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Analysis of the fibroblast growth factor receptor ( FGFR ) signalling network with heparin as coreceptor: evidence for the expansion of the core FGFR signalling network
Author(s) -
Xu Ruoyan,
Rudd Timothy R.,
Hughes Ashley J,
Siligardi Giuliano,
Fernig David G.,
Yates Edwin A.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12201
Subject(s) - fibroblast growth factor , fibroblast growth factor receptor , fibroblast growth factor receptor 4 , biology , microbiology and biotechnology , receptor , fibroblast growth factor receptor 1 , biochemistry
The evolution of the fibroblast growth factor ( FGF )– FGF receptor ( FGFR ) signalling system has closely followed that of multicellular organisms. The abilities of nine FGF s ( FGF ‐1 to FGF ‐9; examples of FGF subfamilies 1, 4, 7, 8, and 9) and seven FGFR s or isoforms ( FGFR 1b, FGFR 1c, FGFR 2b, FGFR 2c, FGFR 3b, FGFR 3c, and FGFR 4) 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 FGFR s was defined as their mutual ability to signal with a particular FGF . The network contained a core of four receptors ( FGFR 1c, FGFR 2c, FGFR 3c, and FGFR 4) 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 FGF s with heparin revealed no overall common structural change, suggesting the existence of distinct heparin‐binding sites throughout the FGF s. 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.