title: Divalent cations and heparin/heparan sulfate cooperate to control assembly and activity of the fibroblast growth factor receptor complex.
abstract: Polypeptides of the fibroblast growth factor (FGF) family are ubiquitous bioregulators within tissues whose activity is controlled by heparan sulfates within the pericellular matrix. FGF and the ectodomain of their transmembrane tyrosine kinase receptors (FGFR) exhibit heparin-binding domains that when juxtaposed in a FGF middle dotFGFR complex can accommodate a single, potentially bivalent, decameric polysaccharide chain in a ternary complex. Here we show that the interaction of heparin with FGF ligands is not affected by divalent cations. In contrast, the high affinity interaction (apparent Kd = 10 nM) of heparin with FGFR requires Ca2+ or Mg2+ at physiological concentrations. Divalent cations maintain FGFR in a heparan sulfate-dependent state in respect to FGF binding and an FGF- and heparan sulfate-dependent state in respect to autophosphorylation. A model is proposed where divalent cations and heparan sulfate cooperate to maintain FGFR in a conformation that restricts trans-phosphorylation between intracellular kinase domains. The restriction is overcome by FGF or constitutively as a common consequence of diverse mutations in FGFR associated with skeletal and craniofacial abnormalities.
authors.affiliation: Center for Cancer Biology and Nutrition, Albert B. Alkek Institute of Biosciences and Technology, Department of Biochemistry and Biophysics, Texas A&M University, Houston, Texas 77030-3303, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kan
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: To
authors.forename: J L
authors.initials: JL
authors.lastname: Gabriel
authors.forename: W L
authors.initials: WL
authors.lastname: McKeehan
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004492:Edetic Acid / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006493:Heparin / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism; D008345:Manganese / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002118:Calcium; D002413:Cations, Divalent; D004492:Edetic Acid; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D006493:Heparin; D006497:Heparan Sulfate; D008274:Magnesium; D008345:Manganese; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor