Pathway Human Homo sapiens

Nuclear signaling by ERBB4

R-HSA-1251985 in Reactome release 97: under Signaling by ERBB4, with 32 genes placed in it by the mapping files and 0 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-1251985 (mouse), R-RNO-1251985 (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-1251985.7
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2011-12-06
Last updated: 2019-06-12
Events inside: 34, counted from the record

Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006). ERBB4s80 may inhibit transcription of telomerase reverse transcriptase (TERT) by increasing methylation of the TERT gene promoter through an unknown mechanism (Ishibashi et al. 2012).

The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006).

Literature Reactome attaches

WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional functionCancer Res, 2005, vol. 65, p. 6764-72PubMed 16061658
Ectodomain cleavage of ErbB-4: characterization of the cleavage site and m80 fragmentJ Biol Chem, 2003, vol. 278, p. 38421-7PubMed 12869563
Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4J Biol Chem, 2000, vol. 275, p. 10379-87PubMed 10744726
Nuclear ErbB4 signaling through H3K9me3 is antagonized by EGFR-activated c-SrcJ. Cell. Sci., 2013, vol. 126, p. 625-37PubMed 23230144
WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleusJ Biol Chem, 2003, vol. 278, p. 33334-41PubMed 12807903
Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiationMol Endocrinol, 2008, vol. 22, p. 2307-21PubMed 18653779
The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells

Reactome's record lists 10 orthologous events, R-MMU-1251985 (Mus musculus), R-RNO-1251985 (Rattus norvegicus) among the species this site serves, and 8 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"Nuclear signaling by ERBB4". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-1251985 with StableID: R-HSA-1251985.7 (accessed 2026-10-01 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 32 genes in this human pathway; showing 1 to 32, 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
GeneADAM17	AuthorityHGNC:195	Mapping file id6868 NCBI file	EvidenceIEA
GeneADAP1	AuthorityHGNC:16486	Mapping file id11033 NCBI file	EvidenceTAS
GeneAPH1A	AuthorityHGNC:29509	Mapping file id51107 NCBI file	EvidenceTAS
GeneAPH1B	AuthorityHGNC:24080	Mapping file id83464 NCBI file	EvidenceTAS
GeneAPOE	AuthorityHGNC:613	Mapping file id348 NCBI file	EvidenceTAS
GeneBTC	AuthorityHGNC:1121	Mapping file id685 NCBI file	EvidenceIEA
GeneCSN2	AuthorityHGNC:2447	Mapping file id1447 NCBI file	EvidenceTAS
GeneCXCL12	AuthorityHGNC:10672	Mapping file id6387 NCBI file	EvidenceTAS
GeneERBB4	AuthorityHGNC:3432	Mapping file id2066 NCBI file	EvidenceIEA, TAS
GeneEREG	AuthorityHGNC:3443	Mapping file id2069 NCBI file	EvidenceIEA
GeneESR1	AuthorityHGNC:3467	Mapping file id2099 NCBI file	EvidenceTAS
GeneGFAP	AuthorityHGNC:4235	Mapping file id2670 NCBI file	EvidenceTAS
GeneHBEGF	AuthorityHGNC:3059	Mapping file id1839 NCBI file	EvidenceIEA
GeneMXD4	AuthorityHGNC:13906	Mapping file id10608 NCBI file	EvidenceTAS
GeneNCOR1	AuthorityHGNC:7672	Mapping file id9611 NCBI file	EvidenceIEA, TAS
GeneNCSTN	AuthorityHGNC:17091	Mapping file id23385 NCBI file	EvidenceTAS
GeneNRG1	AuthorityHGNC:7997	Mapping file id3084 NCBI file	EvidenceIEA
GeneNRG2	AuthorityHGNC:7998	Mapping file id9542 NCBI file	EvidenceIEA
GeneNRG3	AuthorityHGNC:7999	Mapping file id10718 NCBI file	EvidenceIEA
GeneNRG4	AuthorityHGNC:29862	Mapping file id145957 NCBI file	EvidenceIEA
GenePGR	AuthorityHGNC:8910	Mapping file id5241 NCBI file	EvidenceTAS
GenePSEN1	AuthorityHGNC:9508	Mapping file id5663 NCBI file	EvidenceTAS
GenePSEN2	AuthorityHGNC:9509	Mapping file id5664 NCBI file	EvidenceTAS
GenePSENEN	AuthorityHGNC:30100	Mapping file id55851 NCBI file	EvidenceTAS
GeneS100B	AuthorityHGNC:10500	Mapping file id6285 NCBI file	EvidenceTAS
GeneSPARC	AuthorityHGNC:11219	Mapping file id6678 NCBI file	EvidenceTAS
GeneSRC	AuthorityHGNC:11283	Mapping file id6714 NCBI file	EvidenceTAS
GeneSTAT5A	AuthorityHGNC:11366	Mapping file id6776 NCBI file	EvidenceTAS
GeneSTMN1	AuthorityHGNC:6510	Mapping file id3925 NCBI file	EvidenceTAS
GeneTAB2	AuthorityHGNC:17075	Mapping file id23118 NCBI file	EvidenceIEA, TAS
GeneWWOX	AuthorityHGNC:12799	Mapping file id51741 NCBI file	EvidenceTAS
GeneYAP1	AuthorityHGNC:16262	Mapping file id10413 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 ERBB4R-HSA-123639458 genes

Children

None: no pathway of this release's list names this one as a parent.

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.