Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein

Fibroblast growth factor-binding protein (FGF-BP) I is a secreted protein t hat can bind fibroblast growth factors (FGFs) 1 and 2. These FGFs are typic ally stored on heparan sulfate proteoglycans in the extracellular matrix in an inactive form, and it has been proposed that FGF-BP1 functions as a cha perone molecule that can mobilize locally stored FGF and present the growth factor to its tyrosine kinase receptor. FGF-BP1 is upregulated in squamous cell, colon, and breast cancers and can act as an angiogenic switch during malignant progression of epithelial cells. For the present studies, we foc used on FGF-1 and -2 and investigated interactions with recombinant human F GF-BP1 protein as well as effects on signal transduction, cell proliferatio n, and angiogenesis. We show that recombinant FGF-BP1 specifically binds FG F-2 and that this binding is inhibited by FGF-1, heparan sulfate, and hepar inoids. Furthermore, FGF-BP1 enhances FGF-1- and FGF-2-dependent proliferat ion of NIH-3T3 fibroblasts and FGF-2-induced extracellular signal-regulated kinase 2 phosphorylation. Finally, in the chicken chorioallantoic membrane angiogenesis assay, FGF-BP1 synergizes with exogenously added FGF-2. We co nclude that FGF-BP1 binds directly to FGF-1 and FGF-2 and positively modula tes the biological activities of these growth factors.