ErbB Signaling Pathway (Homo sapiens)

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2, 3, 5-1744ERPancreaticCancerMigration / InvasionProliferationMetabolismEndometrialcancerDifferentiationDNAColoncancerSurvivalDNADNAGliomaReceptor ubiquitylationProteinsynthesisAngiogenesis(HER2/Neu)No signalingAdhesionMigrationDNACell cycleprogressionNon-smallcell lungcancerCell survivalCellular targetsAdhesionDegradationCellular targetsActivation by ErbB2overexpression (cancers)(EGFR)MAPK Signaling PathwayERBB1FAKBADELKAKT3HBEGFERBB4SHCABLCalcium Signaling PathwaySRCERBB1mTORMIR21HRASJNKERBB2IP3p27SOSPI3KApoptosisCell CyclePLCGEGFEREGmTor Signaling PathwayMYCJUNERBB3ERBB1ERBB3ARAFCRKBTCSTAT5PRKCAGSK3MEK1eIF-4EBPTGFASTAT5ERBB4CCND1FOXO1GRB2BIMP70S6KERBB2CBLJnkk2NRG1p53ERBB2NCKNRG4CAMK2Ap21ERKPIP3MIR21AREGKRASMycPIP2DiacylglycerolGAB1Ca2+GRB2ERBB4NRG3ERBB3PAK4PDK1MDM2ERBB2ERBB2NRG2PPPPPPPPPELKPPPP1PPPPPPPP444


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.

Based on KEGG.

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Ontology Terms



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  1. 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
  2. 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
  3. Olayioye MA, Neve RM, Lane HA, Hynes NE; ''The ErbB signaling network: receptor heterodimerization in development and cancer.''; EMBO J, 2000 PubMed
  4. Oda K, Matsuoka Y, Funahashi A, Kitano H; ''A comprehensive pathway map of epidermal growth factor receptor signaling.''; Mol Syst Biol, 2005 PubMed
  5. Scaltriti M, Baselga J; ''The epidermal growth factor receptor pathway: a model for targeted therapy.''; Clin Cancer Res, 2006 PubMed
  6. Yarden Y, Sliwkowski MX; ''Untangling the ErbB signalling network.''; Nat Rev Mol Cell Biol, 2001 PubMed
  7. Schulze WX, Deng L, Mann M; ''Phosphotyrosine interactome of the ErbB-receptor kinase family.''; Mol Syst Biol, 2005 PubMed
  8. 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
  9. 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
  10. Holbro T, Hynes NE; ''ErbB receptors: directing key signaling networks throughout life.''; Annu Rev Pharmacol Toxicol, 2004 PubMed
  11. 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
  12. McCarty JH; ''The Nck SH2/SH3 adaptor protein: a regulator of multiple intracellular signal transduction events.''; Bioessays, 1998 PubMed
  13. 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
  14. Hynes NE, Lane HA; ''ERBB receptors and cancer: the complexity of targeted inhibitors.''; Nat Rev Cancer, 2005 PubMed
  15. Citri A, Yarden Y; ''EGF-ERBB signalling: towards the systems level.''; Nat Rev Mol Cell Biol, 2006 PubMed
  16. Marmor MD, Skaria KB, Yarden Y; ''Signal transduction and oncogenesis by ErbB/HER receptors.''; Int J Radiat Oncol Biol Phys, 2004 PubMed
  17. Liang J, Slingerland JM; ''Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression.''; Cell Cycle, 2003 PubMed


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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
28814view16:20, 6 March 2009UomoamareSpecify description
28813view16:18, 6 March 2009UomoamareSpecify description
28812view16:13, 6 March 2009UomoamareSpecify description
28811view16:08, 6 March 2009UomoamareSpecify description

External references


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NameTypeDatabase referenceComment
ABLGeneProduct25 (Entrez Gene)
AKT3GeneProduct10000 (Entrez Gene)
ARAFGeneProduct369 (Entrez Gene)
AREGGeneProduct374 (Entrez Gene)
ApoptosisPathwayWP254 (WikiPathways)
BADGeneProduct572 (Entrez Gene)
BIMGeneProduct10018 (Entrez Gene)
BTCGeneProduct685 (Entrez Gene)
CAMK2AGeneProduct815 (Entrez Gene)
CBLGeneProduct23624 (Entrez Gene)
CCND1GeneProduct595 (Entrez Gene)
CRKGeneProduct1398 (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)
ERKGeneProduct5594 (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)
JNKGeneProduct5599 (Entrez Gene)
JUNGeneProduct3725 (Entrez Gene)
Jnkk2GeneProduct5609 (Entrez Gene)
KRASGeneProduct3845 (Entrez Gene)
MAPK Signaling PathwayPathwayWP382 (WikiPathways)
MDM2GeneProduct4193 (Entrez Gene)
MEK1GeneProduct5604 (Entrez Gene)
MIR21RnaENSG00000199004 (Ensembl)
MYCGeneProduct4609 (Entrez Gene)
MycGeneProduct4609 (Entrez Gene)
NCKGeneProduct4690 (Entrez Gene)
NRG1GeneProduct3084 (Entrez Gene)
NRG2GeneProduct9542 (Entrez Gene)
NRG3GeneProduct10718 (Entrez Gene)
NRG4GeneProduct145957 (Entrez Gene)
P70S6KGeneProduct6198 (Entrez Gene)
PAK4GeneProduct10298 (Entrez Gene)
PDK1GeneProduct5163 (Entrez Gene)
PI3KGeneProduct23533 (Entrez Gene)
PIP2MetaboliteCHEBI:18348 (ChEBI)
PIP3MetaboliteHMDB04249 (HMDB)
PLCGGeneProduct5335 (Entrez Gene)
PRKCAGeneProduct5578 (Entrez Gene)
SHCGeneProduct25759 (Entrez Gene)
SOSGeneProduct6654 (Entrez Gene)
SRCGeneProduct6714 (Entrez Gene)
STAT5GeneProduct6776 (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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