Pathway Human Homo sapiens

Signaling by FGFR3 in disease

R-HSA-5655332 in Reactome release 97: under Signaling by FGFR in disease, with 22 genes placed in it by the mapping files and 1 child pathway 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; neither of the other two lists holds it. Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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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-5655332.6
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: yes, as Reactome flags it
Released: 2012-06-12
Last updated: 2021-12-08
Events inside: 12, counted from the record

The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically.

Activating mutations in FGFR3 are associated with the development of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Harada et al, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau et al, 1994; Shiang et al, 1994; Bellus et al, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus et al, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau et al, 1995; Rousseau et al, 1996, D'Avis et al,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina et al, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina et al, 1999; Bellus et al, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski et al, 1996; Bellus et al, 2000)

In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus et al, 1996; Reardon et al, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi et al, 2004b).

Of all the FGF receptors, FGFR3 has perhaps the best established link to the development in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen et al, 1999; Naski et al, 1996; di Martino et al, 2009, Sibley et al, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe et al, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997).

More recently, a number of fusion proteins of FGFR3 have been identified in various cancers (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; Wu et al, 2013; Wang et al, 2014; Yuan et al, 2014; reviewed in Parker et al, 2014). The most common fusion protein is TACC3, a coiled coil protein involved in mitotic spindle assembly. FGFR3 fusion proteins are constitutively active and appear to contribute to proliferation and tumorigenesis through activation of the ERK and AKT signaling pathways (reviewed in Parker et al, 2014).

Literature Reactome attaches

FGFR activation in skeletal disorders: too much of a good thingTrends Genet, 1997, vol. 13, p. 178-82PubMed 9154000
Fibroblast growth factor receptors: lessons from the genesTrends Biochem Sci, 1998, vol. 23, p. 59-62PubMed 9538690
FGFR3-related dwarfism and cell signalingJ Bone Miner Metab, 2009, vol. 27, p. 9-15PubMed 19066716
High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignanciesCancer Res, 1998, vol. 58, p. 5640-5PubMed 9865713
Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1)Hum Mol Genet, 1996, vol. 5, p. 509-12PubMed 8845844
Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasiaNature, 1994, vol. 371, p. 252-4PubMed 8078586
Stop codon FGFR3 mutations in thanatophoric dwarfism type 1Nat Genet, 1995, vol. 10, p. 11-2PubMed 7647778

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"Signaling by FGFR3 in disease". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-5655332 with StableID: R-HSA-5655332.6 (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 22 genes in this human pathway; showing 1 to 22, 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
GeneFGF1	AuthorityHGNC:3665	Mapping file id2246 NCBI file	EvidenceTAS
GeneFGF16	AuthorityHGNC:3672	Mapping file id8823 NCBI file	EvidenceTAS
GeneFGF17	AuthorityHGNC:3673	Mapping file id8822 NCBI file	EvidenceTAS
GeneFGF18	AuthorityHGNC:3674	Mapping file id8817 NCBI file	EvidenceTAS
GeneFGF2	AuthorityHGNC:3676	Mapping file id2247 NCBI file	EvidenceTAS
GeneFGF20	AuthorityHGNC:3677	Mapping file id26281 NCBI file	EvidenceTAS
GeneFGF23	AuthorityHGNC:3680	Mapping file id8074 NCBI file	EvidenceTAS
GeneFGF4	AuthorityHGNC:3682	Mapping file id2249 NCBI file	EvidenceTAS
GeneFGF5	AuthorityHGNC:3683	Mapping file id2250 NCBI file	EvidenceTAS
GeneFGF8	AuthorityHGNC:3686	Mapping file id2253 NCBI file	EvidenceTAS
GeneFGF9	AuthorityHGNC:3687	Mapping file id2254 NCBI file	EvidenceTAS
GeneFGFR3	AuthorityHGNC:3690	Mapping file id2261 NCBI file	EvidenceTAS
GeneFRS2	AuthorityHGNC:16971	Mapping file id10818 NCBI file	EvidenceTAS
GeneGAB1	AuthorityHGNC:4066	Mapping file id2549 NCBI file	EvidenceTAS
GeneGRB2	AuthorityHGNC:4566	Mapping file id2885 NCBI file	EvidenceTAS
GeneHRAS	AuthorityHGNC:5173	Mapping file id3265 NCBI file	EvidenceTAS
GeneKRAS	AuthorityHGNC:6407	Mapping file id3845 NCBI file	EvidenceTAS
GeneNRAS	AuthorityHGNC:7989	Mapping file id4893 NCBI file	EvidenceTAS
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	EvidenceTAS
GeneSOS1	AuthorityHGNC:11187	Mapping file id6654 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

Signaling by FGFR in diseaseR-HSA-122609963 genes

Children

FGFR3 mutant receptor activationR-HSA-203351412 genes

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.