Pathway Human Homo sapiens

RET signaling

R-HSA-8853659 in Reactome release 97: under Axon guidance, with 41 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-8853659 (mouse), R-RNO-8853659 (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-8853659.7
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2016-06-15
Last updated: 2017-09-27
Events inside: 24, counted from the record

The RET proto-oncogene encodes a receptor tyrosine kinase expressed primarily in urogenital precursor cells, spermatogonocytes, dopaminergic neurons, motor neurons and neural crest progenitors and derived cells. . It is essential for kidney genesis, spermatogonial self-renewal and survivial, specification, migration, axonal growth and axon guidance of developing enteric neurons, motor neurons, parasympathetic neurons and somatosensory neurons (Schuchardt et al. 1994, Enomoto et al. 2001, Naughton et al. 2006, Kramer et al. 2006, Luo et al. 2006, 2009). RET was identified as the causative gene for human papillary thyroid carcinoma (Grieco et al. 1990), multiple endocrine neoplasia (MEN) type 2A (Mulligan et al. 1993), type 2B (Hofstra et al. 1994, Carlson et al. 1994), and Hirschsprung's disease (Romeo et al. 1994, Edery et al. 1994).

RET contains a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands, GDNF (Lin et al. 1993), neurturin (NRTN) (Kotzbauer et al. 1996), artemin (ARTN) (Baloh et al. 1998), and persephin (PSPN) (Milbrandt et al. 1998), which form a family of neurotrophic factors. To stimulate RET, these ligands need a glycosylphosphatidylinositol (GPI)-anchored co-receptor, collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996). The four members of this family have different, overlapping ligand preferences. GFRA1, GFRA2, GFRA3, and GFRA4 preferentially bind GDNF, NRTN, ARTN and PSPN, respectively (Jing et al. 1996, 1997, Creedon et al. 1997, Baloh et al. 1997, 1998, Masure et al. 2000). The GFRA co-receptor can come from the same cell as RET, or from a different cell. When the co-receptor is produced by the same cell as RET, it is termed cis signaling. When the co-receptor is produced by another cell, it is termed trans signaling. Cis and trans activation has been proposed to diversify RET signaling, either by recruiting different downstream effectors or by changing the kinetics or efficacy of kinase activation (Tansey et al. 2000, Paratcha et al. 2001). Whether cis and trans signaling has significant differences in vivo is unresolved (Fleming et al. 2015). Different GDNF family members could activate similar downstream signaling pathways since all GFRAs bind to and activate the same tyrosine kinase and induce coordinated phosphorylation of the same four RET tyrosines (Tyr905, Tyr1015, Tyr1062, and Tyr1096) with similar kinetics (Coulpier et al. 2002). However the exact RET signaling pathways in different types of cells and neurons remain to be determined.

Literature Reactome attaches

RET and neuroendocrine tumorsCancer Lett., 2004, vol. 204, p. 197-211PubMed 15013219
RET and neuroendocrine tumorsPituitary, 2006, vol. 9, p. 179-92PubMed 17036197

Reactome's record lists 10 orthologous events, R-RNO-8853659 (Rattus norvegicus), R-MMU-8853659 (Mus musculus) 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 2026-10-02 ET · Reactome pathway browser"RET signaling". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-8853659 with StableID: R-HSA-8853659.7 (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 41 genes in this human pathway; showing 1 to 41, 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
GeneARTN	AuthorityHGNC:727	Mapping file id9048 NCBI file	EvidenceTAS
GeneDOK1	AuthorityHGNC:2990	Mapping file id1796 NCBI file	EvidenceTAS
GeneDOK2	AuthorityHGNC:2991	Mapping file id9046 NCBI file	EvidenceTAS
GeneDOK4	AuthorityHGNC:19868	Mapping file id55715 NCBI file	EvidenceTAS
GeneDOK5	AuthorityHGNC:16173	Mapping file id55816 NCBI file	EvidenceTAS
GeneDOK6	AuthorityHGNC:28301	Mapping file id220164 NCBI file	EvidenceTAS
GeneFRS2	AuthorityHGNC:16971	Mapping file id10818 NCBI file	EvidenceTAS
GeneGAB1	AuthorityHGNC:4066	Mapping file id2549 NCBI file	EvidenceTAS
GeneGAB2	AuthorityHGNC:14458	Mapping file id9846 NCBI file	EvidenceTAS
GeneGDNF	AuthorityHGNC:4232	Mapping file id2668 NCBI file	EvidenceTAS
GeneGFRA1	AuthorityHGNC:4243	Mapping file id2674 NCBI file	EvidenceTAS
GeneGFRA2	AuthorityHGNC:4244	Mapping file id2675 NCBI file	EvidenceTAS
GeneGFRA3	AuthorityHGNC:4245	Mapping file id2676 NCBI file	EvidenceTAS
GeneGFRA4	AuthorityHGNC:13821	Mapping file id64096 NCBI file	EvidenceTAS
GeneGRB10	AuthorityHGNC:4564	Mapping file id2887 NCBI file	EvidenceTAS
GeneGRB2	AuthorityHGNC:4566	Mapping file id2885 NCBI file	EvidenceTAS
GeneGRB7	AuthorityHGNC:4567	Mapping file id2886 NCBI file	EvidenceTAS
GeneIRS2	AuthorityHGNC:6126	Mapping file id8660 NCBI file	EvidenceTAS
GeneMAPK7	AuthorityHGNC:6880	Mapping file id5598 NCBI file	EvidenceTAS
GeneNRTN	AuthorityHGNC:8007	Mapping file id4902 NCBI file	EvidenceTAS
GenePDLIM7	AuthorityHGNC:22958	Mapping file id9260 NCBI file	EvidenceTAS
GenePIK3CA	AuthorityHGNC:8975	Mapping file id5290 NCBI file	EvidenceTAS
GenePIK3CB	AuthorityHGNC:8976	Mapping file id5291 NCBI file	EvidenceTAS
GenePIK3CD	AuthorityHGNC:8977	Mapping file id5293 NCBI file	EvidenceTAS
GenePIK3R1	AuthorityHGNC:8979	Mapping file id5295 NCBI file	EvidenceTAS
GenePIK3R2	AuthorityHGNC:8980	Mapping file id5296 NCBI file	EvidenceTAS
GenePIK3R3	AuthorityHGNC:8981	Mapping file id8503 NCBI file	EvidenceTAS
GenePLCG1	AuthorityHGNC:9065	Mapping file id5335 NCBI file	EvidenceTAS
GenePRKACA	AuthorityHGNC:9380	Mapping file id5566 NCBI file	EvidenceTAS
GenePRKACB	AuthorityHGNC:9381	Mapping file id5567 NCBI file	EvidenceTAS
GenePRKACG	AuthorityHGNC:9382	Mapping file id5568 NCBI file	EvidenceTAS
GenePRKCA	AuthorityHGNC:9393	Mapping file id5578 NCBI file	EvidenceTAS
GenePSPN	AuthorityHGNC:9579	Mapping file id5623 NCBI file	EvidenceTAS
GenePTPN11	AuthorityHGNC:9644	Mapping file id5781 NCBI file	EvidenceTAS
GeneRAP1GAP	AuthorityHGNC:9858	Mapping file id5909 NCBI file	EvidenceTAS
GeneRET	AuthorityHGNC:9967	Mapping file id5979 NCBI file	EvidenceTAS
GeneSHANK3	AuthorityHGNC:14294	Mapping file id85358 NCBI file	EvidenceTAS
GeneSHC1	AuthorityHGNC:10840	Mapping file id6464 NCBI file	EvidenceTAS
GeneSHC3	AuthorityHGNC:18181	Mapping file id53358 NCBI file	EvidenceTAS
GeneSOS1	AuthorityHGNC:11187	Mapping file id6654 NCBI file	EvidenceTAS
GeneSRC	AuthorityHGNC:11283	Mapping file id6714 NCBI file	EvidenceTAS

Evidence codes on this page: 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

Axon guidanceR-HSA-422475538 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.