FGF signalling: A mechanism on the way of being decipherered

Fibroblast growth factors (FGF) are encoded by at least nine distinct genes. They share a broad spectrum of biological functions and appear to be involved in various physiopathological processes including tumor development, atherogenesis, neurodegenerative diseases, neovascularization and genetic disorders. Signalling by FGF is mainly mediated through binding to both high-affinity tyrosine kinase receptors and low-affinity heparan sulfate proteoglycans associated with plasma membrane and extracellular matrix. Matrix proteoglycans appear to act as a storage depot or sink for FGF, whereas membrane proteoglycans function as co-receptors and facilitate signalling by the high-affinity receptors. Four genes encoding tyrosine kinase receptors have been identified, but alternative splicing produces multiple isoforms, some of which are putative secreted receptors. Signal transduction of tyrosine kinase receptors involves dimerization and autophosphorylation which mediate the activation of a myriad of signalling proteins and second-messengers, leading to changes in gene expression. However, there is mounting evidence to suggest that these receptors may not he sufficient for all aspects of FGF signalling: The fact that the nuclear localization of FGF(1), FGF(2) and FGF(3) is found to be regulated in parallel with mitogenesis and differentiation, indeed, supports also a potential role for FGF in the direct regulation of transcription, replication or other nuclear events.