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

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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2006-03, Vol.281 (11), p.6924-6930
Main Authors: McDowell, Lynda M., Frazier, Beth A., Studelska, Daniel R., Giljum, Kari, Chen, Jinghua, Liu, Jian, Yu, Kai, Ornitz, David M., Zhang, Lijuan
Format: Article
Language:English
Subjects:
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
Glycosaminoglycans - metabolism
Heparin - chemistry
Humans
Interleukin-3 - metabolism
Ligands
Mutation
Neoplasms - metabolism
Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 2 - metabolism
Signal Transduction
Swine
Trachea - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M512932200