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Gene Review

FGFR3  -  fibroblast growth factor receptor 3

Homo sapiens

Synonyms: ACH, CD333, CEK2, FGFR-3, Fibroblast growth factor receptor 3, ...
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Disease relevance of FGFR3


Psychiatry related information on FGFR3


High impact information on FGFR3

  • We show, in mice and humans, that a core ACH is developmentally conserved and consists of the hypersensitive sites (HS1-HS6) of the locus control region (LCR), the upstream 5' HS-60/-62 and downstream 3' HS1 [9].
  • Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas [10].
  • The abnormal phenotypes of the Hspg2-/- skeleton are similar to those of thanatophoric dysplasia (TD) type I, which is caused by activating mutations in FGFR3 (refs 7, 8, 9), and to those of Fgfr3 gain-of-function mice [11].
  • The chromosome-4 breakpoints are clustered in a 70-kb region centromeric to the fibroblast growth factor receptor 3 gene (FGFR3), the apparent dysregulated oncogene [12].
  • Interestingly, this common mutation occurs precisely at the analogous position within the FGFR3 protein as the mutations in FGFR1 (Pro252Arg) and FGFR2 (Pro253Arg) previously reported in Pfeiffer and Apert syndromes, respectively [13].

Chemical compound and disease context of FGFR3


Biological context of FGFR3

  • Furthermore, expression of TDII FGFR3 induced nuclear translocation of Stat1, expression of the cell-cycle inhibitor p21(WAF1/CIP1), and growth arrest of the cell [19].
  • Overexpression of mutant FGFR3 resulted in IL-6 independence, decreased apoptosis, and an enhanced proliferative response to IL-6 [2].
  • Mutations in the fibroblast growth factor receptor (FGFR) gene family recently have been shown to underlie several hereditary disorders of bone development, with specific FGFR3 mutations causing achondroplasia (Ach) and thanatophoric dysplasia (TD) [20].
  • B9 clones expressing either wild-type FGFR3 at high levels or mutant FGFR3 displayed increased phosphorylation of STAT3 and higher levels of bcl-x(L) expression than did parental B9 cells after cytokine withdrawal [2].
  • The variant domain corresponded precisely to the splicing junctions of the exon encoding the carboxyl terminal half of the third immunoglobulin-like domain, suggesting that two forms of FGFR3 result from splicing of alternate exons in a manner similar to that previously found for FGFR1 and FGFR2 [21].

Anatomical context of FGFR3


Associations of FGFR3 with chemical compounds


Physical interactions of FGFR3

  • Activated FGFR3 predominantly interacts with GRB2.Sos in complex with a previously identified 90-kDa protein and designated protein 80K-H [28].
  • Three different progression pathways were proposed: The first operative pathway is from dysplasia to superficial papillary pathologic Ta (pTa) tumors to pT1 tumors and, ultimately, to pT2 tumors with FGFR3 and tuberous sclerosis complex 1 (TSC1) the responsible genes [29].

Regulatory relationships of FGFR3

  • FGFRs 1 and 3, thought to negatively regulate chondrogenesis, were expressed at greater levels and at later stages of chondrocyte differentiation, with FGFR1 upregulated in the hypertrophic zone and FGFR3 upregulated in both proliferative and hypertrophic zones [30].
  • However, only FGFR3 induced STAT1 phosphorylation that mediates the transcriptional induction of p21(CIP1), although both FGFR3 isoforms could induce a strong activation of mitogen-activated protein (MAP) kinases [31].
  • CONCLUSIONS: Our data suggest that excessive activation of signaling cascades mediated by the FGFR3 mutants inhibits the expression of PTHrP and Bcl-2, resulting in apoptosis of chondrocytes, possibly leading to short-limb dwarfism [32].
  • In this study, to clarify the mechanism by which GH treatment improved the phenotype of ACH patients, we examined the possible effects of IGF-1 on an apoptosis induced by FGFR3 mutant in ATDC5 [33].
  • The t(4;14)(p16.3;q32) translocation that occurs uniquely in a subset of multiple myeloma tumors results in ectopic expression of wild-type FGFR3 and enhanced expression of MMSET, a gene that is homologous to the MLL gene that is involved in acute myeloid leukemias [34].

Other interactions of FGFR3


Analytical, diagnostic and therapeutic context of FGFR3


  1. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Meyers, G.A., Orlow, S.J., Munro, I.R., Przylepa, K.A., Jabs, E.W. Nat. Genet. (1995) [Pubmed]
  2. Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Plowright, E.E., Li, Z., Bergsagel, P.L., Chesi, M., Barber, D.L., Branch, D.R., Hawley, R.G., Stewart, A.K. Blood (2000) [Pubmed]
  3. Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors. Funato, N., Ohtani, K., Ohyama, K., Kuroda, T., Nakamura, M. Mol. Cell. Biol. (2001) [Pubmed]
  4. Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Tomlinson, D.C., Hurst, C.D., Knowles, M.A. Oncogene (2007) [Pubmed]
  5. Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis. Reardon, W., Wilkes, D., Rutland, P., Pulleyn, L.J., Malcolm, S., Dean, J.C., Evans, R.D., Jones, B.M., Hayward, R., Hall, C.M., Nevin, N.C., Baraister, M., Winter, R.M. J. Med. Genet. (1997) [Pubmed]
  6. A simple and fast method for the simultaneous detection of nine fibroblast growth factor receptor 3 mutations in bladder cancer and voided urine. van Oers, J.M., Lurkin, I., van Exsel, A.J., Nijsen, Y., van Rhijn, B.W., van der Aa, M.N., Zwarthoff, E.C. Clin. Cancer Res. (2005) [Pubmed]
  7. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Shiang, R., Thompson, L.M., Zhu, Y.Z., Church, D.M., Fielder, T.J., Bocian, M., Winokur, S.T., Wasmuth, J.J. Cell (1994) [Pubmed]
  8. Distribution of fibroblast growth factor receptor-1 (FGFR-1) and FGFR-3 in the hippocampus of patients with Alzheimer's disease. Ferrer, I., Martí, E. Neurosci. Lett. (1998) [Pubmed]
  9. The beta-globin nuclear compartment in development and erythroid differentiation. Palstra, R.J., Tolhuis, B., Splinter, E., Nijmeijer, R., Grosveld, F., de Laat, W. Nat. Genet. (2003) [Pubmed]
  10. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Cappellen, D., De Oliveira, C., Ricol, D., de Medina, S., Bourdin, J., Sastre-Garau, X., Chopin, D., Thiery, J.P., Radvanyi, F. Nat. Genet. (1999) [Pubmed]
  11. Perlecan is essential for cartilage and cephalic development. Arikawa-Hirasawa, E., Watanabe, H., Takami, H., Hassell, J.R., Yamada, Y. Nat. Genet. (1999) [Pubmed]
  12. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Chesi, M., Nardini, E., Brents, L.A., Schröck, E., Ried, T., Kuehl, W.M., Bergsagel, P.L. Nat. Genet. (1997) [Pubmed]
  13. Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Bellus, G.A., Gaudenz, K., Zackai, E.H., Clarke, L.A., Szabo, J., Francomano, C.A., Muenke, M. Nat. Genet. (1996) [Pubmed]
  14. The cytoplasmic tyrosine kinase Pyk2 as a novel effector of fibroblast growth factor receptor 3 activation. Meyer, A.N., Gastwirt, R.F., Schlaepfer, D.D., Donoghue, D.J. J. Biol. Chem. (2004) [Pubmed]
  15. Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients. Benoist-Lasselin, C., de Margerie, E., Gibbs, L., Cormier, S., Silve, C., Nicolas, G., LeMerrer, M., Mallet, J.F., Munnich, A., Bonaventure, J., Zylberberg, L., Legeai-Mallet, L. Bone (2006) [Pubmed]
  16. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Bellus, G.A., Hefferon, T.W., Ortiz de Luna, R.I., Hecht, J.T., Horton, W.A., Machado, M., Kaitila, I., McIntosh, I., Francomano, C.A. Am. J. Hum. Genet. (1995) [Pubmed]
  17. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Rousseau, F., el Ghouzzi, V., Delezoide, A.L., Legeai-Mallet, L., Le Merrer, M., Munnich, A., Bonaventure, J. Hum. Mol. Genet. (1996) [Pubmed]
  18. FGFR3 P250R mutation increases the risk of reoperation in apparent 'nonsyndromic' coronal craniosynostosis. Thomas, G.P., Wilkie, A.O., Richards, P.G., Wall, S.A. The Journal of craniofacial surgery. (2005) [Pubmed]
  19. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Su, W.C., Kitagawa, M., Xue, N., Xie, B., Garofalo, S., Cho, J., Deng, C., Horton, W.A., Fu, X.Y. Nature (1997) [Pubmed]
  20. Mutations causing achondroplasia and thanatophoric dysplasia alter bFGF-induced calcium signals in human diploid fibroblasts. Nguyen, H.B., Estacion, M., Gargus, J.J. Hum. Mol. Genet. (1997) [Pubmed]
  21. Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFR3 IIIb) in human colonic epithelium. Murgue, B., Tsunekawa, S., Rosenberg, I., deBeaumont, M., Podolsky, D.K. Cancer Res. (1994) [Pubmed]
  22. Transforming property of TEL-FGFR3 mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML. Maeda, T., Yagasaki, F., Ishikawa, M., Takahashi, N., Bessho, M. Blood (2005) [Pubmed]
  23. Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation. Hart, K.C., Robertson, S.C., Donoghue, D.J. Mol. Biol. Cell (2001) [Pubmed]
  24. A novel alternatively spliced fibroblast growth factor receptor 3 isoform lacking the acid box domain is expressed during chondrogenic differentiation of ATDC5 cells. Shimizu, A., Tada, K., Shukunami, C., Hiraki, Y., Kurokawa, T., Magane, N., Kurokawa-Seo, M. J. Biol. Chem. (2001) [Pubmed]
  25. Comparative localization of fibroblast growth factor receptor-1, -2, and -3 mRNAs in the rat brain: in situ hybridization analysis. Belluardo, N., Wu, G., Mudo, G., Hansson, A.C., Pettersson, R., Fuxe, K. J. Comp. Neurol. (1997) [Pubmed]
  26. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. Webster, M.K., Donoghue, D.J. EMBO J. (1996) [Pubmed]
  27. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Toydemir, R.M., Brassington, A.E., Bayrak-Toydemir, P., Krakowiak, P.A., Jorde, L.B., Whitby, F.G., Longo, N., Viskochil, D.H., Carey, J.C., Bamshad, M.J. Am. J. Hum. Genet. (2006) [Pubmed]
  28. Signal transduction pathway of human fibroblast growth factor receptor 3. Identification of a novel 66-kDa phosphoprotein. Kanai, M., Göke, M., Tsunekawa, S., Podolsky, D.K. J. Biol. Chem. (1997) [Pubmed]
  29. Genetic alterations in urothelial bladder carcinoma: an updated review. Mhawech-Fauceglia, P., Cheney, R.T., Schwaller, J. Cancer (2006) [Pubmed]
  30. Fibroblast growth factor expression in the postnatal growth plate. Lazarus, J.E., Hegde, A., Andrade, A.C., Nilsson, O., Baron, J. Bone (2007) [Pubmed]
  31. FGFR3 isoforms have distinct functions in the regulation of growth and cell morphology. Shimizu, A., Takashima, Y., Kurokawa-Seo, M. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  32. PTHrP rescues ATDC5 cells from apoptosis induced by FGF receptor 3 mutation. Yamanaka, Y., Tanaka, H., Koike, M., Nishimura, R., Seino, Y. J. Bone Miner. Res. (2003) [Pubmed]
  33. Insulin-like growth factor-1 rescues the mutated FGF receptor 3 (G380R) expressing ATDC5 cells from apoptosis through phosphatidylinositol 3-kinase and MAPK. Koike, M., Yamanaka, Y., Inoue, M., Tanaka, H., Nishimura, R., Seino, Y. J. Bone Miner. Res. (2003) [Pubmed]
  34. The enigma of ectopic expression of FGFR3 in multiple myeloma: a critical initiating event or just a target for mutational activation during tumor progression. Chesi, M., Bergsagel, P.L., Kuehl, W.M. Curr. Opin. Hematol. (2002) [Pubmed]
  35. Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation. Yagasaki, F., Wakao, D., Yokoyama, Y., Uchida, Y., Murohashi, I., Kayano, H., Taniwaki, M., Matsuda, A., Bessho, M. Cancer Res. (2001) [Pubmed]
  36. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Hart, K.C., Robertson, S.C., Kanemitsu, M.Y., Meyer, A.N., Tynan, J.A., Donoghue, D.J. Oncogene (2000) [Pubmed]
  37. Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling. Ben-Zvi, T., Yayon, A., Gertler, A., Monsonego-Ornan, E. J. Cell. Sci. (2006) [Pubmed]
  38. The expression of fibroblast growth factors and their receptors in Hodgkin's lymphoma. Khnykin, D., Troen, G., Berner, J.M., Delabie, J. J. Pathol. (2006) [Pubmed]
  39. Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation. Martínez-Torrecuadrada, J., Cifuentes, G., López-Serra, P., Saenz, P., Martínez, A., Casal, J.I. Clin. Cancer Res. (2005) [Pubmed]
  40. Synovial chondromatosis: the possible role of FGF 9 and FGF receptor 3 in its pathology. Robinson, D., Hasharoni, A., Evron, Z., Segal, M., Nevo, Z. International journal of experimental pathology. (2000) [Pubmed]
  41. Basic fibroblast growth factor activates ERK and induces c-fos in human embryonic stem cell line MizhES1. Kang, H.B., Kim, J.S., Kwon, H.J., Nam, K.H., Youn, H.S., Sok, D.E., Lee, Y. Stem cells and development. (2005) [Pubmed]
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