Inhibition or activation of Apert syndrome FGFR2 (S252W) signaling by specific glycosaminoglycans.

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.

• Authors: Lynda M McDowell, Beth A Frazier, Daniel R Studelska, Kari Giljum, Jinghua Chen, Jian Liu, Kai Yu, David M Ornitz, Lijuan Zhang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 11 Pg. 6924-30 (Mar 17 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16373332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Glycosaminoglycans
• Interleukin-3
• Ligands
• Fibroblast Growth Factors
• Heparin
• Receptor, Fibroblast Growth Factor, Type 2

Topics

• Acrocephalosyndactylia (metabolism)
• Animals
• Cartilage (metabolism)
• Cattle
• Cell Line
• Cell Proliferation
• Chromatography, High Pressure Liquid
• Decapodiformes
• Dose-Response Relationship, Drug
• Fibroblast Growth Factors (metabolism)
• Glycosaminoglycans (chemistry, metabolism)
• Heparin (chemistry)
• Humans
• Interleukin-3 (metabolism)
• Ligands
• Mutation
• Neoplasms (metabolism)
• Receptor, Fibroblast Growth Factor, Type 2 (antagonists & inhibitors, metabolism)
• Signal Transduction
• Swine
• Trachea (metabolism)