Pathway Human Homo sapiens

Signaling by ERBB2

R-HSA-1227986 in Reactome release 97: under Signaling by Receptor Tyrosine Kinases, with 50 genes placed in it by the mapping files and 9 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-1227986 (mouse), R-RNO-1227986 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-1227986.10
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2011-12-06
Last updated: 2019-12-10
Events inside: 14, counted from the record

ERBB2, also known as HER2 or NEU, is a receptor tyrosine kinase (RTK) belonging to the EGFR family. ERBB2 possesses an extracellular domain that does not bind any known ligand, contrary to other EGFR family members, a single transmembrane domain, and an intracellular domain consisting of an active kinase and a C-tail with multiple tyrosine phosphorylation sites. Inactive ERBB2 is associated with a chaperone heat shock protein 90 (HSP90) and its co-chaperone CDC37 (Xu et al. 2001, Citri et al. 2004, Xu et al. 2005). In addition, ERBB2 is associated with ERBB2IP (also known as ERBIN or LAP2), a protein responsible for proper localization of ERBB2. In epithelial cells, ERBB2IP restricts expression of ERBB2 to basolateral plasma membrane regions (Borg et al. 2000).

ERBB2 becomes activated by forming a heterodimer with another ligand-activated EGFR family member, either EGFR, ERBB3 or ERBB4, which is accompanied by dissociation of chaperoning proteins HSP90 and CDC37 (Citri et al. 2004), as well as ERBB2IP (Borg et al. 2000) from ERBB2. ERBB2 heterodimers function to promote cell proliferation, cell survival and differentiation, depending on the cellular context. ERBB2 can also be activated by homodimerization when it is overexpressed, in cancer for example.

In cells expressing both ERBB2 and EGFR, EGF stimulation of EGFR leads to formation of both ERBB2:EGFR heterodimers (Wada et al. 1990, Karunagaran et al. 1996) and EGFR homodimers. Heterodimers of ERBB2 and EGFR trans-autophosphorylate on twelve tyrosine residues, six in the C-tail of EGFR and six in the C-tail of ERBB2 - Y1023, Y1139, Y1196, Y1221, Y1222 and Y1248 (Margolis et al. 1989, Hazan et al. 1990,Walton et al. 1990, Helin et al. 1991, Ricci et al. 1995, Pinkas-Kramarski 1996). Phosphorylated tyrosine residues in the C-tail of EGFR and ERBB2 serve as docking sites for downstream signaling molecules. Three key signaling pathways activated by ERBB2:EGFR heterodimers are RAF/MAP kinase cascade, PI3K-induced AKT signaling, and signaling by phospholipase C gamma (PLCG1). Downregulation of EGFR signaling is mediated by ubiquitin ligase CBL, and is shown under Signaling by EGFR.

In cells expressing ERBB2 and ERBB3, ERBB3 activated by neuregulin NRG1 or NRG2 binding (Tzahar et al. 1994) forms a heterodimer with ERBB2 (Pinkas-Kramarski et al. 1996, Citri et al. 2004). ERBB3 is the only EGFR family member with no kinase activity, and can only function in heterodimers, with ERBB2 being its preferred heterodimerization partner. After heterodimerization, ERBB2 phosphorylates ten tyrosine residues in the C-tail of ERBB3, Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 (Prigent et al. 1994, Pinkas-Kramarski et al. 1996, Vijapurkar et al. 2003, Li et al. 2007) that subsequently serve as docking sites for downstream signaling molecules, resulting in activation of PI3K-induced AKT signaling and RAF/MAP kinase cascade. Signaling by ERBB3 is downregulated by the action of RNF41 ubiquitin ligase, also known as NRDP1.

In cells expressing ERBB2 and ERBB4, ligand stimulated ERBB4 can either homodimerize or form heterodimers with ERBB2 (Li et al. 2007), resulting in trans-autophosphorylation of ERBB2 and ERBB4 on C-tail tyrosine residues that will subsequently serve as docking sites for downstream signaling molecules, leading to activation of RAF/MAP kinase cascade and, in the case of ERBB4 CYT1 isoforms, PI3K-induced AKT signaling (Hazan et al. 1990, Cohen et al. 1996, Li et al. 2007, Kaushansky et al. 2008). Signaling by ERBB4 is downregulated by the action of WWP1 and ITCH ubiquitin ligases, and is shown under Signaling by ERBB4.

Literature Reactome attaches

Reactome's record attaches no literature to this pathway.

Reactome's record lists 12 orthologous events, R-MMU-1227986 (Mus musculus), R-RNO-1227986 (Rattus norvegicus) among the species this site serves, and 10 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-02 ET · Reactome pathway browser"Signaling by ERBB2". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-1227986 with StableID: R-HSA-1227986.10 (accessed 2026-10-02 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 50 genes in this human pathway; showing 1 to 50, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAKT1	AuthorityHGNC:391	Mapping file id207 NCBI file	EvidenceTAS
GeneAKT2	AuthorityHGNC:392	Mapping file id208 NCBI file	EvidenceTAS
GeneAKT3	AuthorityHGNC:393	Mapping file id10000 NCBI file	EvidenceTAS
GeneBTC	AuthorityHGNC:1121	Mapping file id685 NCBI file	EvidenceIEA, TAS
GeneCDC37	AuthorityHGNC:1735	Mapping file id11140 NCBI file	EvidenceTAS
GeneCUL5	AuthorityHGNC:2556	Mapping file id8065 NCBI file	EvidenceTAS
GeneDIAPH1	AuthorityHGNC:2876	Mapping file id1729 NCBI file	EvidenceTAS
GeneEGF	AuthorityHGNC:3229	Mapping file id1950 NCBI file	EvidenceIEA, TAS
GeneEGFR	AuthorityHGNC:3236	Mapping file id1956 NCBI file	EvidenceIEA, TAS
GeneERBB2	AuthorityHGNC:3430	Mapping file id2064 NCBI file	EvidenceIEA, TAS
GeneERBB3	AuthorityHGNC:3431	Mapping file id2065 NCBI file	EvidenceIEA, TAS
GeneERBB4	AuthorityHGNC:3432	Mapping file id2066 NCBI file	EvidenceIEA, TAS
GeneERBIN	AuthorityHGNC:15842	Mapping file id55914 NCBI file	EvidenceTAS
GeneEREG	AuthorityHGNC:3443	Mapping file id2069 NCBI file	EvidenceIEA, TAS
GeneFYN	AuthorityHGNC:4037	Mapping file id2534 NCBI file	EvidenceTAS
GeneGAB1	AuthorityHGNC:4066	Mapping file id2549 NCBI file	EvidenceTAS
GeneGRB2	AuthorityHGNC:4566	Mapping file id2885 NCBI file	EvidenceIEA, TAS
GeneGRB7	AuthorityHGNC:4567	Mapping file id2886 NCBI file	EvidenceTAS
GeneHBEGF	AuthorityHGNC:3059	Mapping file id1839 NCBI file	EvidenceIEA, TAS
GeneHRAS	AuthorityHGNC:5173	Mapping file id3265 NCBI file	EvidenceIEA, TAS
GeneHSP90AA1	AuthorityHGNC:5253	Mapping file id3320 NCBI file	EvidenceTAS
GeneKRAS	AuthorityHGNC:6407	Mapping file id3845 NCBI file	EvidenceIEA, TAS
GeneMATK	AuthorityHGNC:6906	Mapping file id4145 NCBI file	EvidenceTAS
GeneMEMO1	AuthorityHGNC:14014	Mapping file id51072 NCBI file	EvidenceTAS
GeneNRAS	AuthorityHGNC:7989	Mapping file id4893 NCBI file	EvidenceIEA, TAS
GeneNRG1	AuthorityHGNC:7997	Mapping file id3084 NCBI file	EvidenceIEA, TAS
GeneNRG2	AuthorityHGNC:7998	Mapping file id9542 NCBI file	EvidenceIEA, TAS
GeneNRG3	AuthorityHGNC:7999	Mapping file id10718 NCBI file	EvidenceIEA, TAS
GeneNRG4	AuthorityHGNC:29862	Mapping file id145957 NCBI file	EvidenceIEA, TAS
GenePIK3CA	AuthorityHGNC:8975	Mapping file id5290 NCBI file	EvidenceTAS
GenePIK3R1	AuthorityHGNC:8979	Mapping file id5295 NCBI file	EvidenceTAS
GenePLCG1	AuthorityHGNC:9065	Mapping file id5335 NCBI file	EvidenceIEA
GenePRKCA	AuthorityHGNC:9393	Mapping file id5578 NCBI file	EvidenceTAS
GenePRKCD	AuthorityHGNC:9399	Mapping file id5580 NCBI file	EvidenceTAS
GenePRKCE	AuthorityHGNC:9401	Mapping file id5581 NCBI file	EvidenceTAS
GenePTK6	AuthorityHGNC:9617	Mapping file id5753 NCBI file	EvidenceTAS
GenePTPN12	AuthorityHGNC:9645	Mapping file id5782 NCBI file	EvidenceIEA, TAS
GenePTPN18	AuthorityHGNC:9649	Mapping file id26469 NCBI file	EvidenceTAS
GeneRHOA	AuthorityHGNC:667	Mapping file id387 NCBI file	EvidenceTAS
GeneRNF41	AuthorityHGNC:18401	Mapping file id10193 NCBI file	EvidenceTAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS
GeneSHC1	AuthorityHGNC:10840	Mapping file id6464 NCBI file	EvidenceIEA, TAS
GeneSOS1	AuthorityHGNC:11187	Mapping file id6654 NCBI file	EvidenceIEA, TAS
GeneSRC	AuthorityHGNC:11283	Mapping file id6714 NCBI file	EvidenceTAS
GeneSTUB1	AuthorityHGNC:11427	Mapping file id10273 NCBI file	EvidenceTAS
GeneUBA52	AuthorityHGNC:12458	Mapping file id7311 NCBI file	EvidenceTAS
GeneUBB	AuthorityHGNC:12463	Mapping file id7314 NCBI file	EvidenceTAS
GeneUBC	AuthorityHGNC:12468	Mapping file id7316 NCBI file	EvidenceTAS
GeneUSP8	AuthorityHGNC:12631	Mapping file id9101 NCBI file	EvidenceTAS
GeneYES1	AuthorityHGNC:12841	Mapping file id7525 NCBI file	EvidenceTAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Signaling by Receptor Tyrosine KinasesR-HSA-9006934536 genes

Children

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.