Potential mechanisms for the regulation of growth factor binding by heparin

Heparin and heparan sulfate proteoglycans (HSPG) bind many soluble growth f actors and this binding is now recognized as an important mechanism for mod ulation of cell activity. Fibroblast growth factor-2 (FGF-2) is one of the best characterized of the heparin-binding growth factors and it has been sh own experimentally that heparin regulation of FGF-2 activity is dependent o n the level of cell HSPG and the concentration of heparin. fn this paper, w e explore, using mathematical modeling, proposed mechanisms for heparin reg ulation and determine how they impact FGF receptor binding. We demonstrate that the experimentally observed receptor binding phenomena can be reproduc ed if cells (1) express heparin-binding cell surface molecules and if eithe r (2) these heparin binding sites are FGFR and bind heparin and FGF-2-hepar in complexes or (3) are surface molecules able to bind FGF-2 and couple wit h FGF-2 receptors to form high-affinity FGF-2-bound surface complexes. The ability of heparin to directly interact with the FGFR and bind FGF-2 in the absence of this coupling function was not sufficient to explain heparin ac tivity. These findings have implications with regard to regulation of hepar in-binding growth factors and could help guide the development of highly sp ecific growth regulatory molecules through specific regulation by heparin a nd HSPG. (C) 2000 Academic Press.