ErbB Signaling Pathway (Homo sapiens)

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1-7, 9-13, 15...1414ER(EGFR)DegradationProliferationSurvivalp70S6KAdhesionDNA(HER2/Neu)DNAShcNo signalingMigration / InvasionCblDNACellular targetsMEKGliomaNon-smallcell lungcancerAdhesionMigrationDifferentiationReceptor ubiquitylationRafNckAblPLC-gammaCrkCell cycleprogressionSosPancreaticCancerCellular targetsPI3KActivation by ErbB2overexpression (cancers)ERKJNKSTAT5PKCRasAngiogenesisColoncancerDNACaMK2MetabolismEndometrialcancerProteinsynthesisJNKKPAKPKB/AktCell survivalERBB2JUNERBB2HBEGFp53FAKGRB2BADCAMK2AERBB4GSK3ELKMYCNRG3MAP2K1GAB1MDM2Calcium Signaling PathwaySRCPDK1ERBB2IP3MAPK8EREGERBB2CBLERBB1NRG1ERBB2ARAFMIR21PIP3p27ERBB1p21FOXO1PLCG1 NRG2PRKCAMAPK Signaling PathwayERBB3ABL1MAP2K7ApoptosisPIK3R3TGFAeIF-4EBPAREGNRG4ERBB3CRKPIP2EGFGRB2ERBB3NCK1DiacylglycerolCell CycleMAPK1HRASKRASSOS1ERBB4PAK4CCND1MIR21ERBB1MycmTORAKT3STAT5AmTor Signaling PathwayBIMERBB4BTCCa2+P8PPPPPPPPPELKPPPPPPPP141414PLCG2PCAMK2BCAMK2DCAMK2GPRKCBPRKCGCBLBPSTAT5BPCRKLPABL2NCK2PAK1PAK2PAK3PAK5PAK6BUB1B-PAK6MAP2K4MAPK9PMAPK10PSHC3PSHC4PSHC1PSHC2PSOS2NRASSTAT5STAT5APSTAT5BPBRAFRAF1MAP2K2PMAPK3PPIK3R2PIK3R1PIK3CDPIK3CBPIK3CAAKT2AKT1RPS6KB1PRPS6KB2P


The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease. In mice loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart and brain. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB-1 and ErbB-2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors.

The ErbB protein family consists of 4 members

  • ErbB-1, also named epidermal growth factor receptor (EGFR)
  • ErbB-2, also named HER2 in humans and neu in rodents
  • ErbB-3, also named HER3 and
  • ErbB-4, also named HER4

The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher order oligomers upon activation by a subset of potential growth factor ligands.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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Ontology Terms



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  1. Schulze WX, Deng L, Mann M; ''Phosphotyrosine interactome of the ErbB-receptor kinase family.''; Mol Syst Biol, 2005 PubMed Europe PMC
  2. McCarty JH; ''The Nck SH2/SH3 adaptor protein: a regulator of multiple intracellular signal transduction events.''; Bioessays, 1998 PubMed Europe PMC
  3. Olayioye MA, Neve RM, Lane HA, Hynes NE; ''The ErbB signaling network: receptor heterodimerization in development and cancer.''; EMBO J, 2000 PubMed Europe PMC
  4. Oda K, Matsuoka Y, Funahashi A, Kitano H; ''A comprehensive pathway map of epidermal growth factor receptor signaling.''; Mol Syst Biol, 2005 PubMed Europe PMC
  5. Hashimoto Y, Katayama H, Kiyokawa E, Ota S, Kurata T, Gotoh N, Otsuka N, Shibata M, Matsuda M; ''Phosphorylation of CrkII adaptor protein at tyrosine 221 by epidermal growth factor receptor.''; J Biol Chem, 1998 PubMed Europe PMC
  6. Marmor MD, Skaria KB, Yarden Y; ''Signal transduction and oncogenesis by ErbB/HER receptors.''; Int J Radiat Oncol Biol Phys, 2004 PubMed Europe PMC
  7. Liang J, Slingerland JM; ''Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression.''; Cell Cycle, 2003 PubMed Europe PMC
  8. Ryan DP, Engelman JA, Ferrone CR, Sahani DV, Lisovsky M; ''Case records of the Massachusetts General Hospital. Case 19-2010. A 35-year-old man with adenocarcinoma of the cecum.''; N Engl J Med, 2010 PubMed Europe PMC
  9. Clark DE, Williams CC, Duplessis TT, Moring KL, Notwick AR, Long W, Lane WS, Beuvink I, Hynes NE, Jones FE; ''ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events.''; J Biol Chem, 2005 PubMed Europe PMC
  10. Hynes NE, Lane HA; ''ERBB receptors and cancer: the complexity of targeted inhibitors.''; Nat Rev Cancer, 2005 PubMed Europe PMC
  11. Holbro T, Hynes NE; ''ErbB receptors: directing key signaling networks throughout life.''; Annu Rev Pharmacol Toxicol, 2004 PubMed Europe PMC
  12. Muthuswamy SK, Gilman M, Brugge JS; ''Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers.''; Mol Cell Biol, 1999 PubMed Europe PMC
  13. Scaltriti M, Baselga J; ''The epidermal growth factor receptor pathway: a model for targeted therapy.''; Clin Cancer Res, 2006 PubMed Europe PMC
  14. Huang TH, Wu F, Loeb GB, Hsu R, Heidersbach A, Brincat A, Horiuchi D, Lebbink RJ, Mo YY, Goga A, McManus MT; ''Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion.''; J Biol Chem, 2009 PubMed Europe PMC
  15. Citri A, Yarden Y; ''EGF-ERBB signalling: towards the systems level.''; Nat Rev Mol Cell Biol, 2006 PubMed Europe PMC
  16. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS; ''Epidermal growth factor receptor (EGFR) signaling in cancer.''; Gene, 2006 PubMed Europe PMC
  17. Yarden Y, Sliwkowski MX; ''Untangling the ErbB signalling network.''; Nat Rev Mol Cell Biol, 2001 PubMed Europe PMC


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106821view13:30, 17 September 2019MaintBotHMDB identifier normalization
106405view21:33, 28 August 2019KhanspersModified description
105438view04:50, 8 August 2019KhanspersModified description
105003view04:54, 28 June 2019KhanspersModified description
102179view23:07, 5 December 2018Ejaehnigfurther improved alignment of nodes
102176view22:36, 5 December 2018Ejaehnigimproved alignment of nodes in groups
102175view22:18, 5 December 2018EjaehnigThis pathway was ported from KEGG, but the KEGG pathway used a single protein node for multiple genes in many cases. For these nodes, I split the node into groups containing all of the genes underlying each node in the KEGG pathway (interchangeable genes
98355view05:36, 24 August 2018EgonwUpdated the MIR21 identifier.
96366view07:28, 10 March 2018EgonwReplaced a secondary ChEBI identifier with a primary identifier.
94739view15:06, 5 October 2017Mkutmonfix unconnected line
91869view22:17, 31 March 2017KhanspersModified description
91868view22:13, 31 March 2017Khanspersupdated phosphorylation states, interactions, metabolites, cell components etc
86901view07:59, 14 July 2016MkutmonOntology Term : 'oxidative phosphorylation pathway' added !
86900view07:59, 14 July 2016MkutmonOntology Term : 'PW:0000034' removed !
80202view19:32, 22 May 2015Khanspersadded mir21 targeting of ERBB2 and MYC
69914view19:37, 11 July 2013AlexanderPicoModified title
68012view07:32, 29 June 2013EgonwAdded a missing metabolite identifier.
67205view10:20, 26 June 2013Christine ChichesterOntology Term : 'epidermal growth factor/neuregulin signaling pathway' added !
63184view20:44, 8 May 2013MaintBotUpdating gpml version
41091view23:21, 1 March 2011MaintBotRemoved redundant pathway information and comments
38179view04:20, 22 August 2010AlexanderPicoConverted pathway objects
38178view04:16, 22 August 2010AlexanderPicoAdded literature references
38177view04:10, 22 August 2010AlexanderPicoConverted pathway objects
38176view04:01, 22 August 2010AlexanderPicoSpecify description
38175view03:59, 22 August 2010AlexanderPicoAdded reference and more EGFR connections
38174view03:49, 22 August 2010AlexanderPicoPeriodical save, work in progress
38173view03:39, 22 August 2010AlexanderPicoPeriodical save, work in progress
38172view03:28, 22 August 2010AlexanderPicoModified description
29836view10:01, 4 June 2009UomoamareAll nodes annotated through NCBI-GeneID
29835view09:56, 4 June 2009UomoamarePeriodical save, work in progress
29834view09:46, 4 June 2009UomoamarePeriodical save, work in progress
29833view09:35, 4 June 2009UomoamarePeriodical save, work in progress
29829view09:24, 4 June 2009UomoamarePeriodical save, work in progress
29738view22:34, 1 June 2009KhanspersModified categories
28873view15:02, 9 March 2009UomoamareSpecify description
28851view10:39, 8 March 2009UomoamareSpecify description
28828view13:45, 7 March 2009UomoamareModified description
28827view13:40, 7 March 2009Uomoamare1 revision
28826view13:36, 7 March 2009UomoamarePeriodical save, work in progress
28825view12:59, 7 March 2009UomoamarePeriodical save, work in progress
28824view12:48, 7 March 2009UomoamarePeriodical save, work in progress
28823view18:07, 6 March 2009UomoamarePeriodical save, work in progress
28822view18:04, 6 March 2009UomoamareSpecify description
28821view17:56, 6 March 2009UomoamareErbB Signaling Pathway
28820view17:53, 6 March 2009UomoamareErbB
28819view17:47, 6 March 2009UomoamarePeriodical save, work in progress
28818view17:36, 6 March 2009UomoamarePeriodical save, work in progress
28817view17:32, 6 March 2009UomoamareSpecify description
28816view16:35, 6 March 2009UomoamarePeriodical save, work in progress
28815view16:22, 6 March 2009UomoamareERBB SIGNALING PATHWAY

External references


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NameTypeDatabase referenceComment
ABL1GeneProduct25 (Entrez Gene)
ABL2GeneProduct27 (Entrez Gene)
AKT1GeneProduct207 (Entrez Gene)
AKT2GeneProduct208 (Entrez Gene)
AKT3GeneProduct10000 (Entrez Gene)
ARAFGeneProduct369 (Entrez Gene)
AREGGeneProduct374 (Entrez Gene)
ApoptosisPathwayWP254 (WikiPathways)
BADGeneProduct572 (Entrez Gene)
BIMGeneProduct10018 (Entrez Gene)
BRAFGeneProduct673 (Entrez Gene)
BTCGeneProduct685 (Entrez Gene)
BUB1B-PAK6GeneProduct106821730 (Entrez Gene)
CAMK2AGeneProduct815 (Entrez Gene)
CAMK2BGeneProduct816 (Entrez Gene)
CAMK2DGeneProduct817 (Entrez Gene)
CAMK2GGeneProduct818 (Entrez Gene)
CBLGeneProduct867 (Entrez Gene)
CBLBGeneProduct868 (Entrez Gene)
CCND1GeneProduct595 (Entrez Gene)
CRKGeneProduct1398 (Entrez Gene)
CRKLGeneProduct1399 (Entrez Gene)
Ca2+MetaboliteCHEBI:22984 (ChEBI)
Calcium Signaling PathwayPathway
Cell CyclePathwayWP179 (WikiPathways)
DiacylglycerolMetaboliteCHEBI:18035 (ChEBI)
EGFGeneProduct1950 (Entrez Gene)
ELKGeneProduct2002 (Entrez Gene)
ERBB1GeneProduct1956 (Entrez Gene)
ERBB2GeneProduct2064 (Entrez Gene)
ERBB3GeneProduct2065 (Entrez Gene)
ERBB4GeneProduct2066 (Entrez Gene)
EREGGeneProduct2069 (Entrez Gene)
FAKGeneProduct5747 (Entrez Gene)
FOXO1GeneProduct2308 (Entrez Gene)
GAB1GeneProduct2549 (Entrez Gene)
GRB2GeneProduct2885 (Entrez Gene)
GSK3GeneProduct2932 (Entrez Gene)
HBEGFGeneProduct1839 (Entrez Gene)
HRASGeneProduct3265 (Entrez Gene)
IP3MetaboliteCHEBI:16595 (ChEBI)
JUNGeneProduct3725 (Entrez Gene)
KRASGeneProduct3845 (Entrez Gene)
MAP2K1GeneProduct5604 (Entrez Gene)
MAP2K2GeneProduct5605 (Entrez Gene)
MAP2K4GeneProduct6416 (Entrez Gene)
MAP2K7GeneProduct5609 (Entrez Gene)
MAPK Signaling PathwayPathwayWP382 (WikiPathways)
MAPK10GeneProduct5602 (Entrez Gene)
MAPK1GeneProduct5594 (Entrez Gene)
MAPK3GeneProduct5595 (Entrez Gene)
MAPK8GeneProduct5599 (Entrez Gene)
MAPK9GeneProduct5601 (Entrez Gene)
MDM2GeneProduct4193 (Entrez Gene)
MIR21RnaENSG00000284190 (Ensembl)
MYCGeneProduct4609 (Entrez Gene)
MycGeneProduct4609 (Entrez Gene)
NCK1GeneProduct4690 (Entrez Gene)
NCK2GeneProduct8440 (Entrez Gene)
NRASGeneProduct4893 (Entrez Gene)
NRG1GeneProduct3084 (Entrez Gene)
NRG2GeneProduct9542 (Entrez Gene)
NRG3GeneProduct10718 (Entrez Gene)
NRG4GeneProduct145957 (Entrez Gene)
PAK1GeneProduct5058 (Entrez Gene)
PAK2GeneProduct5062 (Entrez Gene)
PAK3GeneProduct5063 (Entrez Gene)
PAK4GeneProduct10298 (Entrez Gene)
PAK5GeneProduct57144 (Entrez Gene)
PAK6GeneProduct56924 (Entrez Gene)
PDK1GeneProduct5163 (Entrez Gene)
PIK3CAGeneProduct5290 (Entrez Gene)
PIK3CBGeneProduct5291 (Entrez Gene)
PIK3CDGeneProduct5293 (Entrez Gene)
PIK3R1GeneProduct5295 (Entrez Gene)
PIK3R2GeneProduct5296 (Entrez Gene)
PIK3R3GeneProduct8503 (Entrez Gene)
PIP2MetaboliteCHEBI:18348 (ChEBI)
PIP3MetaboliteHMDB0004249 (HMDB)
PLCG1 GeneProduct5335 (Entrez Gene)
PLCG2GeneProduct5336 (Entrez Gene)
PRKCAGeneProduct5578 (Entrez Gene)
PRKCBGeneProduct5579 (Entrez Gene)
PRKCGGeneProduct5582 (Entrez Gene)
RAF1GeneProduct5894 (Entrez Gene)
RPS6KB1GeneProduct6198 (Entrez Gene)
RPS6KB2GeneProduct6199 (Entrez Gene)
SHC1GeneProduct6464 (Entrez Gene)
SHC2GeneProduct25759 (Entrez Gene)
SHC3GeneProduct53358 (Entrez Gene)
SHC4GeneProduct399694 (Entrez Gene)
SOS1GeneProduct6654 (Entrez Gene)
SOS2GeneProduct6655 (Entrez Gene)
SRCGeneProduct6714 (Entrez Gene)
STAT5AGeneProduct6776 (Entrez Gene)
STAT5BGeneProduct6777 (Entrez Gene)
TGFAGeneProduct7039 (Entrez Gene)
eIF-4EBPGeneProduct1978 (Entrez Gene)
mTORGeneProduct2475 (Entrez Gene)
mTor Signaling PathwayPathway
p21GeneProduct1026 (Entrez Gene)
p27GeneProduct1027 (Entrez Gene)
p53GeneProduct7157 (Entrez Gene)

Annotated Interactions

No annotated interactions

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