Fibroblast growth factor receptor 3

FGFR3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFGFR3, ACH, CD333, CEK2, HSFGFR3EX, JTK4, fibroblast growth factor receptor 3
External IDsMGI: 95524 HomoloGene: 55437 GeneCards: FGFR3
Gene location (Human)
Chr.Chromosome 4 (human)[1]
Band4p16.3Start1,793,293 bp[1]
End1,808,872 bp[1]
RNA expression pattern


More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

2261

14184

Ensembl

ENSG00000068078

ENSMUSG00000054252

UniProt

P22607

Q61851

RefSeq (mRNA)

NM_000142
NM_001163213
NM_022965
NM_001354809
NM_001354810

RefSeq (protein)

NP_000133
NP_001156685
NP_075254
NP_001341738
NP_001341739

n/a

Location (UCSC)Chr 4: 1.79 – 1.81 MbChr 5: 33.72 – 33.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene.[5] FGFR3 surrounds the gene for achondroplasia FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.[6]

The FGFR3 gene produces various forms of the FGFR3 protein; the location varies depending on the isoform of the FGFR3 protein. Since the different forms are found within different tissues the protein is resposible for multiple growth factor interactions.[7]

Function

The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals which ultimately influencing cell mitogenesis and differentiation.

This particular family member binds both acidic and basic fibroblast growth factor and plays a role in bone development and maintenance. The FGFR3 protein plays a role in bone growth by regulating ossification.[7] Alternative splicing occurs and additional variants have been described, including those utilizing alternate exon 8 rather than 9, but their full-length nature has not been determined.[8]

Mutations

Mutations in this gene can develop dysfunctional proteins "impede cartilage growth and development and affect chondrocyte proliferation and calcification"[6] which can lead to craniosynostosis and multiple types of skeletal dysplasia (Osteochondrodysplasia). The point mutation in the FGFR3 gene causes hydrogen bonds to form between two arginine side chains leading to ligand-independent stabilization FGFR3 dimers. Point mutations in the FGFR3 gene, "causes defective growth of long tubular bones".[9] By inhibiting chondrocyte proliferation, FGFR3 restricts long bone length.[10] In achondroplasia, the FGFR3 gene has a missense mutation at nucleotide 1138 resulting from either a G>A or G>C.[10] The missense mutation occur in a CpG site resulting in a codon. FGFR3 mutations are linked with spermatocytic seminoma, which occur more frequently in older men.[9]

Disease linkage

Defects in the FGFR3 gene has been associated with several conditions, including:

As a drug target

FGFR3 inhibitors are in early clinical trials as a cancer treatment,[14] eg. BGJ398 for urothelial carcinoma.[15]

Interactions

Fibroblast growth factor receptor 3 has been shown to interact with FGF1[16][17] and FGF9.[16][17]

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000068078 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000054252 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Keegan K, Johnson DE, Williams LT, Hayman MJ (February 1991). "Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3". Proceedings of the National Academy of Sciences of the United States of America. 88 (4): 1095–9. doi:10.1073/pnas.88.4.1095. PMC 50963. PMID 1847508.
  6. 1 2 Wang Y, Liu Z, Liu Z, Zhao H, Zhou X, Cui Y, Han J (May 2013). "Advances in research on and diagnosis and treatment of achondroplasia in China". Intractable & Rare Diseases Research. 2 (2): 45–50. doi:10.5582/irdr.2013.v2.2.45. PMC 4204580. PMID 25343101.
  7. 1 2 "FGFR3 gene". Genetics Home Reference. Retrieved 2018-09-27.
  8. ↑ "Entrez Gene: FGFR3 fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)".
  9. 1 2 Kelleher FC, O'Sullivan H, Smyth E, McDermott R, Viterbo A (2013). "Fibroblast growth factor receptors, developmental corruption and malignant disease". Carcinogenesis. 34 (10): 2198–205. doi:10.1093/carcin/bgt254. PMID 23880303.
  10. 1 2 Foldynova-Trantirkova S, Wilcox WR, Krejci P (2012). "Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias". Human Mutation. 33 (1): 29–41. doi:10.1002/humu.21636. PMC 3240715. PMID 22045636.
  11. ↑ Hafner C, Hartmann A, Vogt T (July 2007). "FGFR3 mutations in epidermal nevi and seborrheic keratoses: lessons from urothelium and skin". The Journal of Investigative Dermatology. 127 (7): 1572–3. doi:10.1038/sj.jid.5700772. PMID 17568799.
  12. ↑ Lamy A, Gobet F, Laurent M, Blanchard F, Varin C, Moulin C, Andreou A, Frebourg T, Pfister C (December 2006). "Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations". The Journal of Urology. 176 (6 Pt 1): 2686–9. doi:10.1016/j.juro.2006.07.132. PMID 17085196.
  13. ↑ Mulliken JB, Steinberger D, Kunze S, Müller U (November 1999). "Molecular diagnosis of bilateral coronal synostosis". Plastic and Reconstructive Surgery. 104 (6): 1603–15. doi:10.1097/00006534-199911000-00001. PMID 10541159.
  14. ↑ Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, Matsangou M, Costa R, Carneiro B, Villaflor VM, Cristofanilli M, Giles FJ (February 2017). "Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application". Oncotarget. 8 (9): 16052–16074. doi:10.18632/oncotarget.14109. PMC 5362545. PMID 28030802.
  15. ↑ Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, Galsky MD, et al. (May 2018). "Efficacy of BGJ398, a fibroblast growth factor receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations". Cancer Discovery. doi:10.1158/2159-8290.CD-18-0229. PMID 29848605. Lay summary – Cancer Therapy Advisor.
  16. 1 2 Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM (January 1996). "Expression and biological activity of mouse fibroblast growth factor-9". The Journal of Biological Chemistry. 271 (3): 1726–31. doi:10.1074/jbc.271.3.1726. PMID 8576175.
  17. 1 2 Chellaiah A, Yuan W, Chellaiah M, Ornitz DM (December 1999). "Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity". The Journal of Biological Chemistry. 274 (49): 34785–94. doi:10.1074/jbc.274.49.34785. PMID 10574949.

Further reading

  • Schweitzer DN, Graham JM, Lachman RS, Jabs EW, Okajima K, Przylepa KA, Shanske A, Chen K, Neidich JA, Wilcox WR (January 2001). "Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3". American Journal of Medical Genetics. 98 (1): 75–91. doi:10.1002/1096-8628(20010101)98:1<75::AID-AJMG1010>3.0.CO;2-6. PMID 11426459.
  • Horton WA, Lunstrum GP (December 2002). "Fibroblast growth factor receptor 3 mutations in achondroplasia and related forms of dwarfism". Reviews in Endocrine & Metabolic Disorders. 3 (4): 381–5. PMID 12424440.
  • Bonaventure J, Silve C (November 2005). "[Hereditary skeletal dysplasias and FGFR3 and PTHR1 signaling pathways]". Médecine Sciences. 21 (11): 954–61. doi:10.1051/medsci/20052111954. PMID 16274647.
  • Hernández S, Toll A, Baselga E, Ribé A, Azua-Romeo J, Pujol RM, Real FX (July 2007). "Fibroblast growth factor receptor 3 mutations in epidermal nevi and associated low grade bladder tumors". The Journal of Investigative Dermatology. 127 (7): 1664–6. doi:10.1038/sj.jid.5700705. PMID 17255960.
  • Olsen SK, Ibrahimi OA, Raucci A, Zhang F, Eliseenkova AV, Yayon A, Basilico C, Linhardt RJ, Schlessinger J, Mohammadi M (January 2004). "Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity". Proceedings of the National Academy of Sciences of the United States of America. 101 (4): 935–40. doi:10.1073/pnas.0307287101. PMC 327120. PMID 14732692.

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