HEPARIN-INDUCED OLIGOMERIZATION OF FGF MOLECULES IS RESPONSIBLE FOR FGF RECEPTOR DIMERIZATION, ACTIVATION, AND CELL-PROLIFERATION

Heparin is required for fibroblast growth factor (FGF) stimulation of biological responses. Using isothermal titration calorimetry, we show that acidic FGF (aFGF) forms a 1:1 complex with the soluble extracellu lar domain of FGF receptor (FGFR). Heparin exerts its effect by bindin g to many molecules of aFGF. The resulting aFGF-heparin complex can bi nd to several receptor molecules, leading to FGFR dimerization. In two cell lines lacking endogenous heparan sulfate, exogenous heparin is r equired for FGFR dimerization, tyrosine kinase activation, c-fos mRNA transcription, and cell proliferation. Moreover, a synthetic heparin a nalog that binds monovalently to aFGF blocks FGFR dimerization, activa tion, and signaling via FGFR. We propose that heparin causes oligomeri zation of aFGF such that its binding to FGFR results in dimerization a nd activation. This represents a novel mechanism for transmembrane sig naling and may account for the action of many heparin-bound growth fac tors.