Fibroblast growth factor receptor signalling is dictated by specific heparan sulphate saccharides.
Signalling by fibroblast growth factors (FGFs) through FGF receptors (FGFRs) depends on the cell-surface polysaccharide heparan sulphate (HS) [1] [2]. HS has an ordered domain structure of highly diverse saccharide motifs that present unique displays of sulphate, carboxyl and hydroxyl groups [3]. These motifs interact with many proteins, particularly growth factors. HS binds both to FGFs [4] [5] [6] and FGFRs [7], and probably activates signalling by facilitating ligand-induced receptor dimerisation [8] [9]. Nevertheless, the extent to which specific HS saccharide sequences play a regulatory role has not been established. By screening a library of structurally diverse HS decasaccharides in bioassays of FGF signalling mediated by three different FGFR isoforms, we found that saccharides showed specificity for both ligands and receptors; some saccharides selectively activated FGF signalling through different FGFR isoforms, others acted as negative regulators. We conclude that HS saccharides play critical roles in dictating the specificity of ligand-receptor interactions in FGFR signalling. Controlled alterations in HS structures [10] would provide a mechanism for regulation of cellular responsiveness to growth factors that bind HS.
Guimond
S E
SE
School of Biosciences, Molecular Cell Biology Research Laboratories, University of Birmingham, Edgbaston, B15 2TT, England, UK.
Turnbull
J E
JE
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D019281:Dimerization; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006497:Heparan Sulfate / Q000502:physiology*; D008024:Ligands; D051379:Mice; D009844:Oligosaccharides / Q000302:isolation & purification / Q000378:metabolism*; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011485:Protein Binding; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D005346:Fibroblast Growth Factors; D006493:Heparin; D006497:Heparan Sulfate; D008024:Ligands; D009844:Oligosaccharides; D011133:Polysaccharide-Lyases; D017468:Receptors, Fibroblast Growth Factor; C021349:heparitinsulfate lyase