Unique interactions of fibroblast growth factor-2 with sub-populations of heparan sulfate

A. H. Herr, D. M. Ornitz, R. Sasisekharan, G. Venkataraman, U. Waksman

Research output: Contribution to journalArticlepeer-review

Abstract

It is well known that fibroblast growth factors (FGFs) ran activate their receptor tyrosine kinase 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 US is a highly heterogeneous polysaccharide, 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 octasacrharide 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 disarrharide that emulates a highly oversulfated heparan sulfate. We have used crystallography, analytical ultracentrifugation, computational modeling, mutational analvsis, 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-8, the biologically active compounds, induce formation of a "side-by-side" FGF-2 dimer conformation, whereas SOS, which is biologically 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.

Original languageEnglish
Pages (from-to)A833
JournalFASEB Journal
Volume11
Issue number9
StatePublished - Dec 1 1997

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