Pathway Human Homo sapiens

Signaling by ERBB4

R-HSA-1236394 in Reactome release 97: under Signaling by Receptor Tyrosine Kinases, with 58 genes placed in it by the mapping files and 4 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-1236394 (mouse), R-RNO-1236394 (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-1236394.6
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: 11, counted from the record

ERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR/HER1), ERBB2 (HER2/NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains an active tyrosine kinase and a C-tail with multiple phosphorylation sites. At least three and possibly four splicing isoforms of ERBB4 exist that differ in their C-tail and/or the extracellular juxtamembrane regions: ERBB4 JM-A CYT1, ERBB4 JM-A CYT2 and ERBB4 JM-B CYT1 (the existence of ERBB4 JM-B CYT2 has not been confirmed).

ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the related neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation. The promiscuous heteromerization of ERBBs adds combinatorial diversity to ERBB signaling processes. As ERBB4 binds more ligands than other ERBBs, but has restricted expression, ERBB4 expression channels responses to ERBB ligands. The signaling capabilities of the four receptors have been compared (Schulze et al. 2005).

As for other receptor tyrosine kinases, ERBB4 signaling effectors are largely dictated through binding of effector proteins to ERBB4 peptides that are phosphorylated upon ligand binding. All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000).

The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000).

Besides signaling as a conventional transmembrane receptor kinase, ERBB4 differs from other ERBBs in that JM-A isoforms signal through efficient release of a soluble intracellular domain. 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. For example, in mammary cells, ERBB4 binds SH2 transcription factor STAT5A. ERBB4 s80 shuttles STAT5A to the nucleus, and actsa as a 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 (Jones et al. 1999, Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 binds activated estrogen receptor in the nucleus and acts as a transcriptional co-factor in promoting transcription of some estrogen-regulated genes, including progesterone receptor gene NR3C3 and CXCL12 (SDF1) (Zhu et al. 2006). 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).

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 is a co-regulator of YAP1-mediated transcription in association with TEAD transcription factors (Komuro et al. 2003, Omerovic et al. 2004). Hence, the WW binding motif couples ERBB4 to the major effector arm of the HIPPO signaling pathway. 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).

WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009).

ERBB4 also binds the E3 ubiquitin ligase MDM2, and inhibitor of p53 (Arasada et al. 2005). Other proteins that bind to ERBB4 intracellular domain have been identified by co-immunoprecipitation and mass spectrometry (Gilmore-Hebert et al., 2010), and include transcriptional co-repressor TRIM28/KAP1, which promotes chromatin compaction. DNA damage signaling through ATM releases TRIM28-associated heterochromatinization. Interactions of ERBB4 with TRIM28 and MDM2 may be important for integration of growth factor responses and DNA damage responses.

In human breast cancer cell lines, ERBB4 activation enhances anchorage-independent colony formation in soft agar but inhibits cell growth in a monolayer culture. Different ERBB4 ligands induce different gene expression changes in breast cancer cell lines. Some of the genes induced in response to ERBB4 signaling in breast cancer cell lines are RAB2, EPS15R and GATA4. It is not known if these gene are direct transcriptional targets of ERBB4 (Amin et al. 2004).

Transcriptome and ChIP-seq comparisons of full-length and intracellular domain isoforms in isogenic MCF10A mammary cell background have revealed the diversification of ERBB4 signaling engendered by alternative splicing and cleavage (Wali et al., 2014). ERBB4 broadly affected protease expression, cholesterol biosynthesis, HIF1-alpha signaling, and HIPPO signaling pathways, and other pathways were differentially activated by CYT1 and CYT2 isoforms. For example, CYT1 promoted expression of transcription factors TWIST1 and SNAIL1 that promote epithelial-mesenchymal transition. HIF1-alpha and HIPPO signaling are mediated, respectively, by binding of ERBB4 to HIF1-alpha and to YAP (Paatero et al., 2012, Komuro et al., 2003). ERBB4 increases activity of the transcription factor SREBF2, resulting in increased expression of SREBF2-target genes involved in cholesterol biosynthesis. The mechanism is not known and may involve facilitation of SREBF2 cleavage through ERBB4-mediated PI3K signaling (Haskins et al. 2016).

In some contexts, ERBB4 promotes growth suppression or apoptosis (Penington et al., 2002). Activation of ERBB4 in breast cancer cell lines leads to JNK dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka Cook et al. 2006). The nature of growth responses may be connected with the spliced isoforms expressed. In comparisons of CYT1 vs CYT2 (full-length and ICD) expression in mammary cells, CYT1 was a weaker growth inducer, associated with attenuated MAPK signaling relative to CYT2 (Wali et al., 2014). 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).

ERBB4 plays important roles in the developing and adult nervous system. Erbb4 deficiency in somatostatin-expressing neurons of the thalamic reticular nucleus alters behaviors dependent on sensory selection (Ahrens et al. 2015). NRG1-activated ERBB4 signaling enhances AMPA receptor responses through PKC-dependent AMPA receptor exocytosis. This results in an increased excitatory input to parvalbumin-expressing inhibitory neurons in the visual cortex and regulates visual cortical plasticity (Sun et al. 2016). NRG1-activated ERBB4 signaling is involved in GABAergic activity in amygdala which mediates fear conditioning (fear memory) (Lu et al. 2014). Conditional Erbb4 deletion from fast-spiking interneurons, chandelier and basket cells of the cerebral cortex leads to synaptic defects associated with increased locomotor activity and abnormal emotional, social and cognitive function that can be linked to some of the schizophrenia features. The level of GAD1 (GAD67) protein is reduced in the cortex of conditional Erbb4 mutants. GAD1 is a GABA synthesizing enzyme. Cortical mRNA levels of GAD67 are consistently decreased in schizophrenia (Del Pino et al. 2014). Erbb4 is expressed in the GABAergic neurons of the bed nucleus stria terminalis, a part of the extended amygdala. Inhibition of NRG1-triggered ERBB4 signaling induces anxiety-like behavior, which depends on GABAergic neurotransmission. NRG1-ERBB4 signaling stimulates presynaptic GABA release, but the exact mechanism is not known (Geng et al. 2016). NRG1 protects cortical interneurons against ischemic brain injury through ERBB4-mediated increase in GABAergic transmission (Guan et al. 2015). NRG2-activated ERBB4 can reduce the duration of GABAergic transmission by binding to GABA receptors at the postsynaptic membrane via their GABRA1 subunit and promoting endocytosis of GABA receptors (Mitchell et al. 2013). NRG1 promotes synchronization of prefrontal cortex interneurons in an ERBB4 dependent manner (Hou et al. 2014). NRG1-ERBB4 signaling protects neurons from the cell death induced by a mutant form of the amyloid precursor protein (APP) (Woo et al. 2012).

Clinical relevance of ERBB4 has been identified in several contexts. In cancer, putative and validated gain-of-function mutations or gene amplification that may be drivers have been identified at modest frequencies, and may also contribute to resistance to EGFR and ERBB2-targeted therapies. This is noteworthy as ERBB4 kinase activity is inhibited by pan-ERBB tyrosine kinase inhibitors, including lapatinib, which is approved by the US FDA. The reduced prevalence relative to EGFR and ERBB2 in cancer may reflect more restricted expression of ERBB4, or differential signaling, as specific ERBB4 isoforms have been linked to growth inhibition or apoptosis in experimental systems. ERBB2/ERBB4 heterodimers protect cardiomyocytes, so reduced activity of ERBB4 in patients treated with the ERBB2-targeted therapeutic antibody trastuzumab may contribute to the cardiotoxicity of this agent when used in combination with (cardiotoxic) anthracyclines.

With the importance of ERBB4 in developing and adult nervous system, NRG1 and/or ERBB4 polymorphisms, splicing aberrations and mutations have been linked to nervous system disorders including schizophrenia and amyotrophic lateral sclerosis, although these findings are not yet definitive.

Literature Reactome attaches

Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferationEMBO J, 1997, vol. 16, p. 1268-78PubMed 9135143
Activation of ErbB4 by the bifunctional epidermal growth factor family hormone epiregulin is regulated by ErbB2J Biol Chem, 1998, vol. 273, p. 11288-94PubMed 9556621
ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoformsJ Biol Chem, 1994, vol. 269, p. 25226-33PubMed 7929212
Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinasesNature, 1997, vol. 387, p. 512-6PubMed 9168115
Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4Proc Natl Acad Sci U S A, 1997, vol. 94, p. 9562-7PubMed 9275162
Identification and characterization of novel spliced variants of neuregulin 4 in prostate cancerClin Cancer Res, 2007, vol. 13, p. 3147-55PubMed 17545517
Ligand discrimination in signaling through an ErbB4 receptor homodimer

Reactome's record lists 10 orthologous events, R-MMU-1236394 (Mus musculus), R-RNO-1236394 (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"Signaling by ERBB4". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-1236394 with StableID: R-HSA-1236394.6 (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 58 genes in this human pathway; showing 1 to 58, 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, TAS
GeneCSN2	AuthorityHGNC:2447	Mapping file id1447 NCBI file	EvidenceTAS
GeneCXCL12	AuthorityHGNC:10672	Mapping file id6387 NCBI file	EvidenceTAS
GeneDLG4	AuthorityHGNC:2903	Mapping file id1742 NCBI file	EvidenceIEA
GeneEGF	AuthorityHGNC:3229	Mapping file id1950 NCBI file	EvidenceTAS
GeneEGFR	AuthorityHGNC:3236	Mapping file id1956 NCBI file	EvidenceTAS
GeneERBB3	AuthorityHGNC:3431	Mapping file id2065 NCBI file	EvidenceTAS
GeneERBB4	AuthorityHGNC:3432	Mapping file id2066 NCBI file	EvidenceIEA, TAS
GeneEREG	AuthorityHGNC:3443	Mapping file id2069 NCBI file	EvidenceIEA, TAS
GeneESR1	AuthorityHGNC:3467	Mapping file id2099 NCBI file	EvidenceTAS
GeneGABRA1	AuthorityHGNC:4075	Mapping file id2554 NCBI file	EvidenceIEA
GeneGABRB1	AuthorityHGNC:4081	Mapping file id2560 NCBI file	EvidenceIEA
GeneGABRB2	AuthorityHGNC:4082	Mapping file id2561 NCBI file	EvidenceIEA
GeneGABRB3	AuthorityHGNC:4083	Mapping file id2562 NCBI file	EvidenceIEA
GeneGABRG2	AuthorityHGNC:4087	Mapping file id2566 NCBI file	EvidenceIEA
GeneGABRG3	AuthorityHGNC:4088	Mapping file id2567 NCBI file	EvidenceIEA
GeneGABRQ	AuthorityHGNC:14454	Mapping file id55879 NCBI file	EvidenceIEA
GeneGFAP	AuthorityHGNC:4235	Mapping file id2670 NCBI file	EvidenceTAS
GeneGRB2	AuthorityHGNC:4566	Mapping file id2885 NCBI file	EvidenceTAS
GeneHBEGF	AuthorityHGNC:3059	Mapping file id1839 NCBI file	EvidenceIEA, TAS
GeneHRAS	AuthorityHGNC:5173	Mapping file id3265 NCBI file	EvidenceTAS
GeneITCH	AuthorityHGNC:13890	Mapping file id83737 NCBI file	EvidenceTAS
GeneKRAS	AuthorityHGNC:6407	Mapping file id3845 NCBI file	EvidenceTAS
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
GeneNEDD4	AuthorityHGNC:7727	Mapping file id4734 NCBI file	EvidenceTAS
GeneNRAS	AuthorityHGNC:7989	Mapping file id4893 NCBI file	EvidenceTAS
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
GenePGR	AuthorityHGNC:8910	Mapping file id5241 NCBI file	EvidenceTAS
GenePIK3CA	AuthorityHGNC:8975	Mapping file id5290 NCBI file	EvidenceTAS
GenePIK3R1	AuthorityHGNC:8979	Mapping file id5295 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
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS
GeneS100B	AuthorityHGNC:10500	Mapping file id6285 NCBI file	EvidenceTAS
GeneSHC1	AuthorityHGNC:10840	Mapping file id6464 NCBI file	EvidenceTAS
GeneSOS1	AuthorityHGNC:11187	Mapping file id6654 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
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
GeneWWOX	AuthorityHGNC:12799	Mapping file id51741 NCBI file	EvidenceTAS
GeneWWP1	AuthorityHGNC:17004	Mapping file id11059 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 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.