Heparan Sulfate Domains Required for Fibroblast Growth Factor 1 and 2 Signaling through Fibroblast Growth Factor Receptor 1c.

A small library of well defined heparan sulfate (HS) polysaccharides was chemoenzymatically synthesized and used for a detailed structure-activity study of fibroblast growth factor (FGF) 1 and FGF2 signaling through FGF receptor (FGFR) 1c. The HS polysaccharide tested contained both undersulfated (NA) domains and highly sulfated (NS) domains as well as very well defined non-reducing termini. This study examines differences in the HS selectivity of the positive canyons of the FGF1-FGFR1c and FGF2-FGFR1c HS binding sites of the symmetric FGF-FGFR-HS signal transduction complex. The results suggest that FGF1-FGFR1c binding site prefers a longer NS domain at the non-reducing terminus than FGF2-FGFR1c In addition, FGF2-FGFR1c can tolerate an HS chain having an -acetylglucosamine residue at its non-reducing end. These results clearly demonstrate the different specificity of FGF1-FGFR1c and FGF2-FGFR1c for well defined HS structures and suggest that it is now possible to chemoenzymatically synthesize precise HS polysaccharides that can selectively mediate growth factor signaling. These HS polysaccharides might be useful in both understanding and controlling the growth, proliferation, and differentiation of cells in stem cell therapies, wound healing, and the treatment of cancer.