	O14672 (Uniprot-TrEMBL)
ADAM12 [plasma membrane]	Protein	O43184 (Uniprot-TrEMBL)
ADAM17 [plasma membrane]	Protein	P78536 (Uniprot-TrEMBL)
ADAM:Zn2+	Complex	REACT_9655 (Reactome)
ADP	Metabolite	CHEBI:16761 (ChEBI)
AP-2 complex	Complex	REACT_13288 (Reactome)
AP2A1 [plasma membrane]	Protein	O95782 (Uniprot-TrEMBL)
AP2A2(1-939) [plasma membrane]	Protein	O94973 (Uniprot-TrEMBL)
AP2B1 [plasma membrane]	Protein	P63010 (Uniprot-TrEMBL)
AP2M1 [plasma membrane]	Protein	Q96CW1 (Uniprot-TrEMBL)
AP2S1 [plasma membrane]	Protein	P53680 (Uniprot-TrEMBL)
ARHGEF7 [cytosol]	Protein	Q14155 (Uniprot-TrEMBL)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Active dimers of ligand-responsive EGFR mutants	Complex	REACT_116938 (Reactome)
Afatinib [cytosol]	Metabolite	CHEBI:61390 (ChEBI)
Benzoquinoid ansamycins	Metabolite	REACT_117275 (Reactome)
Beta-Pix:CDC42:GTP	Complex	REACT_12882 (Reactome)
CBL [cytosol]	Protein	P22681 (Uniprot-TrEMBL)
CBL [plasma membrane]	Protein	P22681 (Uniprot-TrEMBL)
CBL:Beta-Pix:CDC42:GTP	Complex	REACT_13219 (Reactome)
CBL:Beta-Pix	Complex	REACT_13162 (Reactome)
CBL:GRB2	Complex	REACT_13333 (Reactome)
CBL:SPRY1/2	Complex	REACT_12947 (Reactome)
CBL:SPRY1/2	Complex	REACT_13051 (Reactome)
CBL	Protein	P22681 (Uniprot-TrEMBL)
CDC37(1-378) [cytosol]	Protein	Q16543 (Uniprot-TrEMBL)
CDC37	Complex	REACT_117086 (Reactome)
CDC42 [cytosol]	Protein	P60953 (Uniprot-TrEMBL)
CDC42:GTP	Complex	REACT_12889 (Reactome)
CIN85:Endophilin	Complex	REACT_12741 (Reactome)
CLTA [plasma membrane]	Protein	P09496 (Uniprot-TrEMBL)
CSK [plasma membrane]	Protein	P41240 (Uniprot-TrEMBL)
CSK	Protein	P41240 (Uniprot-TrEMBL)
Canertinib [cytosol]	Metabolite	CHEBI:61399 (ChEBI)
Cetuximab		REACT_116480 (Reactome)
Clathrin	Complex	REACT_9338 (Reactome)
Covalent EGFR tyrosine kinase inhibitors	Metabolite	REACT_116254 (Reactome)
DAG and IP3 signaling	Pathway	WP2688 (WikiPathways)	This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
EGF(971-1023) [extracellular region]	Protein	P01133 (Uniprot-TrEMBL)
EGF(971-1023)	Protein	P01133 (Uniprot-TrEMBL)
EGF:EGFR Dimer:Covalent EGFR TKIs	Complex	REACT_117215 (Reactome)
EGF:EGFR dimer	Complex	REACT_9820 (Reactome)
EGF:EGFR	Complex	REACT_9893 (Reactome)
EGF:Ligand-responsive EGFR mutants:HSP90:CDC37	Complex	REACT_116916 (Reactome)
EGF:Ligand-responsive EGFR mutants dimer	Complex	REACT_116688 (Reactome)
EGF:Ub-p-6Y-EGFR:p-Y371-CBL:GRB2	Complex	REACT_12838 (Reactome)
EGF:Ub-p-6Y-EGFR:p-Y371-CBL	Complex	REACT_12986 (Reactome)
EGF:p-5Y-EGFR:GRB2:p-5Y-GAB1:SHP2	Complex	REACT_13205 (Reactome)
EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP	Complex	REACT_12733 (Reactome)
EGF:p-6Y-EGFR:CBL:CIN85	Complex	REACT_13382 (Reactome)
EGF:p-6Y-EGFR:CBL:GRB2	Complex	REACT_13163 (Reactome)
EGF:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2	Complex	REACT_12687 (Reactome)
EGF:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2	Complex	REACT_13028 (Reactome)
EGF:p-6Y-EGFR:CBL	Complex	REACT_12959 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3R1	Complex	REACT_13343 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3	Complex	REACT_12738 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1	Complex	REACT_13196 (Reactome)
EGF:p-6Y-EGFR:GRB2:SOS1	Complex	REACT_12657 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2	Complex	REACT_12771 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1	Complex	REACT_12983 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-Y627,659-GAB1:SHP2	Complex	REACT_12652 (Reactome)
EGF:p-6Y-EGFR:PLCG1	Complex	REACT_13280 (Reactome)
EGF:p-6Y-EGFR:SHC1	Complex	REACT_12643 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1	Complex	REACT_13054 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1	Complex	REACT_12720 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15	Complex	REACT_13366 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:SPRY1/2:Endophilin:Epsin:Eps15R:Eps15	Complex	REACT_12661 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:Epsin:Eps15R:Eps15:Clathrin	Complex	REACT_13237 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin	Complex	REACT_12726 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2	Complex	REACT_13256 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:Ub-CIN85:Endophilin:Epsin:Eps15R:Eps15	Complex	REACT_13370 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL	Complex	REACT_13081 (Reactome)
EGF:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1	Complex	REACT_13347 (Reactome)
EGF:p-6Y-EGFR	Complex	REACT_9673 (Reactome)
EGFR [plasma membrane]	Protein	P00533 (Uniprot-TrEMBL)
EGFR:Cetuximab	Complex	REACT_117571 (Reactome)
EGFR	Protein	P00533 (Uniprot-TrEMBL)
EGFRvIII mutant:HSP90:CDC37	Complex	REACT_117752 (Reactome)
EGFRvIII mutant [plasma membrane]	Protein	P00533 (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 dimer	Complex	REACT_117412 (Reactome)
EGFRvIII mutant	Protein	P00533 (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 [plasma membrane]	Protein	Q9Y6I3 (Uniprot-TrEMBL)
EPN1	Protein	Q9Y6I3 (Uniprot-TrEMBL)
EPS15 [cytosol]	Protein	P42566 (Uniprot-TrEMBL)
EPS15L1(2-864) [plasma membrane]	Protein	Q9UBC2 (Uniprot-TrEMBL)
EPS15L1(2-864)	Protein	Q9UBC2 (Uniprot-TrEMBL)
Eps15:HGS:STAM	Complex	REACT_12763 (Reactome)
Erlotinib [cytosol]	Metabolite	CHEBI: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 [cytosol]	Protein	Q13480 (Uniprot-TrEMBL)
GAB1	Protein	Q13480 (Uniprot-TrEMBL)
GDP [cytosol]	Metabolite	CHEBI:17552 (ChEBI)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GRB2-1 [cytosol]	Protein	P62993-1 (Uniprot-TrEMBL)
GRB2-1	Protein	P62993-1 (Uniprot-TrEMBL)
GRB2:GAB1:PIK3R1	Complex	REACT_12870 (Reactome)
GRB2:GAB1:PIP3	Complex	REACT_13218 (Reactome)
GRB2:GAB1	Complex	REACT_12705 (Reactome)
GRB2:SOS1	Complex	REACT_4435 (Reactome)
GTP [cytosol]	Metabolite	CHEBI:15996 (ChEBI)
GTP	Metabolite	CHEBI:15996 (ChEBI)
Gefitinib [cytosol]	Metabolite	CHEBI: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 [cytosol]	Metabolite	CHEBI:5292 (ChEBI)
H2O	Metabolite	CHEBI:15377 (ChEBI)
HGS [cytosol]	Protein	O14964 (Uniprot-TrEMBL)
HKI-272 [cytosol]	Metabolite	CHEBI:61390 (ChEBI)
HRAS(1-186) [plasma membrane]	Protein	P01112 (Uniprot-TrEMBL)
HSP90:Benzoquinoid ansamycins	Complex	REACT_116873 (Reactome)
HSP90AA1 [cytosol]	Protein	P07900 (Uniprot-TrEMBL)
HSP90	Complex	REACT_117107 (Reactome)
Herbimycin A [cytosol]	Metabolite	CHEBI:5674 (ChEBI)
IPI-504 [cytosol]	Metabolite	CHEBI:71956 (ChEBI)
KRAS(1-186) [plasma membrane]	Protein	P01116 (Uniprot-TrEMBL)
LRIG1	Protein	Q96JA1 (Uniprot-TrEMBL)
Lapatinib [cytosol]	Metabolite	CHEBI:49603 (ChEBI)
Ligand-responsive EGFR mutants:HSP90:CDC37	Complex	REACT_116857 (Reactome)
Ligand-responsive EGFR mutants dimer	Complex	REACT_117130 (Reactome)
Ligand-responsive EGFR mutants	Protein	REACT_117041 (Reactome)
Ligand-responsive Ub-p-6Y-EGFR mutants:p-Y371-CBL	Complex	REACT_116599 (Reactome)
Ligand-responsive p-6Y-EGFR mutants:CBL	Complex	REACT_116570 (Reactome)
Ligand-responsive p-6Y-EGFR mutants:p-Y371-CBL	Complex	REACT_117735 (Reactome)
Ligand-responsive p-6Y-EGFR mutant dimers	Complex	REACT_117728 (Reactome)
NRAS [plasma membrane]	Protein	P01111 (Uniprot-TrEMBL)
Non-covalent EGFR tyrosine kinase inhibitors	Metabolite	REACT_117456 (Reactome)
PAG1	Protein	Q9NWQ8 (Uniprot-TrEMBL)
PI(3,4,5)P3 [plasma membrane]	Metabolite	CHEBI:16618 (ChEBI)
PI(3,4,5)P3	Metabolite	CHEBI:16618 (ChEBI)
PI(4,5)P2	Metabolite	CHEBI:18348 (ChEBI)
PIK3CA [cytosol]	Protein	P42336 (Uniprot-TrEMBL)
PIK3CA	Protein	P42336 (Uniprot-TrEMBL)
PIK3R1 [cytosol]	Protein	P27986 (Uniprot-TrEMBL)
PIK3R1	Protein	P27986 (Uniprot-TrEMBL)
PIP3 activates AKT signaling	Pathway	WP2653 (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.
PLCG1(2-1290) [cytosol]	Protein	P19174 (Uniprot-TrEMBL)
PLCG1(2-1290) [plasma membrane]	Protein	P19174 (Uniprot-TrEMBL)
PLCG1(2-1290)	Protein	P19174 (Uniprot-TrEMBL)
PTPN11 [cytosol]	Protein	Q06124 (Uniprot-TrEMBL)
PTPN11	Protein	Q06124 (Uniprot-TrEMBL)
PXN [plasma membrane]	Protein	P49023 (Uniprot-TrEMBL)
PXN:CSK:SRC	Complex	REACT_12813 (Reactome)
PXN:SRC	Complex	REACT_13128 (Reactome)
Pelitinib [cytosol]	Metabolite	CHEBI:38927 (ChEBI)
Pi	Metabolite	CHEBI:18367 (ChEBI)
Pro-EGF	Protein	P01133 (Uniprot-TrEMBL)
RAF/MAP kinase cascade	Pathway	WP2735 (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.
RPS27A(1-76) [cytosol]	Protein	P62979 (Uniprot-TrEMBL)
Resistant ligand-responsive EGFR mutants:Covalent EGFR TKIs	Complex	REACT_117723 (Reactome)
Resistant ligand-responsive EGFR mutants	Complex	REACT_117827 (Reactome)
SH3GL2 [cytosol]	Protein	Q99962 (Uniprot-TrEMBL)
SH3KBP1 [cytosol]	Protein	Q96B97 (Uniprot-TrEMBL)
SH3KBP1 [plasma membrane]	Protein	Q96B97 (Uniprot-TrEMBL)
SH3KBP1	Protein	Q96B97 (Uniprot-TrEMBL)
SHC1 [cytosol]	Protein	P29353 (Uniprot-TrEMBL)
SHC1	Protein	P29353 (Uniprot-TrEMBL)
SOS1 [cytosol]	Protein	Q07889 (Uniprot-TrEMBL)
SOS1	Protein	Q07889 (Uniprot-TrEMBL)
SPRY1(1-?) [cytosol]	Protein	O43609 (Uniprot-TrEMBL)
SPRY1(1-?) [plasma membrane]	Protein	O43609 (Uniprot-TrEMBL)
SPRY1/2		REACT_13097 (Reactome)
SPRY1/2		REACT_13348 (Reactome)
SPRY2 [cytosol]	Protein	O43597 (Uniprot-TrEMBL)
SPRY2 [plasma membrane]	Protein	O43597 (Uniprot-TrEMBL)
SRC-1 [plasma membrane]	Protein	P12931-1 (Uniprot-TrEMBL)
SRC-1	Protein	P12931-1 (Uniprot-TrEMBL)
STAM [cytosol]	Protein	Q92783 (Uniprot-TrEMBL)
STAM2 [cytosol]	Protein	O75886 (Uniprot-TrEMBL)
Sensitive ligand-responsive EGFR mutants:Non-covalent EGFR TKIs	Complex	REACT_117305 (Reactome)
UBA52(1-76) [cytosol]	Protein	P62987 (Uniprot-TrEMBL)
UBB(1-76) [cytosol]	Protein	P0CG47 (Uniprot-TrEMBL)
UBB(153-228) [cytosol]	Protein	P0CG47 (Uniprot-TrEMBL)
UBB(77-152) [cytosol]	Protein	P0CG47 (Uniprot-TrEMBL)
UBC(1-76) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(153-228) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(229-304) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(305-380) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(381-456) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(457-532) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(533-608) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(609-684) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(77-152) [cytosol]	Protein	P0CG48 (Uniprot-TrEMBL)
Ub-Beta-Pix:CDC42:GTP	Complex	REACT_13061 (Reactome)
Ub-SH3KBP1 [cytosol]	Protein	Q96B97 (Uniprot-TrEMBL)
Ub	Protein	REACT_3316 (Reactome)
Vandetanib [cytosol]	Metabolite	CHEBI:49960 (ChEBI)
WZ4002 [cytosol]	Metabolite	CHEBI:61400 (ChEBI)
Zn2+ [plasma membrane]	Metabolite	CHEBI:29105 (ChEBI)
p-4Y-EGFR [plasma membrane]	Protein	P00533 (Uniprot-TrEMBL)
p-4Y-PLCG1 [plasma membrane]	Protein	P19174 (Uniprot-TrEMBL)
p-4Y-PLCG1	Protein	P19174 (Uniprot-TrEMBL)
p-5Y-EGFRvIII mutant dimer	Complex	REACT_116729 (Reactome)
p-5Y-GAB1 [cytosol]	Protein	Q13480 (Uniprot-TrEMBL)
p-6Y-EGFR [plasma membrane]	Protein	P00533 (Uniprot-TrEMBL)
p-EGFR mutants:GRB2:GAB1:PI3K	Complex	REACT_116903 (Reactome)
p-EGFR mutants:GRB2:GAB1:PIK3R1	Complex	REACT_117295 (Reactome)
p-EGFR mutants:GRB2:SOS1	Complex	REACT_116562 (Reactome)
p-EGFR mutants:p-Y349,350-SHC1:GRB2:SOS1	Complex	REACT_116797 (Reactome)
p-EGFR mutants:p-Y349,350-SHC1	Complex	REACT_117226 (Reactome)
p-EGFR mutants:p-Y472,771,783,1254-PLCG1	Complex	REACT_116620 (Reactome)
p-EGFR mutants dimer	Complex	REACT_117763 (Reactome)
p-EGFR mutants:PLCG1	Complex	REACT_117319 (Reactome)
p-EGFR mutants:SHC1	Complex	REACT_116600 (Reactome)
p-EGFRvIII mutant [plasma membrane]	Protein	P00533 (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-PAG1	Protein	Q9NWQ8 (Uniprot-TrEMBL)
p-Y349,Y350-SHC1 [cytosol]	Protein	P29353 (Uniprot-TrEMBL)
p-Y371-CBL [cytosol]	Protein	P22681 (Uniprot-TrEMBL)
p-Y371-CBL [plasma membrane]	Protein	P22681 (Uniprot-TrEMBL)
p-Y53-SPRY1(1-?) [cytosol]	Protein	O43609 (Uniprot-TrEMBL)
p-Y55-SPRY2 [cytosol]	Protein	O43597 (Uniprot-TrEMBL)
p-Y55-SPRY2	Protein	O43597 (Uniprot-TrEMBL)
p-Y627,Y659-GAB1 [cytosol]	Protein	Q13480 (Uniprot-TrEMBL)
p21 RAS:GDP	Complex	REACT_2657 (Reactome)
p21 RAS:GTP	Complex	REACT_4782 (Reactome)

Annotated Interactions

View all...

Source	Target	Type	Database reference	Comment
ADAM:Zn2+		mim-catalysis	REACT_9423 (Reactome)
	ADP	Arrow	REACT_115610 (Reactome)
	ADP	Arrow	REACT_115627 (Reactome)
	ADP	Arrow	REACT_115772 (Reactome)
	ADP	Arrow	REACT_115796 (Reactome)
	ADP	Arrow	REACT_115841 (Reactome)
	ADP	Arrow	REACT_115884 (Reactome)
	ADP	Arrow	REACT_12424 (Reactome)
	ADP	Arrow	REACT_12490 (Reactome)
	ADP	Arrow	REACT_12491 (Reactome)
	ADP	Arrow	REACT_12569 (Reactome)
	ADP	Arrow	REACT_12592 (Reactome)
	ADP	Arrow	REACT_12636 (Reactome)
	ADP	Arrow	REACT_9388 (Reactome)
	ADP	Arrow	REACT_9401 (Reactome)
AP-2 complex			REACT_12495 (Reactome)
ATP			REACT_115610 (Reactome)
ATP			REACT_115627 (Reactome)
ATP			REACT_115772 (Reactome)
ATP			REACT_115796 (Reactome)
ATP			REACT_115841 (Reactome)
ATP			REACT_115884 (Reactome)
ATP			REACT_12424 (Reactome)
ATP			REACT_12490 (Reactome)
ATP			REACT_12491 (Reactome)
ATP			REACT_12569 (Reactome)
ATP			REACT_12592 (Reactome)
ATP			REACT_12636 (Reactome)
ATP			REACT_9388 (Reactome)
ATP			REACT_9401 (Reactome)
Active dimers of ligand-responsive EGFR mutants			REACT_115609 (Reactome)
Active dimers of ligand-responsive EGFR mutants			REACT_115772 (Reactome)
Active dimers of ligand-responsive EGFR mutants		mim-catalysis	REACT_115772 (Reactome)
Benzoquinoid ansamycins			REACT_115865 (Reactome)
Beta-Pix:CDC42:GTP			REACT_12412 (Reactome)
	CBL:Beta-Pix:CDC42:GTP	Arrow	REACT_12465 (Reactome)
CBL:Beta-Pix			REACT_12465 (Reactome)
	CBL:GRB2	Arrow	REACT_12635 (Reactome)
CBL:GRB2			REACT_12626 (Reactome)
	CBL:SPRY1/2	Arrow	REACT_12441 (Reactome)
	CBL:SPRY1/2	Arrow	REACT_12500 (Reactome)
CBL			REACT_115614 (Reactome)
CBL			REACT_12441 (Reactome)
CBL			REACT_12500 (Reactome)
CBL			REACT_12632 (Reactome)
CBL			REACT_12635 (Reactome)
CDC37			REACT_115549 (Reactome)
CDC37			REACT_115768 (Reactome)
CDC42:GTP			REACT_12465 (Reactome)
CIN85:Endophilin			REACT_12521 (Reactome)
CIN85:Endophilin			REACT_12527 (Reactome)
	CSK	Arrow	REACT_12601 (Reactome)
Cetuximab			REACT_115741 (Reactome)
Clathrin			REACT_12495 (Reactome)
Covalent EGFR tyrosine kinase inhibitors			REACT_115744 (Reactome)
Covalent EGFR tyrosine kinase inhibitors			REACT_116096 (Reactome)
	EGF(971-1023)	Arrow	REACT_9423 (Reactome)
EGF(971-1023)			REACT_115811 (Reactome)
EGF(971-1023)			REACT_9481 (Reactome)
	EGF:EGFR Dimer:Covalent EGFR TKIs	Arrow	REACT_116096 (Reactome)
	EGF:EGFR dimer	Arrow	REACT_9397 (Reactome)
EGF:EGFR dimer			REACT_116096 (Reactome)
EGF:EGFR dimer			REACT_9388 (Reactome)
EGF:EGFR dimer			REACT_9401 (Reactome)
EGF:EGFR dimer		mim-catalysis	REACT_9388 (Reactome)
	EGF:EGFR	Arrow	REACT_9481 (Reactome)
EGF:EGFR			REACT_9397 (Reactome)
	EGF:Ligand-responsive EGFR mutants:HSP90:CDC37	Arrow	REACT_115811 (Reactome)
EGF:Ligand-responsive EGFR mutants:HSP90:CDC37			REACT_115623 (Reactome)
	EGF:Ligand-responsive EGFR mutants dimer	Arrow	REACT_115623 (Reactome)
	EGF:Ub-p-6Y-EGFR:p-Y371-CBL:GRB2	Arrow	REACT_12562 (Reactome)
	EGF:Ub-p-6Y-EGFR:p-Y371-CBL	Arrow	REACT_12515 (Reactome)
	EGF:p-5Y-EGFR:GRB2:p-5Y-GAB1:SHP2	Arrow	REACT_12629 (Reactome)
	EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP	Arrow	REACT_12412 (Reactome)
EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP			REACT_12451 (Reactome)
EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP		mim-catalysis	REACT_12451 (Reactome)
EGF:p-6Y-EGFR:CBL:CIN85			REACT_12412 (Reactome)
	EGF:p-6Y-EGFR:CBL:GRB2	Arrow	REACT_12626 (Reactome)
EGF:p-6Y-EGFR:CBL:GRB2			REACT_12491 (Reactome)
EGF:p-6Y-EGFR:CBL:GRB2		mim-catalysis	REACT_12491 (Reactome)
	EGF:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2	Arrow	REACT_12381 (Reactome)
	EGF:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2	Arrow	REACT_12432 (Reactome)
EGF:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2			REACT_12381 (Reactome)
EGF:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2		mim-catalysis	REACT_12381 (Reactome)
	EGF:p-6Y-EGFR:CBL	Arrow	REACT_12451 (Reactome)
	EGF:p-6Y-EGFR:CBL	Arrow	REACT_12632 (Reactome)
EGF:p-6Y-EGFR:CBL			REACT_12424 (Reactome)
EGF:p-6Y-EGFR:CBL		mim-catalysis	REACT_12424 (Reactome)
	EGF:p-6Y-EGFR:GRB2:GAB1:PIK3	Arrow	REACT_12501 (Reactome)
	EGF:p-6Y-EGFR:GRB2:GAB1:PIK3R1	Arrow	REACT_12425 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3R1			REACT_12501 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1:PIK3		mim-catalysis	REACT_12636 (Reactome)
	EGF:p-6Y-EGFR:GRB2:GAB1	Arrow	REACT_12423 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1			REACT_12490 (Reactome)
EGF:p-6Y-EGFR:GRB2:GAB1		mim-catalysis	REACT_12490 (Reactome)
	EGF:p-6Y-EGFR:GRB2:SOS1	Arrow	REACT_12392 (Reactome)
EGF:p-6Y-EGFR:GRB2:SOS1		mim-catalysis	REACT_12386 (Reactome)
	EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2	Arrow	REACT_12466 (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:SHP2		mim-catalysis	REACT_12390 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2		mim-catalysis	REACT_12601 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2		mim-catalysis	REACT_12605 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2		mim-catalysis	REACT_12629 (Reactome)
	EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1	Arrow	REACT_12490 (Reactome)
EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1			REACT_12466 (Reactome)
	EGF:p-6Y-EGFR:GRB2:p-Y627,659-GAB1:SHP2	Arrow	REACT_12605 (Reactome)
	EGF:p-6Y-EGFR:PLCG1	Arrow	REACT_12401 (Reactome)
EGF:p-6Y-EGFR:PLCG1			REACT_12569 (Reactome)
EGF:p-6Y-EGFR:PLCG1		mim-catalysis	REACT_12569 (Reactome)
	EGF:p-6Y-EGFR:SHC1	Arrow	REACT_12580 (Reactome)
EGF:p-6Y-EGFR:SHC1			REACT_12592 (Reactome)
EGF:p-6Y-EGFR:SHC1		mim-catalysis	REACT_12592 (Reactome)
	EGF:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1	Arrow	REACT_12514 (Reactome)
EGF:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1		mim-catalysis	REACT_12402 (Reactome)
	EGF:p-6Y-EGFR:p-Y349,350-SHC1	Arrow	REACT_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	Arrow	REACT_12527 (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:CIN85:Endophilin:Epsin:Eps15R:Eps15		mim-catalysis	REACT_12520 (Reactome)
	EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:SPRY1/2:Endophilin:Epsin:Eps15R:Eps15	Arrow	REACT_12387 (Reactome)
	EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:Epsin:Eps15R:Eps15:Clathrin	Arrow	REACT_12495 (Reactome)
	EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin	Arrow	REACT_12521 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin			REACT_12495 (Reactome)
	EGF:p-6Y-EGFR:p-Y371-CBL:GRB2	Arrow	REACT_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:GRB2		mim-catalysis	REACT_12562 (Reactome)
	EGF:p-6Y-EGFR:p-Y371-CBL:Ub-CIN85:Endophilin:Epsin:Eps15R:Eps15	Arrow	REACT_12520 (Reactome)
	EGF:p-6Y-EGFR:p-Y371-CBL	Arrow	REACT_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-Y371-CBL		mim-catalysis	REACT_12432 (Reactome)
EGF:p-6Y-EGFR:p-Y371-CBL		mim-catalysis	REACT_12515 (Reactome)
	EGF:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1	Arrow	REACT_12569 (Reactome)
EGF:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1			REACT_12407 (Reactome)
	EGF:p-6Y-EGFR	Arrow	REACT_12407 (Reactome)
	EGF:p-6Y-EGFR	Arrow	REACT_9388 (Reactome)
	EGF:p-6Y-EGFR	Arrow	REACT_9401 (Reactome)
EGF:p-6Y-EGFR			REACT_12392 (Reactome)
EGF:p-6Y-EGFR			REACT_12401 (Reactome)
EGF:p-6Y-EGFR			REACT_12423 (Reactome)
EGF:p-6Y-EGFR			REACT_12425 (Reactome)
EGF:p-6Y-EGFR			REACT_12580 (Reactome)
EGF:p-6Y-EGFR			REACT_12626 (Reactome)
EGF:p-6Y-EGFR			REACT_12632 (Reactome)
	EGFR:Cetuximab	Arrow	REACT_115741 (Reactome)
EGFR			REACT_115741 (Reactome)
EGFR			REACT_9481 (Reactome)
	EGFRvIII mutant:HSP90:CDC37	Arrow	REACT_115549 (Reactome)
EGFRvIII mutant:HSP90:CDC37			REACT_115887 (Reactome)
	EGFRvIII mutant dimer	Arrow	REACT_115887 (Reactome)
EGFRvIII mutant dimer			REACT_115610 (Reactome)
EGFRvIII mutant dimer		mim-catalysis	REACT_115610 (Reactome)
EGFRvIII mutant			REACT_115549 (Reactome)
EPN1			REACT_12495 (Reactome)
EPN1			REACT_12527 (Reactome)
EPS15L1(2-864)			REACT_12495 (Reactome)
EPS15L1(2-864)			REACT_12527 (Reactome)
Eps15:HGS:STAM			REACT_12495 (Reactome)
Eps15:HGS:STAM			REACT_12527 (Reactome)
GAB1			REACT_12535 (Reactome)
	GDP	Arrow	REACT_115809 (Reactome)
	GDP	Arrow	REACT_116154 (Reactome)
	GDP	Arrow	REACT_12386 (Reactome)
	GDP	Arrow	REACT_12402 (Reactome)
GRB2-1			REACT_12535 (Reactome)
GRB2-1			REACT_12635 (Reactome)
GRB2-1			REACT_2257 (Reactome)
	GRB2:GAB1:PIK3R1	Arrow	REACT_12616 (Reactome)
GRB2:GAB1:PIK3R1			REACT_115604 (Reactome)
GRB2:GAB1:PIK3R1			REACT_12425 (Reactome)
	GRB2:GAB1:PIP3	Arrow	REACT_12534 (Reactome)
GRB2:GAB1:PIP3			REACT_12423 (Reactome)
	GRB2:GAB1	Arrow	REACT_12535 (Reactome)
GRB2:GAB1			REACT_12534 (Reactome)
GRB2:GAB1			REACT_12616 (Reactome)
	GRB2:SOS1	Arrow	REACT_2257 (Reactome)
GRB2:SOS1			REACT_115562 (Reactome)
GRB2:SOS1			REACT_116141 (Reactome)
GRB2:SOS1			REACT_12392 (Reactome)
GRB2:SOS1			REACT_12514 (Reactome)
GTP			REACT_115809 (Reactome)
GTP			REACT_116154 (Reactome)
GTP			REACT_12386 (Reactome)
GTP			REACT_12402 (Reactome)
H2O			REACT_12390 (Reactome)
H2O			REACT_12601 (Reactome)
H2O			REACT_12605 (Reactome)
H2O			REACT_12629 (Reactome)
	HSP90:Benzoquinoid ansamycins	Arrow	REACT_115865 (Reactome)
HSP90			REACT_115549 (Reactome)
HSP90			REACT_115768 (Reactome)
HSP90			REACT_115865 (Reactome)
LRIG1		TBar	REACT_9481 (Reactome)
	Ligand-responsive EGFR mutants:HSP90:CDC37	Arrow	REACT_115768 (Reactome)
Ligand-responsive EGFR mutants:HSP90:CDC37			REACT_115811 (Reactome)
Ligand-responsive EGFR mutants:HSP90:CDC37			REACT_115980 (Reactome)
	Ligand-responsive EGFR mutants dimer	Arrow	REACT_115980 (Reactome)
Ligand-responsive EGFR mutants			REACT_115768 (Reactome)
	Ligand-responsive Ub-p-6Y-EGFR mutants:p-Y371-CBL	Arrow	REACT_115732 (Reactome)
	Ligand-responsive p-6Y-EGFR mutants:CBL	Arrow	REACT_115614 (Reactome)
Ligand-responsive p-6Y-EGFR mutants:CBL			REACT_115796 (Reactome)
Ligand-responsive p-6Y-EGFR mutants:CBL		TBar	REACT_115732 (Reactome)
Ligand-responsive p-6Y-EGFR mutants:CBL		mim-catalysis	REACT_115796 (Reactome)
	Ligand-responsive p-6Y-EGFR mutants:p-Y371-CBL	Arrow	REACT_115796 (Reactome)
Ligand-responsive p-6Y-EGFR mutants:p-Y371-CBL			REACT_115732 (Reactome)
Ligand-responsive p-6Y-EGFR mutants:p-Y371-CBL		mim-catalysis	REACT_115732 (Reactome)
	Ligand-responsive p-6Y-EGFR mutant dimers	Arrow	REACT_115772 (Reactome)
Ligand-responsive p-6Y-EGFR mutant dimers			REACT_115614 (Reactome)
Non-covalent EGFR tyrosine kinase inhibitors			REACT_115609 (Reactome)
	PAG1	Arrow	REACT_12390 (Reactome)
	PI(3,4,5)P3	Arrow	REACT_115884 (Reactome)
	PI(3,4,5)P3	Arrow	REACT_12423 (Reactome)
	PI(3,4,5)P3	Arrow	REACT_12636 (Reactome)
PI(3,4,5)P3			REACT_12534 (Reactome)
PI(4,5)P2			REACT_115884 (Reactome)
PI(4,5)P2			REACT_12495 (Reactome)
PI(4,5)P2			REACT_12636 (Reactome)
PIK3CA			REACT_116004 (Reactome)
PIK3CA			REACT_12501 (Reactome)
PIK3R1			REACT_12616 (Reactome)
PLCG1(2-1290)			REACT_115745 (Reactome)
PLCG1(2-1290)			REACT_12401 (Reactome)
PTPN11			REACT_12466 (Reactome)
PXN:CSK:SRC			REACT_12601 (Reactome)
	PXN:SRC	Arrow	REACT_12601 (Reactome)
	Pi	Arrow	REACT_12390 (Reactome)
	Pi	Arrow	REACT_12601 (Reactome)
	Pi	Arrow	REACT_12605 (Reactome)
	Pi	Arrow	REACT_12629 (Reactome)
Pro-EGF			REACT_9423 (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 mutants:Covalent EGFR TKIs	Arrow	REACT_115744 (Reactome)
	Resistant ligand-responsive EGFR mutants	Arrow	REACT_115609 (Reactome)
Resistant ligand-responsive EGFR mutants			REACT_115744 (Reactome)
	SH3KBP1	Arrow	REACT_12412 (Reactome)
SHC1			REACT_116063 (Reactome)
SHC1			REACT_12580 (Reactome)
SOS1			REACT_2257 (Reactome)
SPRY1/2			REACT_12387 (Reactome)
SPRY1/2			REACT_12432 (Reactome)
SRC-1		mim-catalysis	REACT_9401 (Reactome)
	Sensitive ligand-responsive EGFR mutants:Non-covalent EGFR TKIs	Arrow	REACT_115609 (Reactome)
	Ub-Beta-Pix:CDC42:GTP	Arrow	REACT_12451 (Reactome)
Ub			REACT_115732 (Reactome)
Ub			REACT_12381 (Reactome)
Ub			REACT_12432 (Reactome)
Ub			REACT_12451 (Reactome)
Ub			REACT_12515 (Reactome)
Ub			REACT_12520 (Reactome)
Ub			REACT_12562 (Reactome)
	p-4Y-PLCG1	Arrow	REACT_115903 (Reactome)
	p-4Y-PLCG1	Arrow	REACT_12407 (Reactome)
	p-5Y-EGFRvIII mutant dimer	Arrow	REACT_115610 (Reactome)
	p-EGFR mutants:GRB2:GAB1:PI3K	Arrow	REACT_116004 (Reactome)
p-EGFR mutants:GRB2:GAB1:PI3K		mim-catalysis	REACT_115884 (Reactome)
	p-EGFR mutants:GRB2:GAB1:PIK3R1	Arrow	REACT_115604 (Reactome)
p-EGFR mutants:GRB2:GAB1:PIK3R1			REACT_116004 (Reactome)
	p-EGFR mutants:GRB2:SOS1	Arrow	REACT_116141 (Reactome)
p-EGFR mutants:GRB2:SOS1		mim-catalysis	REACT_116154 (Reactome)
	p-EGFR mutants:p-Y349,350-SHC1:GRB2:SOS1	Arrow	REACT_115562 (Reactome)
p-EGFR mutants:p-Y349,350-SHC1:GRB2:SOS1		mim-catalysis	REACT_115809 (Reactome)
	p-EGFR mutants:p-Y349,350-SHC1	Arrow	REACT_115841 (Reactome)
p-EGFR mutants:p-Y349,350-SHC1			REACT_115562 (Reactome)
	p-EGFR mutants:p-Y472,771,783,1254-PLCG1	Arrow	REACT_115627 (Reactome)
p-EGFR mutants:p-Y472,771,783,1254-PLCG1			REACT_115903 (Reactome)
	p-EGFR mutants dimer	Arrow	REACT_115903 (Reactome)
p-EGFR mutants dimer			REACT_115604 (Reactome)
p-EGFR mutants dimer			REACT_115745 (Reactome)
p-EGFR mutants dimer			REACT_116063 (Reactome)
p-EGFR mutants dimer			REACT_116141 (Reactome)
	p-EGFR mutants:PLCG1	Arrow	REACT_115745 (Reactome)
p-EGFR mutants:PLCG1			REACT_115627 (Reactome)
p-EGFR mutants:PLCG1		mim-catalysis	REACT_115627 (Reactome)
	p-EGFR mutants:SHC1	Arrow	REACT_116063 (Reactome)
p-EGFR mutants:SHC1			REACT_115841 (Reactome)
p-EGFR mutants:SHC1		mim-catalysis	REACT_115841 (Reactome)
p-Y317-PAG1			REACT_12390 (Reactome)
p-Y55-SPRY2			REACT_12441 (Reactome)
p-Y55-SPRY2			REACT_12500 (Reactome)
p21 RAS:GDP			REACT_115809 (Reactome)
p21 RAS:GDP			REACT_116154 (Reactome)
p21 RAS:GDP			REACT_12386 (Reactome)
p21 RAS:GDP			REACT_12402 (Reactome)
	p21 RAS:GTP	Arrow	REACT_115809 (Reactome)
	p21 RAS:GTP	Arrow	REACT_116154 (Reactome)
	p21 RAS:GTP	Arrow	REACT_12386 (Reactome)
	p21 RAS:GTP	Arrow	REACT_12402 (Reactome)

Signaling by EGFR (Homo sapiens)

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