The FGFR Receptor Family

Fibroblast Growth Factors (FGFs), in a complex with their receptors (FGFRs) and heparan sulphate (HS), impact on a wide range of cellular functions, regulating processes from embryogenesis to metabolism. Upon ligand binding and receptor dimerisation, four key downstream pathways are initiated: MAPK, PI3K/AKT, STAT and PLCγ. Regulation of FGF signalling is critical to ensure a balanced response to receptor stimulation. This occurs through negative feedback mechanisms, including internalisation, cleavage and induction of negative regulators. FGF signalling has been studied in depth by developmental biologists, in a variety of model systems, and plays a critical role in developmental patterning and the establishment of paracrine signalling loops. Both germ line and somatic FGFR mutations are known to play a role in a range of diseases, most notably developmentally regulated diseases such as craniosynostosis dysplasias, dwarfism and hearing loss. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival, FGFRs are readily co-opted by cancer cells. Mutations in, and amplifications of, these receptors are found in a range of cancers. Here, we outline the molecular mechanisms of FGFR signalling and discuss the role of this pathway in development and disease. We also address the rationale for therapeutic intervention and the need for FGFR-targeted therapy to selectively target cancer cells in view of the fundamental roles of FGF signalling in normal physiology.