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

  1. Robert J. Linhardt‡,§,‡‡,§§1
  1. From the Departments of ‡Chemistry and Chemical Biology,
  2. §Biology,
  3. ‡‡Biomedical Engineering, and
  4. §§Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180,
  5. the Wadsworth Center, New York State Department of Health, Albany, New York 12201,
  6. the ‖Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73126, and
  7. the **Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599
  1. ↵1 To whom correspondence should be addressed: Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Ave., Troy, NY 12180. Tel.: 518-276-3404; Fax: 518-276-3405; E-mail: linhar{at}rpi.edu.

  1. Edited by Gerald W. Hart

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.

Footnotes

  • ↵* This work was supported by National Institutes of Health Grants HL094463 and HL62244. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Received October 3, 2016.
  • Revision received December 16, 2016.
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  1. First Published on December 28, 2016 doi: 10.1074/jbc.M116.761585 The Journal of Biological Chemistry 292, 2495-2509.
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