Analysis of the fibroblast growth factor receptor (FGFR) signalling network with heparin as coreceptor: evidence for the expansion of the core FGFR signalling network

作者：Xu Ruoyan; Rudd Timothy R; Hughes Ashley J; Siligardi Giuliano; Fernig David G; Yates Edwin A^*

来源：FEBS Journal, 2013, 280(10): 2260-2270.

DOI：10.1111/febs.12201

• fibroblast growth factor
• fibroblast growth factor receptor
• glycosaminoglycans
• heparan sulfate
• signalling network

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 subfamilies1, 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 subgroups1, 4 and 9 from FGF subgroup8 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 FGFFGFR combinations, or areas of the signalling network, for experimental or therapeutic purposes.

• 出版日期2013-5