Downstream signaling triggered by the binding of fibroblast growth factor-2 (FGF2) to its tyrosine-kinase receptors involves the activation of mitogen-activated protein kinase kinase (MEK) with consequent phosphorylation of extracellular signal-regulated kinases

Basic fibroblast growth factor (FGF2) belongs to the family of the heparin-binding growth factors (Basilico and Moscatelli, 1992). The single copy human FGF2 gene encodes multiple FGF2 isoforms with Mr ranging from 24,000 to 18,000 (Florkiewicz and Sommer, 1989). FGF2 isoforms are angiogenic in vivo and induce cell proliferation, protease production and chemotaxis in endothelial cells in vitro (Gualandris et al., 1994). FGF2 stimulates endothelial cells to form capillary-like structures in collagen gels (Montesano et al., 1986) and to invade the amniotic membrane in vitro (Mignatti et al., 1989). Also, the phenotype induced by FGF2 in endothelial cell cultures includes modulation of integrin expression (Klein et al., 1993), gap-junctional intercellular communication (Pepper and Meda, 1992) and urokinase receptor upregulation (Mignatti et al., 1991). FGF2 exerts its activity on target cells by interacting with specific tyrosine-kinase receptors (FGFRs) and heparan sulfate proteoglycans (HSPGs) of the cell surface (Johnson and Williams, 1993). Following ligand binding, tyrosine-kinase receptors dimerize and undergo autophosphorylation. Phosphorylated tyrosines serve as docking sites for downstream signal transduction molecules containing either Src-homology 2 or phosphotyrosine-binding domains (Pawson, 1995). Thus, the capacity of growth factors to exert an array of biological responses on the same cell type is thought to reflect the 2597 Journal of Cell Science 112, 2597-2606 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 JCS0413