Heparan sulfate domains required for fibroblast growth factor 1 and 2 signaling through fibroblast growth factor receptor 1c

Victor Schultz, Mathew Suflita, Xinyue Liu, Xing Zhang, Yanlei Yu, Lingyun Li, Dixy E. Green, Yongmei Xu, Fuming Zhang, Paul L. DeAngelis, Jian Liu, Robert J. Linhardt

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

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-FGFR2-HS2 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 an HS chain having an 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 the treatment of cancer.

Original languageEnglish
Pages (from-to)2495-2509
Number of pages15
JournalJournal of Biological Chemistry
Volume292
Issue number6
DOIs
StatePublished - 10 Feb 2017
Externally publishedYes

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