ErbB signaling pathway (Homo sapiens)

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


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118930view17:21, 4 June 2021Finterlyspelling parentsybol corrected to parent symbol for state comment
116519view11:00, 7 May 2021EweitzModified title
112158view18:14, 29 September 2020Khanspersfixed ptm state comments
111993view04:38, 15 September 2020KhanspersAdded lit refs for phosphosites on ELK1 and MEK
111175view04:54, 22 July 2020EgonwMade another three pathways clickable
110910view22:18, 19 June 2020Khanspersfixed unconnected interaction
108898view19:18, 5 February 2020Khanspersupdated label for EIF4EBP1
108897view19:16, 5 February 2020Khanspersadded phosphosite to eiF-4EBP
108887view23:14, 4 February 2020Khanspersupdated phosphosite
108882view19:45, 4 February 2020Khanspersupdated ligand binding
108881view19:42, 4 February 2020Khanspersupdated ERBBs as complexes
108880view19:41, 4 February 2020Khansperstest
108831view00:20, 1 February 2020Khanspersupdated interaction with PDPK1
108769view02:13, 29 January 2020Khanspersfinal touches
108765view01:32, 29 January 2020Khanspersmore phosphosites
108761view01:12, 29 January 2020Khanspersupdated to official symbols
108760view01:10, 29 January 2020Khanspersupdated xref for PDK1 (PDPK1)
108759view22:53, 28 January 2020Khanspersadded phosphosites and updated node sizing and layout
108758view19:00, 28 January 2020Khanspersadded phosphosites for MAPK8/9/10
108757view17:43, 28 January 2020Khanspersupdated MEK/ERK
108752view05:58, 28 January 2020Khanspersadded phosphosites
108751view05:29, 28 January 2020Khanspersadded phospho sites
108750view05:05, 28 January 2020Khanspersupdated phospho sites
108749view01:19, 28 January 2020KhanspersAdding phosphosites
108748view00:50, 28 January 2020Khanspersadded phosphosite
108747view22:11, 27 January 2020KhanspersAdded phospho sites
108256view14:22, 3 December 2019L DupuisConnected unconnected lines
108194view10:56, 29 November 2019FehrhartOntology Term : 'multiple sclerosis' added !
108193view10:56, 29 November 2019FehrhartOntology Term : 'Alzheimer's disease' added !
108192view10:56, 29 November 2019FehrhartOntology Term : 'cancer' added !
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

External references


View all...
NameTypeDatabase referenceComment
ABL1GeneProduct25 (Entrez Gene)
ABL2GeneProduct27 (Entrez Gene)
AKT1GeneProduct207 (Entrez Gene)
AKT2GeneProduct208 (Entrez Gene)
AKT3GeneProduct10000 (Entrez Gene)
ARAFGeneProductENSG00000078061 (Ensembl)
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)
CDKN1AGeneProduct1026 (Entrez Gene)
CRKGeneProduct1398 (Entrez Gene)
CRKLGeneProduct1399 (Entrez Gene)
Ca2+MetaboliteCHEBI:22984 (ChEBI)
Calcium Signaling PathwayPathway
Cell CyclePathwayWP179 (WikiPathways)
DiacylglycerolMetaboliteCHEBI:18035 (ChEBI)
EGFGeneProduct1950 (Entrez Gene)
EGFRGeneProduct1956 (Entrez Gene)
EIF4EBP1GeneProduct1978 (Entrez Gene)
ELK1GeneProduct2002 (Entrez Gene)
ERBB2GeneProduct2064 (Entrez Gene)
ERBB3GeneProduct2065 (Entrez Gene)
ERBB4GeneProduct2066 (Entrez Gene)
EREGGeneProduct2069 (Entrez Gene)
FOXO1GeneProduct2308 (Entrez Gene)
GAB1GeneProduct2549 (Entrez Gene)
GRB2GeneProduct2885 (Entrez Gene)
GSK3BGeneProductENSG00000082701 (Ensembl)
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)
MTORGeneProduct2475 (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)
PDPK1GeneProductENSG00000140992 (Ensembl)
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)
PTK2GeneProduct5747 (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)
mTor Signaling PathwayPathway
p27GeneProduct1027 (Entrez Gene)
p53GeneProduct7157 (Entrez Gene)

Annotated Interactions

No annotated interactions

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