[{"@context":"http:\/\/schema.org\/","@type":"BlogPosting","@id":"https:\/\/wiki.edu.vn\/en\/wiki40\/fibroblast-growth-factor-receptor-3\/#BlogPosting","mainEntityOfPage":"https:\/\/wiki.edu.vn\/en\/wiki40\/fibroblast-growth-factor-receptor-3\/","headline":"Fibroblast growth factor receptor 3","name":"Fibroblast growth factor receptor 3","description":"Gene involved in the most common form of dwarfism Fibroblast growth factor receptor 3 is a protein that in humans","datePublished":"2016-02-18","dateModified":"2016-02-18","author":{"@type":"Person","@id":"https:\/\/wiki.edu.vn\/en\/wiki40\/author\/lordneo\/#Person","name":"lordneo","url":"https:\/\/wiki.edu.vn\/en\/wiki40\/author\/lordneo\/","image":{"@type":"ImageObject","@id":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","url":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","height":96,"width":96}},"publisher":{"@type":"Organization","name":"Enzyklop\u00e4die","logo":{"@type":"ImageObject","@id":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","url":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","width":600,"height":60}},"image":{"@type":"ImageObject","@id":"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/b\/b9\/PDB_1ry7_EBI.jpg\/180px-PDB_1ry7_EBI.jpg","url":"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/b\/b9\/PDB_1ry7_EBI.jpg\/180px-PDB_1ry7_EBI.jpg","height":"135","width":"180"},"url":"https:\/\/wiki.edu.vn\/en\/wiki40\/fibroblast-growth-factor-receptor-3\/","about":["Wiki"],"wordCount":8961,"articleBody":"Gene involved in the most common form of dwarfismFibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene.[5] FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location q16.3, 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 responsible for multiple growth factor interactions.[7] Gain of function mutations in FGFR3 inhibits chondrocyte proliferation and underlies achondroplasia and hypochondroplasia.Table of ContentsFunction[edit]Mutations[edit]Disease linkage[edit]Bladder cancer[edit]Glioblastoma[edit]Achondroplasia[edit]Thanatophoric dysplasia[edit]Muenke syndrome[edit]As a drug target[edit]Interactions[edit]See also[edit]References[edit]Further reading[edit]External links[edit]Function[edit]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 influence 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[edit]Simplification on the mutation 46 XX 4q16.3 (female), 46XY 4q16.3 (male).Gain of function 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).In achondroplasia, the FGFR3 gene has a missense mutation at nucleotide 1138 resulting from either a G>A or G>C.[9] This point mutation in the FGFR3 gene causes hydrogen bonds to form between two arginine side chains leading to ligand-independent stabilization of FGFR3 dimers. Overactivity of FGFR3 inhibits chondrocyte proliferation and restricts long bone length.[7]FGFR3 mutations are also linked with spermatocytic tumor, which occur more frequently in older men.[10]Disease linkage[edit]Defects in the FGFR3 gene has been associated with several conditions, including craniosynostosis and  seborrheic keratosis.[11]Bladder cancer[edit]Mutations of FGFR3, FGFR3\u2013TACC3 and FGFR3\u2013BAIAP2L1 fusion proteins are frequently associated with bladder cancer, while some FGFR3 mutations are also associated with a better prognosis.  Hence FGFR3 represents a potential therapeutic target for the treatment of bladder cancer.[12]Post-translational modification of FGFR3 occur in bladder cancer that do not occur in normal cells and can be targeted by immunotherapeutic antibodies.[13]Glioblastoma[edit]FGFR3-TACC3 fusions have been identified as the primary mitogenic drivers in a subset of glioblastomas (approximately 4%) and other gliomas and may be associated with slightly improved overall survival.[14] The FGFR3-TACC3 fusion represents a possible therapeutic target in glioblastoma.Achondroplasia[edit]Achondroplasia is a dominant genetic disorder caused by mutations in FGFR3 that make the resulting protein overactive. Individuals with these mutation have a head size that is larger than normal and are significantly shorter in height.[15][16] Only a single copy of the mutated FGFR3 gene results in achondroplasia.[17]  It is generally caused by spontaneous mutations in germ cells; roughly 80 percent of the time, parents with children that have this disorder are normal size.[16][17]Thanatophoric dysplasia[edit]Thanatophoric dysplasia is a genetic disorder caused by gain-of-function mutations in FGFR3 that is often fatal during the perinatal period because the child cannot breathe.[18][19]   There are two types.  TD type I is caused by a stop codon mutation that is located in part of the gene coding for the extracellular domain of the protein.[18] TD type II is a result of a substitution in a Lsy650Glu which is located in the tyrosine kinase area of FGFR3.[18]Muenke syndrome[edit]Muenke syndrome, a disorder characterized by craniosynostosis, is caused by protein changes on FGFR3. The specific pathogenic variant c.749C>G changes the protein p.Pro250Arg, in turn resulting in this condition.[20] Characteristics of Muenke syndrome include coronal synostosis (usually bilateral), midfacial retrusion, strabismus, hearing loss, and developmental delay. Turribrachycephaly, cloverleaf skull, and frontal bossing are also possible.[21]As a drug target[edit]FGFR3 inhibitors are in early clinical trials as a cancer treatment,[citation needed] eg. BGJ398 for urothelial carcinoma.[22] The FGFR3 receptor has a tyrosine kinase signaling pathway that is associated with many biological developments embryonically and in tissues.[citation needed]  Studying the tyrosine kinase signaling pathway that FGFR3 displays has played a crucial role in the development of research of several cell activities such as cell proliferation and cellular resistance to anti-cancer medications.[citation needed]Interactions[edit]Fibroblast growth factor receptor 3 has been shown to interact with FGF8[23][24] and FGF9.[23][24]See also[edit]References[edit]^ a b c GRCh38: Ensembl release 89: ENSG00000068078 – Ensembl, May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000054252 – Ensembl, May 2017^ “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.^ “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.^ 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\u20139. Bibcode:1991PNAS…88.1095K. doi:10.1073\/pnas.88.4.1095. PMC\u00a050963. PMID\u00a01847508.^ a b 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\u201350. doi:10.5582\/irdr.2013.v2.2.45. PMC\u00a04204580. PMID\u00a025343101.^ a b c “FGFR3 gene”. Genetics Home Reference. U.S. National Library of Medicine. Retrieved 2018-09-27.^ “Entrez Gene: FGFR3 fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)”.^ Foldynova-Trantirkova S, Wilcox WR, Krejci P (January 2012). “Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias”. Human Mutation. 33 (1): 29\u201341. doi:10.1002\/humu.21636. PMC\u00a03240715. PMID\u00a022045636.^ Kelleher FC, O’Sullivan H, Smyth E, McDermott R, Viterbo A (October 2013). “Fibroblast growth factor receptors, developmental corruption and malignant disease”. Carcinogenesis. 34 (10): 2198\u2013205. doi:10.1093\/carcin\/bgt254. PMID\u00a023880303.^ 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\u20133. doi:10.1038\/sj.jid.5700772. PMID\u00a017568799.^ di Martino E, Tomlinson DC, Williams SV, Knowles MA (October 2016). “A place for precision medicine in bladder cancer: targeting the FGFRs”. Future Oncology (London, England). 12 (19): 2243\u201363. doi:10.2217\/fon-2016-0042. PMC\u00a05066128. PMID\u00a027381494.^ Oo HZ, Seiler R, Black PC, Daugaard M (October 2018). “Post-translational modifications in bladder cancer: Expanding the tumor target repertoire”. Urologic Oncology. 38 (12): 858\u2013866. doi:10.1016\/j.urolonc.2018.09.001. PMID\u00a030342880. S2CID\u00a053041768.^ Mata, Douglas A.; Benhamida, Jamal K.; Lin, Andrew L.; Vanderbilt, Chad M.; Yang, Soo-Ryum; Villafania, Liliana B.; Ferguson, Donna C.; Jonsson, Philip; Miller, Alexandra M.; Tabar, Viviane; Brennan, Cameron W.; Moss, Nelson S.; Sill, Martin; Benayed, Ryma; Mellinghoff, Ingo K.; Rosenblum, Marc K.; Arcila, Maria E.; Ladanyi, Marc; Bale, Tejus A. (2020). “Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions”. Acta Neuropathologica Communications. 8 (1): 186. doi:10.1186\/s40478-020-01058-6. PMC\u00a07653727. PMID\u00a033168106.^ “Achondroplasia”. Genetic and Rare Diseases Information Center (GARD).^ a b “FGFR3 gene”. Genetics Home Reference. U.S. National Library of Medicine.^ a b “Learning about Achondroplasia”. National Human Genome Research Institute. Retrieved July 15, 2016.^ a b c Karczeski B, Cutting GR (1993).  Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). Thanatophoric Dysplasia. GeneReviews. University of Washington, Seattle. PMID\u00a020301540. Retrieved 2018-11-17.^ Nissenbaum M, Chung SM, Rosenberg HK, Buck BE (August 1977). “Thanatophoric dwarfism. Two case reports and survey of the literature”. Clinical Pediatrics. 16 (8): 690\u20137. doi:10.1177\/000992287701600803. PMID\u00a0872478. S2CID\u00a030837380.^ “Muenke syndrome (Concept Id: C1864436)”. MedGen. NCBI. Retrieved March 18, 2023.^ “Orphanet: Muenke syndrome”. Orphanet. Orphanet. Retrieved March 18, 2023.^ Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, Galsky MD, Wolf J, Dittrich C, Keam B, Delord JP, Schellens JH, Gravis G, Medioni J, Maroto P, Sriuranpong V, Charoentum C, Burris HA, Gr\u00fcnwald V, Petrylak D, Vaishampayan U, Gez E, De Giorgi U, Lee JL, Voortman J, Gupta S, Sharma S, Mortazavi A, Vaughn DJ, Isaacs R, Parker K, Chen X, Yu K, Porter D, Graus Porta D, Bajorin DF (July 2018). “FGFR3 Alterations”. Cancer Discovery. 8 (7): 812\u2013821. doi:10.1158\/2159-8290.CD-18-0229. PMC\u00a06716598. PMID\u00a029848605.^ a b 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\u201331. doi:10.1074\/jbc.271.3.1726. PMID\u00a08576175.^ a b 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\u201394. doi:10.1074\/jbc.274.49.34785. PMID\u00a010574949.Further reading[edit]Duperret EK, Oh SJ, McNeal A, Prouty SM, Ridky TW (2014). “Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors”. Cell Cycle. 13 (10): 1551\u20139. doi:10.4161\/cc.28492. PMC\u00a04050160. PMID\u00a024626198.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\u201391. doi:10.1002\/1096-8628(20010101)98:13.0.CO;2-6. PMID\u00a011426459.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\u20135. doi:10.1023\/A:1020914026829. PMID\u00a012424440. S2CID\u00a07425804.Bonaventure J, Silve C (November 2005). “[Hereditary skeletal dysplasias and FGFR3 and PTHR1 signaling pathways]”. M\u00e9decine\/Sciences. 21 (11): 954\u201361. doi:10.1051\/medsci\/20052111954. PMID\u00a016274647.Hern\u00e1ndez S, Toll A, Baselga E, Rib\u00e9 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\u20136. doi:10.1038\/sj.jid.5700705. PMID\u00a017255960.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\u201340. Bibcode:2004PNAS..101..935O. doi:10.1073\/pnas.0307287101. PMC\u00a0327120. PMID\u00a014732692.External links[edit]This article incorporates text from the United States National Library of Medicine, which is in the public domain.PDB gallery1ry7: Crystal Structure of the 3 Ig form of FGFR3c in complex with FGF1AngiopoietinCNTFEGF (ErbB)FGFFGFR1FGFR2Agonists: ErsoferminFGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22)PaliferminRepiferminSelpercatinibSpriferminTraferminFGFR3FGFR4UnsortedHGF (c-Met)IGFLNGF (p75NTR)PDGFRET (GFL)SCF (c-Kit)TGF\u03b2TrkTrkANegative allosteric modulators: VM-902ATrkBAgonists: 3,7-DHF3,7,8,2′-THF4′-DMA-7,8-DHF7,3′-DHF7,8-DHF7,8,2′-THF7,8,3′-THFAmitriptylineBDNFBNN-20DeoxygeduninDeprenylDiosmetinDMAQ-B1HIOCLM22A-4N-AcetylserotoninNT-3NT-4Norwogonin (5,7,8-THF)R7R13TDP6TrkCVEGFOthersAdditional growth factors: AdrenomedullinColony-stimulating factors (see here instead)Connective tissue growth factor (CTGF)Ephrins (A1, A2, A3, A4, A5, B1, B2, B3)Erythropoietin (see here instead)Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)Glia maturation factor (GMF)Hepatoma-derived growth factor (HDGF)Interleukins\/T-cell growth factors (see here instead)Leukemia inhibitory factor (LIF)Macrophage-stimulating protein (MSP; HLP, HGFLP)Midkine (NEGF2)Migration-stimulating factor (MSF; PRG4)OncomodulinPituitary adenylate cyclase-activating peptide (PACAP)PleiotrophinRenalaseThrombopoietin (see here instead)Wnt signaling proteinsAdditional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)"},{"@context":"http:\/\/schema.org\/","@type":"BreadcrumbList","itemListElement":[{"@type":"ListItem","position":1,"item":{"@id":"https:\/\/wiki.edu.vn\/en\/wiki40\/#breadcrumbitem","name":"Enzyklop\u00e4die"}},{"@type":"ListItem","position":2,"item":{"@id":"https:\/\/wiki.edu.vn\/en\/wiki40\/fibroblast-growth-factor-receptor-3\/#breadcrumbitem","name":"Fibroblast growth factor receptor 3"}}]}]