Summary

Fibroblast growth factor receptors (FGFRs) are members of the receptor tyrosine kinase family which consists of four structurally related members: FGFR 1, 2, 3, 4, and their alternatively spliced variants. Each receptor contains two to three immunoglobulin (Ig)-like domains in the extracellular region, an acidic box between Ig-1 and Ig-2, a transmembrane domain, and a split intracellular tyrosine kinase domain (Fig. 1). Normal activation of FGFRs relies on interaction with their ligands: fibroblast growth factors (FGFs). At least 22 FGFs are known to date, and each FGFR member interacts with a specific subset of FGFs, as summarized in Fig. 1 (reviewed in [38] and reviewed in [11]). Heparan sulfate proteoglycans facilitate FGF binding with FGFR to induce FGFR dimerization and activation [44]. Crystal structure analyses have indicated that heparin binds to two FGFs such that the FGFs are not directly interacting with each other, and that each FGF is binding to an FGFR (reviewed in [19]). Another study has shown, however, that the heparin-FGF monomer alone can activate FGFR dimerization [39]. After ligand stimulation, FGFRs undergo dimerization and autotyrosine phosphorylation, resulting in kinase activation. The phosphorylated tyrosine residues may then serve as binding sites for secondary signaling molecules.