title: Analysis of the fibroblast growth factor receptor (FGFR) signalling network with heparin as coreceptor: evidence for the expansion of the core FGFR signalling network.
abstract: The evolution of the fibroblast growth factor (FGF)-FGF receptor (FGFR) signalling system has closely followed that of multicellular organisms. The abilities of nine FGFs (FGF-1 to FGF-9; examples of FGF subfamilies 1, 4, 7, 8, and 9) and seven FGFRs or isoforms (FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4) to support signalling in the presence of heparin, a proxy for the cellular heparan sulfate coreceptor, were assembled into a network. A connection between two FGFRs was defined as their mutual ability to signal with a particular FGF. The network contained a core of four receptors (FGFR1c, FGFR2c, FGFR3c, and FGFR4) with complete connectivity and high redundancy. Analysis of the wider network indicated that neither FGF-3 nor FGF-7 was well connected to this core of four receptors, and that divergence of a precursor of FGF subgroups 1, 4 and 9 from FGF subgroup 8 may have allowed expansion from a three-member FGFR core signalling system to the four-member core network. This increases by four-fold the number of possible signalling combinations. Synchrotron radiation CD spectra of the FGFs with heparin revealed no overall common structural change, suggesting the existence of distinct heparin-binding sites throughout the FGFs. The approach provides a potential method of identifying agents capable of influencing particular FGF-FGFR combinations, or areas of the signalling network, for experimental or therapeutic purposes.
authors: Department of Structural and Chemical Biology, Institute of Integrative Biology, University of Liverpool, UK.
authors: Ruoyan
authors: R
authors: Xu
authors: Timothy R
authors: TR
authors: Rudd
authors: Ashley J
authors: AJ
authors: Hughes
authors: Giuliano
authors: G
authors: Siligardi
authors: David G
authors: DG
authors: Fernig
authors: Edwin A
authors: EA
authors: Yates
mesh_terms: D001665:Binding Sites; D002942:Circular Dichroism / Q000379:methods; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D051523:Fibroblast Growth Factor 7 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006493:Heparin / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D017433:Protein Structure, Secondary; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006493:Heparin; D006497:Heparan Sulfate; D046912:Multiprotein Complexes; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2