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 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.
McDowell
Lynda M
LM
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Frazier
Beth A
BA
Studelska
Daniel R
DR
Giljum
Kari
K
Chen
Jinghua
J
Liu
Jian
J
Yu
Kai
K
Ornitz
David M
DM
Zhang
Lijuan
L
D000168:Acrocephalosyndactylia / Q000378:metabolism*; D000818:Animals; D002356:Cartilage / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D049832:Decapodiformes; D004305:Dose-Response Relationship, Drug; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006025:Glycosaminoglycans / Q000737:chemistry* / Q000378:metabolism; D006493:Heparin / Q000737:chemistry; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D008024:Ligands; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction; D013552:Swine; D014132:Trachea / Q000378:metabolism
D006025:Glycosaminoglycans; D007377:Interleukin-3; D008024:Ligands; D005346:Fibroblast Growth Factors; D006493:Heparin; D051497:Receptor, Fibroblast Growth Factor, Type 2