EGF/EGFR Signaling Pathway (Homo sapiens)

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SHC1DAGPIP2IP3Internalization, degradation and recycling of EGFRPIP3PIP2PathwayCYNUpolymerizationCa2+NUReleaseRegulation ofNFKBNUNUEGFR signal transduction pathwayCYCYNUCYactinAKT1RPS6KA2NCK2LIMK2EIF4EBP1PDPK1CDC42INPP5DMAP2K5PTPN11ATF1AP2B1SOS1NCOA3SH3GL2EGFREGFAP2S1PIK3R2EPS15FOSMYBL2USP8RPS6KA3EGFRSOS2MAPK9BRAFSTAMGRB2CSKMAPK7PCNAVAV2NEDD4PRKCDSHC1JAK2EPS8STAM2PRKCZHGSCOX2CREB1PIK3R1NCK1GRB10PTENCAV2STAT5BSH3KBP1RAP1ARAF1GRIM19CRKLSP1GJA1GAB1PTK6MTORKRASMEF2DTWIST1SPRY2SH2D2AMAPK14PLSCR1ROCK1RPS6KA5RIN1STAT1EGFRELK4HRASSTMN1PLD1PRKCINEDD8PLCE1RALBP1PIK3C2BINPPL1MAP2K2PLD2NOS3ABL1PTK2BITCHAURKAPTPN12ELK1FOXO1EPS15L1PRKCBRAB5AMAPK3MAP2K1GAB2STAT3VAV3JAK1CRKMAP3K2SYNJ1ABI1PEBP1RALGDSTNK2ASAP1RALARPS6KA1ARF6MAPK8PIAS3ARHGEF1JUNDPTPRRATXN2SRCJUNAP2A1E2F1STAT5AERBB2STAMBPRICTORRASA1IQGAP1IQSEC1PTPN5PRKCAMAP3K3STXBP1BCAR1REPS2DOK2MAP4K1RALBRPS6KB1MAP3K1MAP3K4CAMK2ARAC1VAV1FOXO4CAV1DNM1MAPK1PLSCR1PLCG1EPN1USP6NLFOSBERRFI1SH3GL3PPPPPGTPGTPPPPPPPPGTPPPPPPPPGTPPUbPPGTPPPPGTPPPPPPPPPPPPPPPPpPPGTPPPGTPPUbPPPPEGFREGFRCBLBCBLCBLCSRCPGRB2PSOS1RALBP1CBLBCBLPCBLCPLD1PAK1PSTAT3PSTAT1STAT5BPSTAT5APPCFL1PTK2PEGFAP2M1PIAS3MEF2ASRCPXNEndosome/Multivesicular bodies/LysozomeHRASVAV2GTPPSP1PEPS8MEF2CRPS6KA3MAPK3MAPK1MAPK9PMAPK8PMAPK7MAP2K2MAP2K1NUCYCYNUNUNUCYNUCYCYEnzyme complexInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationProteinmRNAProteinReceptorLigandDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavage


Description

Epidermal growth factor receptor (EGFR) also known as ErbB1/HER1 is a member of the ErbB family of receptor tyrosine kinases which also includes ErbB2 (Neu, HER2), ErbB3 (HER3) and ErbB4 (HER4). Several ligands such as epidermal growth factor, transforming growth factor-alpha, epigen, amphiregulin, betacellulin, heparin-binding EGF and epiregulin are known to specifically bind to EGFR. Epidermal growth factor (EGF) is one of the high affinity ligands of EGFR. EGF/EGFR system induces growth, differentiation, migration, adhesion and cell survival through various inter-acting signaling pathways.

The binding of EGF to the extracellular domain of EGFR induces the dimerization, activation of intrinsic kinase activity and subsequent autophosphorylation of EGFR at multiple residues in the cytoplasmic region such as Tyr 1092, Tyr 1172, Tyr 1197, Tyr 1110, Tyr 1016). Activated EGFR recruits various cytoplasmic proteins which transduce and regulate the EGFR function. The proteins recruited to active EGFR include many Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain containing proteins which binds to the tyrosine phosphorylated residues in EGFR, enzymes which act on EGFR and also various EGFR substrates.

One of the adapter proteins, GRB2, binds to the phosphotyrosine residue at 1068 and recruits SOS to the membrane. SOS activates GDP/GTP exchange which recruits RAF to the membrane. RAF phosphorylates MEKs, which then activates the extracellular signal regulated kinase (ERK). ERK activates a number of transcriptional regulators to induce cell growth and proliferation. GRB2 or other adaptor proteins such as GABs recruits PI3Ks, another major mediator of EGFR signaling. PI3Ks convert Phosphatidylinositol-4,5-bisphosphate (PIP2) to Phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 binds to PH domain of AKT and recruits it to plasma membrane. PDK1 phosphorylates AKT which in turn regulate the activity of various proteins that mediate cell survival. EGFR also activate phospholipase C which hydrolyses PIP2 to generate Inositol trisphosphate (IP3) and 1,2-Diacylglycerol (DAG). IP3 induces the release of Ca2+ from endoplasmic reticulum to activate calcium regulated pathways. DAG activates protein kinase C pathway. One of the signaling modules regulated by PKC in EGFR pathway is the NFKB module. The protein SRC is a key player in the activation of various pathways such as RAS, PLC and also the STAT proteins in various cells. Other signaling modules activated by EGFR include the FAK, JNK, p38MAPK and ERK5 modules. EGFR induces the JNK pathway through the activation of G proteins such as RAC and CDC42 which recruits JNK kinases as well as regulate the actin polymerization. EGFR also translocates from the plasma membrane to other cellular compartments including nucleus where it directly regulate the expression of several genes in cooperation with other transcriptional regulators such as STATs, PCNA and E2F family of proteins.

Being a growth, differentiation and cell survival factor; mutations and overexpression of EGFR and also the defective regulation of its signal transduction pathways has been established to be associated with oncogenesis. Thus, EGFR and its signaling components are promising targets for effective therapy for various cancers. There are several proteins which have been reported to regulate the EGFR signaling such as CBL, CSK, PKC and PTEN which promotes endocytosis or reduction in the EGFR activity or its signaling mediators. The major endocytic pathway of EGFR is established to be the clathrin coated pits which delivers them to endosomes. The endosomal pathway recycles the membraneous form of EGFR or form multivesicular bodies (MVB) and fuse with lysosomes for to the degradation pathway.

NetPath (http://www.netpath.org) is a collaborative effort between PandeyLab at Johns Hopkins University (http://pandeylab.igm.jhmi.edu) and Institute of Bioinformatics (http://www.ibioinformatics.org). This version of the pathway is available at NetSlim (http://www.netpath.org/netslim). If you use this pathway, please cite the NetPath website.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
111019view14:22, 30 June 2020L DupuisConverted interaction lines in legend to graphical lines
106392view21:27, 28 August 2019KhanspersModified description
105574view06:29, 9 August 2019KhanspersModified description
79266view20:32, 19 March 2015ZariChenged Identifier for PXN
78502view10:29, 7 January 2015MaintBotadded missing graphIds
72106view22:03, 24 October 2013AlexanderPicoadded xrefs
71357view18:35, 17 October 2013MaintBotAutomated update of data sources
70625view21:22, 16 August 2013MaintBotUpdated xrefs from Anatoly Urisman
67174view10:16, 26 June 2013Christine ChichesterOntology Term : 'epidermal growth factor/neuregulin signaling pathway' added !
63177view20:30, 8 May 2013MaintBotUpdating gpml version
47973view14:23, 23 April 2012NetPathModified description
44600view21:09, 21 September 2011KhanspersUpdating content to NetSlim
44120view20:50, 24 August 2011KhanspersReverted to version '23:15, 1 March 2011' by Khanspers
44017view22:41, 22 August 2011Khanspers
44009view22:10, 22 August 2011KhanspersModified description
44008view22:05, 22 August 2011KhanspersModified description
44007view22:03, 22 August 2011KhanspersModified description
44006view22:00, 22 August 2011KhanspersUpdating pathway from NetSlim
41034view23:15, 1 March 2011MaintBotRemoved redundant pathway information and comments
35716view23:27, 12 February 2010AlexanderPico
35432view11:23, 12 February 2010MichielChanged literature reference
35428view11:06, 12 February 2010MichielAdded literature reference
35300view23:23, 11 February 2010NsalomonisModified description
21600view11:32, 14 November 2008MaintBot[[Pathway:Homo sapiens:EGFR1 NetPath 4]] moved to [[Pathway:WP437]]: Moved to stable identifier
7996view13:46, 7 January 2008MaintBot[[Pathway:Human:EGFR1 NetPath 4]] moved to [[Pathway:Homo sapiens:EGFR1 NetPath 4]]: Renaming species
7621view16:05, 18 December 2007MaintBotfixed category names
7215view12:33, 4 November 2007MaintBotAdded categories to GPML
6309view22:17, 22 May 2007A.Pandeygpml file for [[Human:EGFR1_NetPath_4]]

External references

DataNodes

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NameTypeDatabase referenceComment
ABI1GeneProduct10006 (Entrez Gene)
ABL1GeneProduct25 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
AP2A1Protein160 (Entrez Gene)
AP2B1Protein163 (Entrez Gene)
AP2M1Protein1173 (Entrez Gene)
AP2S1Protein1175 (Entrez Gene)
ARF6GeneProduct382 (Entrez Gene)
ARHGEF1Protein9138 (Entrez Gene)
ASAP1GeneProduct50807
ATF1GeneProduct466 (Entrez Gene)
ATXN2GeneProduct6311 (Entrez Gene)
AURKAGeneProduct6790 (Entrez Gene)
BCAR1GeneProduct9564 (Entrez Gene)
BRAFGeneProduct673 (Entrez Gene)
CAMK2AGeneProduct815 (Entrez Gene)
CAV1Protein857 (Entrez Gene)
CAV2GeneProduct858
CBLGeneProduct867
CBLBGeneProduct868 (Enzyme Nomenclature)
CBLCGeneProduct23624 (Entrez Gene)
CDC42Protein998 (Entrez Gene)
CFL1Protein1072 (Entrez Gene)
COX2GeneProduct
CREB1GeneProduct1385 (Entrez Gene)
CRKGeneProduct1398 (Entrez Gene)
CRKLGeneProduct1399 (Entrez Gene)
CSKGeneProduct1445 (Entrez Gene)
DNM1Protein1759 (Entrez Gene)
DOK2Protein9046 (Entrez Gene)
E2F1GeneProduct1869 (Entrez Gene)
EGFGeneProduct1950 (Entrez Gene)
EGFRGeneProduct1956
EGFRGeneProduct1956 (Entrez Gene)
EIF4EBP1GeneProduct1978
ELK1GeneProduct2002 (Entrez Gene)
ELK4GeneProduct2005 (Entrez Gene)
EPN1Protein29924 (Entrez Gene)
EPS15GeneProduct2060 (Entrez Gene)
EPS15L1Protein58513 (Entrez Gene)
EPS8GeneProduct2059 (Entrez Gene)
ERBB2GeneProduct2064 (Entrez Gene)
ERRFI1GeneProduct54206 (Entrez Gene)
FOSProtein2353 (Entrez Gene)
FOSBProtein2354 (Entrez Gene)
FOXO1GeneProduct2308 (Entrez Gene)
FOXO4GeneProduct4303 (Entrez Gene)
GAB1GeneProduct2549 (Entrez Gene)
GAB2GeneProduct9846 (Entrez Gene)
GJA1GeneProduct2697 (Entrez Gene)
GRB10GeneProduct2887
GRB2Protein2885 (Entrez Gene)
GRIM19GeneProduct51079 (Entrez Gene)
HGSGeneProduct9146 (Entrez Gene)
HRASGeneProduct3265
INPP5DProtein3635 (Entrez Gene)
INPPL1Protein3636 (Entrez Gene)
IQGAP1GeneProduct8826 (Entrez Gene)
IQSEC1GeneProduct9922 (Entrez Gene)
ITCHProtein83737 (Entrez Gene)
JAK1GeneProduct3716 (Entrez Gene)
JAK2GeneProduct3717 (Entrez Gene)
JUNProtein3725 (Entrez Gene)
JUNDProtein3727 (Entrez Gene)
KRASProtein3845 (Entrez Gene)
LIMK2Protein3985 (Entrez Gene)
LigandGeneProduct7040 (Entrez Gene)
MAP2K1Protein5604 (Entrez Gene)
MAP2K2Protein5605 (Entrez Gene)
MAP2K5GeneProduct5607 (Entrez Gene)
MAP3K1GeneProduct4214 (Entrez Gene)
MAP3K2GeneProduct10746 (Entrez Gene)
MAP3K3GeneProduct4215 (Entrez Gene)
MAP3K4GeneProduct4216 (Entrez Gene)
MAP4K1Protein11184 (Entrez Gene)
MAPK14Protein1432 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
MAPK3Protein5596 (Entrez Gene)
MAPK7GeneProduct5598 (Entrez Gene)
MAPK8Protein5599 (Entrez Gene)
MAPK9Protein5601 (Entrez Gene)
MEF2AProtein207 (Entrez Gene)
MEF2CProtein5605 (Entrez Gene)
MEF2DGeneProduct160 (Entrez Gene)
MTORProtein207 (Entrez Gene)
MYBL2GeneProduct4605 (Entrez Gene)
NCK1GeneProduct4690 (Entrez Gene)
NCK2GeneProduct8440 (Entrez Gene)
NCOA3GeneProduct
NEDD4GeneProduct4737
NEDD8GeneProduct4738 (Entrez Gene)
NOS3GeneProduct
PAK1GeneProduct5338
PCNAGeneProduct5111 (Entrez Gene)
PDPK1Protein5170 (Entrez Gene)
PEBP1GeneProduct5037 (Entrez Gene)
PIAS3GeneProduct10401 (Entrez Gene)
PIK3C2BGeneProduct5287 (Entrez Gene)
PIK3R1Protein5295 (Entrez Gene)
PIK3R2Protein5296 (Entrez Gene)
PLCE1Protein51196 (Entrez Gene)
PLCG1GeneProduct5335 (Entrez Gene)
PLD1Protein5337 (Entrez Gene)
PLD2GeneProduct5338
PLSCR1GeneProduct5359 (Entrez Gene)
PRKCAGeneProduct5578 (Entrez Gene)
PRKCBGeneProduct5579 (Entrez Gene)
PRKCDGeneProduct5580 (Entrez Gene)
PRKCIGeneProduct5584 (Entrez Gene)
PRKCZGeneProduct5590 (Entrez Gene)
PTENGeneProduct5728 (Entrez Gene)
PTK2GeneProduct5747 (Entrez Gene)
PTK2BGeneProduct2185 (Entrez Gene)
PTK6GeneProduct5753 (Entrez Gene)
PTPN11GeneProduct5781 (Entrez Gene)
PTPN12GeneProduct5782 (Entrez Gene)
PTPN5GeneProduct84867 (Entrez Gene)
PTPRRGeneProduct5801
PXNGeneProduct38326 (Entrez Gene)
ProteinProtein5894 (Entrez Gene)
ProteinProtein
RAB5AProtein5868 (Entrez Gene)
RAC1Protein5879 (Entrez Gene)
RAF1Protein5894 (Entrez Gene)
RALAProtein5898 (Entrez Gene)
RALBProtein5899 (Entrez Gene)
RALBP1Protein10928 (Entrez Gene)
RALGDSProtein5900 (Entrez Gene)
RAP1AProtein5906 (Entrez Gene)
RASA15921 (Entrez Gene)
REPS2Protein9185 (Entrez Gene)
RICTORGeneProduct253260 (Entrez Gene)
RIN1Protein9610 (Entrez Gene)
ROCK1Protein
RPS6KA1GeneProduct6195 (Entrez Gene)
RPS6KA2GeneProduct6196 (Entrez Gene)
RPS6KA3GeneProduct6197 (Entrez Gene)
RPS6KA5GeneProduct9252 (Entrez Gene)
RPS6KB1GeneProduct6198 (Entrez Gene)
ReceptorGeneProduct7040 (Entrez Gene)
SH2D2AGeneProduct9047 (Entrez Gene)
SH3GL2GeneProduct6456 (Entrez Gene)
SH3GL3GeneProduct6457 (Entrez Gene)
SH3KBP1Protein30011 (Entrez Gene)
SHC1Protein6464 (Entrez Gene)
SOS1Protein6654 (Entrez Gene)
SOS2GeneProduct6655 (Entrez Gene)
SP1GeneProduct6667 (Entrez Gene)
SPRY2GeneProduct10253 (Entrez Gene)
SRCGeneProduct6714
STAM2Protein10254 (Entrez Gene)
STAMProtein8027 (Entrez Gene)
STAMBPGeneProduct10617 (Entrez Gene)
STAT1GeneProduct6772 (Entrez Gene)
STAT3GeneProduct6774 (Entrez Gene)
STAT5AGeneProduct6776 (Entrez Gene)
STAT5BGeneProduct6777 (Entrez Gene)
STMN1GeneProduct3925 (Entrez Gene)
STXBP1GeneProduct6812 (Entrez Gene)
SYNJ1GeneProduct8867 (Entrez Gene)
TNK2GeneProduct10188 (Entrez Gene)
TWIST1GeneProduct7291 (Entrez Gene)
USP6NLProtein9712 (Entrez Gene)
USP8GeneProduct9101 (Entrez Gene)
VAV1Protein7409 (Entrez Gene)
VAV2Protein7410 (Entrez Gene)
VAV3Protein10451 (Entrez Gene)
mRNAProtein

Annotated Interactions

No annotated interactions

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