TY - JOUR
T1 - Inhibition or activation of apert syndrome FGFR2 (S252W) signaling by specific glycosaminoglycans
AU - McDowell, Lynda M.
AU - Frazier, Beth A.
AU - Studelska, Daniel R.
AU - Giljum, Kari
AU - Chen, Jinghua
AU - Liu, Jian
AU - Yu, Kai
AU - Ornitz, David M.
AU - Zhang, Lijuan
PY - 2006/3/17
Y1 - 2006/3/17
N2 - 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- andN-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.
AB - 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- andN-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.
UR - http://www.scopus.com/inward/record.url?scp=33646368157&partnerID=8YFLogxK
U2 - 10.1074/jbc.M512932200
DO - 10.1074/jbc.M512932200
M3 - Article
C2 - 16373332
AN - SCOPUS:33646368157
SN - 0021-9258
VL - 281
SP - 6924
EP - 6930
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -