title: Cooperative dimerization of fibroblast growth factor 1 (FGF1) upon a single heparin saccharide may drive the formation of 2:2:1 FGF1.FGFR2c.heparin ternary complexes.
abstract: The related glycosaminoglycans heparin and heparan sulfate are essential for the activity of the fibroblast growth factor (FGF) family as they form an integral part of the signaling complex at the cell surface. Using size-exclusion chromatography we have studied the capacities of a variety of heparin oligosaccharides to bind FGF1 and FGFR2c both separately and together in ternary complexes. In the absence of heparin, FGF1 had no detectable affinity for FGFR2c. However, 2:2:1 complexes formed spontaneously in solution between FGF1, FGFR2c, and heparin octasaccharide (dp8). The dp8 sample was the shortest chain length that bound FGFR2c, that dimerized FGF1, and that promoted a strong mitogenic response to FGF1 through FGFR2c. Heparin hexasaccharide and various selectively desulfated heparin dp12s failed to bind FGFR2c and could only interact with FGF1 monomerically. These saccharides formed 1:1:1 complexes with FGF1 and FGFR2c, which had no tendency to self-associate, suggesting that binding of two FGF1 molecules to the same saccharide chain is a prerequisite for subsequent FGFR2c dimerization. We found that FGF1 dimerization upon heparin was favored over monomeric interactions even when a large excess of saccharide was present. A cooperative mechanism of FGF1 dimerization could explain how 2:2:1 signaling complexes form at the cell surface, an environment rich in heparan sulfate.
authors.affiliation: Cancer Research UK and Department of Medical Oncology, University of Manchester, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester M20 4BX. Christopher.Robinson@manchester.ac.uk
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Robinson
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Harmer
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Goodger
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
authors.forename: John T
authors.initials: JT
authors.lastname: Gallagher
mesh_terms: D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016220:Fibroblast Growth Factor 1; D006493:Heparin; D051497:Receptor, Fibroblast Growth Factor, Type 2