1. Inhibition or Activation of Apert Syndrome FGFR2 (S252W) Signaling by Specific Glycosaminoglycans.
- Author
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Mcdoweill, Lynda M., Frazier, Beth A., Studelska, Daniel R., Giljum, Kari, Jinghua Chen, Jian Liu, Kai Yu, Ornitz, David M., and Lijuan Zhang
- Subjects
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APERT syndrome , *CRANIOSYNOSTOSES , *AMINO acids , *ORGANIC acids , *GENETIC mutation , *FIBROBLAST growth factors , *GROWTH factors - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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