Insights into the role of heparan sulphate in fibroblast growth factor signalling

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Abstract
Signalling from the FGFs (fibroblast growth factors) is crucial for the correct development and homoeostasis of a wide range of cells and tissues. The FGF/FGFR (FGF receptor) signalling system forms an important paradigm for HS (heparan sulphate)-binding proteins, as both the growth factor and receptor bind to HS, and HS or heparin is an absolute requirement for full signalling. The FGF signalling system has been extremely well structurally characterized, and details of each interaction involved in forming a ternary complex of FGF-FGFR-heparin have been elucidated. Recent work has focused on a more thorough understanding of the nature of the FGF-heparin complex in particular, demonstrating that FGFs preferentially bind to similar sites on the co-receptor, and that FGF-FGFR pairs show greater specificity for heparin sulphation patterns than individual FGFs. Further work has suggested that FGF-FGFR-heparin signalling complexes contain one molecule of heparin only, and that when longer fragments of heparin are used to form FGF-FGFR-heparin complexes, multiple complexes form upon the saccharide. These observations form the basis of a model where the range of interactions that FGFs and FGFRs can form with one another and with HS may lead to the formation of complexes with more than two FGFR units. Therefore HS will be crucial to FGF signalling from the initial signalling event to the formation of large receptor clusters.