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J. Biol. Chem., Vol. 281, Issue 11, 6924-6930, March 17, 2006

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Inhibition or Activation of Apert Syndrome FGFR2 (S252W) Signaling by Specific Glycosaminoglycans^*

Lynda M. McDowell, Beth A. Frazier, Daniel R. Studelska, Kari Giljum, Jinghua Chen, Jian Liu, Kai Yu^¶, David M. Ornitz^¶, and Lijuan Zhang¹

From the Departments of Pathology and Immunology and ^¶Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110 and the Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599

Most Apert syndrome patients harbor a single amino acid mutation (S252W) in fibroblast growth factor (FGF) receptor 2 (FGFR2), which leads to abnormal FGF/FGFR2 signaling. Here we show that specific combinations of FGFs and glycosaminoglycans activate both alternative splice forms of the mutant but not of the wild-type FGF receptors. More importantly, 2-O- and N-sulfated heparan sulfate, prepared by a combined chemical and enzymatic synthesis, antagonized the over-activated FGFR2b (S252W) to basal levels at nanomolar concentrations. These studies demonstrated that specific glycosaminoglycans could be useful in treating ligand-dependent FGFR signaling-related diseases, such as Apert syndrome and cancer.

Received for publication, December 5, 2005

^* This work is supported by National Institutes of Health Grants R01GM69968 (to L. Z), R01AI50050 (to J. L.), and R01HD39952 (to D. M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Depts. of Pathology and Immunology, Campus Box 8118, WA University School of Medicine, St. Louis, MO 63110. Tel.: 314-362-8850; Fax: 314-362-3016; E-mail: ljzhang{at}wustl.edu.

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