Signaling, Internalization, and Intracellular Activity of Fibroblast Growth Factor

Abstract The fibroblast growth factor (FGF) family contains 23 members in mammals including its prototype members FGF-1 and FGF-2. FGFs have been implicated in regulation of many key cellular responses involved in developmental and physiological processes. These includes proliferation, differentiation, migration, apoptosis, angiogenesis, and wound healing. FGFs bind to five related, specific cell surface receptors (FGFRs). Four of these have intrinsic tyrosine kinase activity. Dimerization of the receptor is a prerequisite for receptor transphosphorylation and activation of downstream signaling molecules. All members of the FGF family have a high affinity for heparin and for cell surface heparan sulfate proteoglycans, which participate in formation of stable and active FGF-FGFR complexes. FGF-mediated signaling is an evolutionarily conserved signaling module operative in invertebrates and vertebrates. It seems that some members of the family have a dual mode of action. FGF-1, FGF-2, FGF-3, and FGF-11-14 have been found intranuclearly as endogenous proteins. Exogenous FGF-1 and FGF-2 are internalized by receptor -mediated endocytosis, in a clathrin-dependent and -independent way. Internalized FGF-1 and FGF-2 are able to cross cellular membranes to reach the cytosol and the nuclear compartment. The role of FGF internalization and the intracellular activity of some FGFs are discussed in the context of the known signaling induced by FGF.