It is well known that fibrohlast growth factors (FGFs) can activate, their reteptor tyrosine kinaso receptors in the presence of cell-surface heparan sulfate proteoglycans or soluble heparin. However, determination of the specific role of heparan sulfate (HS) in activating the FGF pathway is difficult, as HS is a highly heterogeneous polysacc.haride. varying in both sequence and sulfation levels along its length- Therefore, we have studied the interactions of FGF-2 with various heparan sulfate mimics. These include HS-8, an active octasaccharide heparin fragment that approximates an "average" heparan sulfate structure; Tri-3, an active nonsulfated trisaccharide that represents a nonsulfated heparan structure; and sucrose octasulfate (SOS), an inactive disaccharide that emulates a highly sulfated heparan sulfate. We have used crystallography, an alytiral ultracentrifugation, computational modeling, mutational analysis, and biological activity assays to determine the mechanism by which heparan sulfate may activate the FGF signaling pathway. We have found that all of the heparan sulfate analogs induce FGF-2 dimerization. However, our results suggest that Tri-3 and HS H. the biologically active compounds, induce formation of a ''side-by-sidev FGF 2 dimor conformation, whereas SOS, which is biolog irally inactive, induces the formation of a "head-to-head" FGF-2 dimer. Our results show that local concentrations of FGF-2 and HS, as well as the specific sequence and sulfation pattern of HS, can regulate FGF signaling activity.
|State||Published - Dec 1 1997|