Heparan sulfate domains required for fibroblast growth factor 1 and 2 signaling through fibroblast growth factor receptor 1c [Signal Transduction]

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 FGF12-FGFR1c2 and FGF22-FGFR1c2 HS-binding sites of the symmetric FGF2-FGFR2HS2 signal transduction complex. The results suggest that FGF12-FGFR1c2 binding site prefers a longer NS domain at the non-reducing terminus than FGF22-FGFR1c2. In addition, FGF22-FGFR1c2 can tolerate a HS chain having a N-acetylglucosamine residue at its non-reducing end. These results clearly demonstrate the different specificity of FGF12-FGFR1c2 and FGF22-FGFR1c2 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 in the treatment of cancer.

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