Signaling by EGFR (Homo sapiens)

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1-4371813532554, 554630323125365718332833132934, 3550, 513022134516, 58521448, 4940-429, 15182034, 35131920, 219, 155626, 2723, 2416, 173943, 4430384726, 2732plasma membranecytosolEGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:GRB2H2OGRB2:SOS-Phospho-SHC:EGF:Phospho-EGFR dimerADPp-PAG1CBLY55-phospho Sprouty 2p-Raf1(S259,S621):14-3-3 protein beta/alphaEGF:Phospho-EGFR (Y1045) dimer:CBL:CIN85Y55-phospho Sprouty 2Shc events in EGFR signalingEGF:Phospho-EGFR (Y1045) dimer Ubiquitinated:Phospho-CBL:GRB2Adaptor protein 2 complexATPp-Raf1(S259,S621)EGF:Phospho-EGFR-SHCGRB2:GAB1CBL:Cool/Pix:CDC42-GTPSHC1H2OADAM metalloprotease:Zinc cofactorEGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:GRB2:CIN85:Endophilin:Epsin:Eps15R:Eps15 complex:ClathrinCBL:SproutyGRB2:SOS1CBL:Cool/PixEGFRGAB1:GRB2-EGF-Phospho-EGFR dimerADPGTPATPGDPCool/Pix Ubiquitinated:CDC42-GTPSHP2-GRB2:Phospho GAB1-EGF-Phospho-EGFR dimerPI3-kinase p110 subunit alphaCBL:GRB2EpsinClathrinGab1 signalosomeADPOrthophosphateEGF:Phospho-EGFR (Y1045) dimer:CBL:Cool/Pix:CDC42-GTPATPPIP3:GAB1:GRB2-EGF-Phospho-EGFR dimerATPH2OATPEGF:Phospho-EGFR-GRB2:GAB1:PI3Kreg:PI3KcatGRB2:GAB1:PI3KregADPEGFATPEGF:EGFRADPunidentified protein tyrosine kinaseEGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:GRB2:CIN85:EndophilinATPEGF:Phospho-EGFR:Phospho-SHCPhospho-Phospholipase C gamma 1ADPSRCGRB2:Phospho GAB1-EGF-Phospho-EGFR dimerCool/Pix:CDC42-GTPp21 RAS:GDPActivated EGFR:Phospho-PLC-gamma1EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85 ubiquitinated:Endophilin:Epsin:Eps15R:Eps15 complexSHP2:GRB2:Phospho GAB1-EGF-Phospho-EGFR (-Y992) dimerEps15:HGS:STAMADPADPEGF:Phospho-EGFR (Y1045) dimerATPGrb2 events in EGFR signalingSon of sevenless protein homolog 1GRB2EGF:Phospho-EGFR (Y1045) dimer Ubiquitinated:Phospho-CBLSHP2-GRB2:Phospho GAB1(dephos)-EGF-Phospho-EGFR dimerEGF:Phospho-EGFR (Y1045) dimer:CBL:Phospho-Sprouty ubiquitinatedPhosphatidylinositol-4,5-bisphosphateEGF:Phospho-EGFR (Y1045) dimer:Phospho-CBLADPCIN85:EndophilinubiquitinEGF:Phospho-EGFR dimer:CBL:Phospho-SproutyTyrosine-protein kinase CSKPhospholipase C gamma 1EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85-Sprouty:Endophilin:Epsin:Eps15R:Eps15 complexOrthophosphateCBLOrthophosphatePAG1pro-EGF precursorp21 RAS:GTPActivated RAF1 complexPI3K-p85CDC42-GTPLeucine-rich repeats and immunoglobulin-like domains protein 1 precursorRAS:RAFEps15RSproutyEGF:Phospho-EGFR (Y992, Y1068, Y1086, Y1148, Y1173) dimerRAF activationSproutyEGF:EGFR dimerEGF:Phospho-EGFR (Y1045) dimer:CBL:GRB2H2OMAP kinase cascadeEGF:Phospho-EGFR (Y1045) dimer:CBLOrthophosphateEGF:Phospho-EGFR-GRB2:GAB1:PI3Kreg14-3-3 protein beta/alphaSHP2EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15 complexGRB2:SOS-EGF-Phospho-EGFR dimerActivated EGFR:PLC-gamma1CBL:SproutyEGFR interacts with phospholipase C-gammaPaxillin:CSK:Src complexPhosphatidylinositol-3,4,5-trisphosphateRAS:RAF:14-3-3CIN85Paxillin:Src complexPhosphatidylinositol-4,5-bisphosphateGAB1ATPEGFR downregulation6, 78-10131256, 11


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 leads to autophosphorylation of tyrosine residues on the receptor and subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival. Ligand binding with EGFR results in receptor homo- or heterodimerization at the cell surface. Trans-autophosphorylation of the EGFR tyrosine kinase domains occurs and the phosphorylated tyrosine kinase residues serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, such as Ras, which then stimulate an intracellular signal transduction cascade.

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Bibliography

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History

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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
14-3-3 protein

beta/alpha

ProteinP31946 (UniProt)
ADAM

metalloprotease:Zinc cofactor

ComplexREACT_9655 (Reactome)
ADP Metabolite16761 (ChEBI)
ATP Metabolite15422 (ChEBI)
Activated EGFR:

Phospho-PLC- gamma1

ComplexREACT_13347 (Reactome)
Activated EGFR:PLC-

gamma1

ComplexREACT_13280 (Reactome)
Activated RAF1

complex

ComplexREACT_4906 (Reactome)
Adaptor protein 2

complex

ComplexREACT_13288 (Reactome)
CBL ProteinP22681 (UniProt)
CBL:Cool/Pix ComplexREACT_13162 (Reactome)
CBL:Cool/Pix:

CDC42-GTP

ComplexREACT_13219 (Reactome)
CBL:GRB2 ComplexREACT_13333 (Reactome)
CBL:Sprouty ComplexREACT_12947 (Reactome)
CBL:Sprouty ComplexREACT_13051 (Reactome)
CDC42-GTP ComplexREACT_12889 (Reactome)
CIN85 ProteinQ96B97 (UniProt)
CIN85:Endophilin ComplexREACT_12741 (Reactome)
Clathrin ComplexREACT_9338 (Reactome)
Cool/Pix

Ubiquitinated: CDC42-GTP

ComplexREACT_13061 (Reactome)
Cool/Pix:CDC42-

GTP

ComplexREACT_12882 (Reactome)
EGF ProteinP01133 (UniProt)
EGF:EGFR ComplexREACT_9893 (Reactome)
EGF:EGFR dimer ComplexREACT_9820 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer

ComplexREACT_13124 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer Ubiquitinated: Phospho-CBL

ComplexREACT_12986 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer Ubiquitinated: Phospho-CBL:GRB2

ComplexREACT_12838 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer: Phospho-CBL

ComplexREACT_13081 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer: Phospho-CBL:CIN85 ubiquitinated: Endophilin:Epsin: Eps15R:Eps15 complex

ComplexREACT_13370 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer: Phospho-CBL:CIN85- Sprouty:Endophilin: Epsin:Eps15R:Eps15 complex

ComplexREACT_12661 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer: Phospho-CBL:CIN85: Endophilin:Epsin: Eps15R:Eps15 complex

ComplexREACT_13366 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer: Phospho-CBL:GRB2

ComplexREACT_13256 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer: Phospho-CBL:GRB2: CIN85:Endophilin

ComplexREACT_12726 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer: Phospho-CBL:GRB2: CIN85:Endophilin: Epsin:Eps15R:Eps15 complex:Clathrin

ComplexREACT_13237 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer:CBL

ComplexREACT_12959 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer:CBL: CIN85

ComplexREACT_13382 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer:CBL: Cool/Pix:CDC42-GTP

ComplexREACT_12733 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer:CBL: GRB2

ComplexREACT_13163 (Reactome)
EGF:Phospho-EGFR

(Y1045) dimer:CBL: Phospho-Sprouty ubiquitinated

ComplexREACT_12687 (Reactome)
EGF:Phospho-EGFR

(Y992, Y1068, Y1086, Y1148, Y1173) dimer

ComplexREACT_9673 (Reactome)
EGF:Phospho-EGFR

dimer:CBL:Phospho- Sprouty

ComplexREACT_13028 (Reactome)
EGF:Phospho-EGFR-

GRB2:GAB1:PI3Kreg

ComplexREACT_13343 (Reactome)
EGF:Phospho-EGFR-

GRB2:GAB1:PI3Kreg: PI3Kcat

ComplexREACT_12738 (Reactome)
EGF:Phospho-EGFR-

SHC

ComplexREACT_12643 (Reactome)
EGF:Phospho-EGFR:

Phospho-SHC

ComplexREACT_12720 (Reactome)
EGFR ProteinP00533 (UniProt)
EGFR downregulation UnknownREACT_12484 (Reactome) Regulation of receptor tyrosine kinase (RTK) activity is implicated in the control of almost all cellular functions. One of the best understood RTKs is epidermal growth factor receptor (EGFR). Growth factors can bind to EGFR and activate it to initiate signalling cascades within the cell. EGFRs can also be recruited to clathrin-coated pits which can be internalised into endocytic vesicles. From here, EGFRs can either be recycled back to the plasma membrane or directed to lysosomes for destruction.This provides a mechanism by which EGFR signalling is negatively regulated and controls the strength and duration of EGFR-induced signals. It also prevents EGFR hyperactivation as commonly seen in tumorigenesis.

The proto-oncogene Cbl can negatively regulate EGFR signalling. The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation. All Cbl proteins have a unique domain that recognises phosphorylated tyrosine residues on activated EGFRs. They also direct the ubiquitination and degradation of activated EGFRs by recruiting ubiquitin-conjugation enzymes. Cbl proteins function by specifically targeting activated EGFRs and mediating their down-regulation, thus providing a means by which signaling processes can be negatively regulated.

Cbl also promotes receptor internalization via it's interaction with an adaptor protein, CIN85 (Cbl-interacting protein of 85kDa). CIN85 binds to Cbl via it's SH3 domain and is enhanced by the EGFR-induced tyrosine phosphorylation of Cbl. The proline-rich region of CIN85 interacts with endophilins which are regulatory components of clathrin-coated vesicles (CCVs). Endophilins bind to membranes and induce membrane curvature, in conjunction with other proteins involved in CCV formation. The rapid recruitment of endophilin to the activated receptor complex by CIN85 is the mechanism which controls receptor internalization.
EGFR interacts with phospholipase C-gamma UnknownREACT_12478 (Reactome) Activated epidermal growth factor receptors (EGFR) can stimulate phosphatidylinositol (PI) turnover. Activated EGFR can activate phospholipase C-gamma1 (PLC-gamma1) which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is instrumental in the release of calcium from intracellular stores and DAG is involved in protein kinase C activation.
Eps15:HGS:STAM ComplexREACT_12763 (Reactome)
Eps15R ProteinQ9UBC2 (UniProt)
Epsin ProteinQ9Y6I3 (UniProt)
GAB1 ProteinQ13480 (UniProt)
GAB1:GRB2-EGF-

Phospho-EGFR dimer

ComplexREACT_13196 (Reactome)
GDP Metabolite17552 (ChEBI)
GRB2 ProteinP62993-1 (UniProt)
GRB2:GAB1 ComplexREACT_12705 (Reactome)
GRB2:GAB1:PI3Kreg ComplexREACT_12870 (Reactome)
GRB2:Phospho

GAB1-EGF- Phospho-EGFR dimer

ComplexREACT_12983 (Reactome)
GRB2:SOS-EGF-

Phospho-EGFR dimer

ComplexREACT_12657 (Reactome)
GRB2:SOS-Phospho-

SHC:EGF:Phospho- EGFR dimer

ComplexREACT_13054 (Reactome)
GRB2:SOS1 ComplexREACT_4435 (Reactome)
GTP Metabolite15996 (ChEBI)
Gab1 signalosome UnknownREACT_12578 (Reactome) SHP2 down-regulates PI3K activation by dephosphorylating GAB1.
Grb2 events in EGFR signaling UnknownREACT_12606 (Reactome) Autophosphorylation of tyrosine residues are docking sites for many downstream effectors in EGFR signaling. SH2-containing phosphotyrosine-binding domains of adaptor proteins like GRB2 is one such example. GRB2 is constitutively associated with SOS, a guanine nucleotide exchange factor of Ras. GRB2 binding to phosphorylated EGFR results in the recruitment of SOS to the plasma membrane where it comes in proximity to Ras. This mechanism has been seen to be the model for Ras activation.
H2O Metabolite15377 (ChEBI)
Leucine-rich repeats

and immunoglobulin- like domains protein 1 precursor

ProteinQ96JA1 (UniProt)
MAP kinase cascade PathwayREACT_634 (Reactome) The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.
Orthophosphate Metabolite18367 (ChEBI)
PAG1 ProteinQ9NWQ8 (UniProt)
PI3-kinase

p110 subunit alpha

ProteinP42336 (UniProt)
PI3K-p85 ProteinP27986 (UniProt)
PIP3:GAB1:GRB2-

EGF-Phospho-EGFR dimer

ComplexREACT_13218 (Reactome)
Paxillin:CSK:Src

complex

ComplexREACT_12813 (Reactome)
Paxillin:Src complex ComplexREACT_13128 (Reactome)
Phosphatidylinositol-

3,4,5-trisphosphate

Metabolite16618 (ChEBI)
Phosphatidylinositol-

4,5-bisphosphate

Metabolite18348 (ChEBI)
Phospho-

Phospholipase C gamma 1

ProteinP19174 (UniProt)
Phospholipase C

gamma 1

ProteinP19174 (UniProt)
RAF activation PathwayREACT_2077 (Reactome) Phosphorylated RAF is activated by Ras binding and stabilised in its active form by transient disassociation and reassociation of 14-3-3, as well as further phosphorylation.
RAS:RAF ComplexREACT_3036 (Reactome)
RAS:RAF:14-3-

3

ComplexREACT_3642 (Reactome)
SHC1 ProteinP29353 (UniProt)
SHP2 ProteinQ06124 (UniProt)
SHP2-GRB2:Phospho

GAB1(dephos)-EGF- Phospho-EGFR dimer

ComplexREACT_12652 (Reactome)
SHP2-GRB2:Phospho

GAB1-EGF-Phospho- EGFR dimer

ComplexREACT_12771 (Reactome)
SHP2:GRB2:Phospho

GAB1-EGF-Phospho- EGFR (-Y992) dimer

ComplexREACT_13205 (Reactome)
SRC ProteinP12931-1 (UniProt)
Shc events in EGFR signaling UnknownREACT_12579 (Reactome) Grb2 can bind EGFR directly or through another SH2-containing protein, Shc. This association is involved in Ras activation.
Son of sevenless

protein homolog 1

ProteinQ07889 (UniProt)
Sprouty UnknownREACT_13097 (Reactome)
Sprouty UnknownREACT_13348 (Reactome)
Tyrosine-protein

kinase CSK

ProteinP41240 (UniProt)
Y55-phospho

Sprouty 2

ProteinO43597 (UniProt)
p-PAG1 ProteinQ9NWQ8 (UniProt)
p-Raf1(S259,

S621)

ProteinP04049 (UniProt)
p-Raf1(S259,S621):

14-3-3 protein beta/alpha

ComplexREACT_4612 (Reactome)
p21 RAS:GDP ComplexREACT_2657 (Reactome)
p21 RAS:GTP ComplexREACT_4782 (Reactome)
pro-EGF precursor ProteinP01133 (UniProt)
ubiquitin ProteinREACT_3316 (Reactome)
unidentified protein

tyrosine kinase

UnknownREACT_4938 (Reactome)

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1910"
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