Fibroblast growth factor receptor explained

The fibroblast growth factor receptors (FGFR) are, as their name implies, receptors that bind to members of the fibroblast growth factor (FGF) 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).

• (see also Fibroblast growth factor receptor 1) (= CD331)
• (see also Fibroblast growth factor receptor 2) (= CD332)
• (see also Fibroblast growth factor receptor 3) (= CD333)
• (see also Fibroblast growth factor receptor 4) (= CD334)
• (see also Fibroblast growth factor receptor-like 1)

As a drug target

The FGF/FGFR signalling pathway is involved in a variety of cancers.^[9]

There are non-selective FGFR inhibitors that act on all of FGFR1-4 and other proteins, and some selective FGFR inhibitors for some/all of FGFR1-4.^[10] Selective FGFR inhibitors include AZD4547, BGJ398, JNJ42756493, and PD173074.^[10]

External links

• GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes
• FGF signaling (with refs)

Notes and References

1. Ornitz DM, Itoh N . Fibroblast growth factors . Genome Biology . 2 . 3 . REVIEWS3005 . 2001 . 11276432 . 138918 . 10.1186/gb-2001-2-3-reviews3005 . free .
2. Belov AA, Mohammadi M . Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology . Cold Spring Harbor Perspectives in Biology . 5 . 6 . a015958 . June 2013 . 23732477 . 3660835 . 10.1101/cshperspect.a015958 .
3. Duchesne L, Tissot B, Rudd TR, Dell A, Fernig DG . N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding . The Journal of Biological Chemistry . 281 . 37 . 27178–89 . September 2006 . 16829530 . 10.1074/jbc.M601248200 . free .
4. Coutts JC, Gallagher JT . Receptors for fibroblast growth factors . Immunology and Cell Biology . 73 . 6 . 584–9 . December 1995 . 8713482 . 10.1038/icb.1995.92 .
5. Kalinina J, Dutta K, Ilghari D, Beenken A, Goetz R, Eliseenkova AV, Cowburn D, Mohammadi M . 6 . The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition . Structure . 20 . 1 . 77–88 . January 2012 . 22244757 . 3378326 . 10.1016/j.str.2011.10.022 .
6. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M . 6 . Receptor specificity of the fibroblast growth factor family . The Journal of Biological Chemistry . 271 . 25 . 15292–7 . June 1996 . 8663044 . 10.1074/jbc.271.25.15292 . free .
7. Davidson D, Blanc A, Filion D, Wang H, Plut P, Pfeffer G, Buschmann MD, Henderson JE . 6 . Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis . The Journal of Biological Chemistry . 280 . 21 . 20509–15 . May 2005 . 15781473 . 10.1074/jbc.M410148200 . free .
8. Sleeman M, Fraser J, McDonald M, Yuan S, White D, Grandison P, Kumble K, Watson JD, Murison JG . 6 . Identification of a new fibroblast growth factor receptor, FGFR5 . Gene . 271 . 2 . 171–82 . June 2001 . 11418238 . 10.1016/S0378-1119(01)00518-2 .
9. Porta R, Borea R, Coelho A, Khan S, Araújo A, Reclusa P, Franchina T, Van Der Steen N, Van Dam P, Ferri J, Sirera R, Naing A, Hong D, Rolfo C . 6 . FGFR a promising druggable target in cancer: Molecular biology and new drugs . Critical Reviews in Oncology/Hematology . 113 . 256–267 . May 2017 . 28427515 . 10.1016/j.critrevonc.2017.02.018 . 10447/238074 . free .
10. Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, Matsangou M, Costa R, Carneiro B, Villaflor VM, Cristofanilli M, Giles FJ . 6 . Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application . Oncotarget . 8 . 9 . 16052–16074 . February 2017 . 28030802 . 5362545 . 10.18632/oncotarget.14109 .