title: 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.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Lynda M
authors.initials: LM
authors.lastname: McDowell
authors.forename: Beth A
authors.initials: BA
authors.lastname: Frazier
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Studelska
authors.forename: Kari
authors.initials: K
authors.lastname: Giljum
authors.forename: Jinghua
authors.initials: J
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
mesh_terms: 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
chemical_list: D006025:Glycosaminoglycans; D007377:Interleukin-3; D008024:Ligands; D005346:Fibroblast Growth Factors; D006493:Heparin; D051497:Receptor, Fibroblast Growth Factor, Type 2