The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR. 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.
The three immunoglobin(Ig)-like domains—D1, D2, and D3—present a stretch of acidicamino acids ("the acid box") between D1 and D2. 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). FGF7, however, can only activate FGFR2b, and FGF18 was recently shown to activate FGFR3.
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. The FGFRs are known to dimerize as heterodimers and homodimers.
So far, five distinct membrane FGFR have been identified in vertebrates and all of them belong to the tyrosine kinase superfamily (FGFR1 to FGFR4).
The FGF/FGFR signalling pathway is involved in a variety of cancers.
There are non-selective FRFR inhibitors that act on all of FGFR1-4 and other proteins, and some selective FGFR inhibitors for some/all of FGFR1-4. Selective FGFR inhibitors include AZD4547, BGJ398, JNJ42756493, and PD173074.
Many FGFR inhibitors are in early clinical trials as a cancer treatment.