Fibroblast growth factor receptor
The fibroblast growth factor receptors are, as their name implies, receptors that bind to members of the fibroblast growth factor family of proteins. Some of these receptors are involved in pathological conditions. For example, a point mutation in FGFR3 can lead to achondroplasia.
Structure
The fibroblast growth factor receptors consist of an extracellular ligand domain composed of three immunoglobulin-like domains, a single transmembrane helix domain, and an intracellular domain with tyrosine kinase activity. These receptors bind fibroblast growth factors, members of the largest family of growth factor ligands, comprising 22 members.[1][2]
The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR.[3] These isoforms vary in their ligand-binding properties and kinase domains, however all share the common extracellular region composed of three immunoglobulin(Ig)-like domains (D1-D3), and thus belong to the immunoglobulin superfamily.[4]
The three immunoglobin(Ig)-like domains - D1, D2, and D3 - present a stretch of acidic amino acids ("the acid box") between D1 and D2.[5] This "acid box" can participate in the regulation of FGF binding to the FGFR. Immunoglobulin-like domains D2 and D3 are sufficient for FGF binding. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor (i.e., FGF1, which binds all seven principal FGFRs[6]). FGF7, however, can only activate FGFR2b,[3] and FGF18 was recently shown to activate FGFR3.[7]
A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic tyrosine kinase domain and one isoform, FGFR5γ, and only contains the extracellular domains D1 and D2.[8] The FGFRs are known to dimerize as heterodimers and homodimers.
Genes
So far, five distinct membrane FGFR have been identified in vertebrates and all of them belong to the tyrosine kinase superfamily (FGFR1 to FGFR4).
- FGFR1 (see also Fibroblast growth factor receptor 1) (= CD331)
- FGFR2 (see also Fibroblast growth factor receptor 2) (= CD332)
- FGFR3 (see also Fibroblast growth factor receptor 3) (= CD333)
- FGFR4 (see also Fibroblast growth factor receptor 4) (= CD334)
- FGFRL1 (see also Fibroblast growth factor receptor-like 1)
- FGFR6
References
- ↑ Ornitz DM.; Itoh, N. (2001). "Fibroblast growth factors". Genome Biol. 2 (3): REVIEWS 3005. doi:10.1186/gb-2001-2-3-reviews3005. PMC 138918
. PMID 11276432. - ↑ Belov AA, Mohammadi M (June 2013). "Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology". Cold Spring Harbor Perspectives in Biology. 5 (6). doi:10.1101/cshperspect.a015958. PMID 23732477.
- 1 2 Duchesne L, Tissot B, et al. (2006). "N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding". J. Biol. Chem. 281 (37): 27178–27189. doi:10.1074/jbc.M601248200. PMID 16829530.
- ↑ Coutts JC, Gallagher JT (1995). "Receptors for fibroblast growth factors". Immunol. Cell. Biol. 73 (6): 584–589. doi:10.1038/icb.1995.92. PMID 8713482.
- ↑ Kalinina J, Dutta K, Ilghari D, Beenken A, Goetz R, Eliseenkova AV, Cowburn D, Mohammadi M (January 2012). "The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition". Structure (London, England : 1993). 20 (1): 77–88. doi:10.1016/j.str.2011.10.022. PMC 3378326. PMID 22244757.
- ↑ Ornitz DM; et al. (1996). "Receptor Specificity of the Fibroblast Growth Factor Family". J. Biol. Chem. 271 (25): 15292–15297. doi:10.1074/jbc.271.25.15292. PMID 8663044.
- ↑ Davidson, D.; Blanc, A.; Filion, D.; Wang, H.; Plut, P.; Pfeffer, G.; Buschmann, M. D.; Henderson, J. E. (2005). "Fibroblast Growth Factor (FGF) 18 Signals through FGF Receptor 3 to Promote Chondrogenesis". Journal of Biological Chemistry. 280 (21): 20509–20515. doi:10.1074/jbc.M410148200. PMID 15781473.
- ↑ Sleeman M, Fraser J, et al. (2001). "Identification of a new fibroblast growth factor receptor, FGFR5". Gene. 271 (2): 171–182. doi:10.1016/S0378-1119(01)00518-2. PMID 11418238.