Differential effects of heparin saccharides on the formation of specific fibroblast growth factor (FGF) and FGF receptor complexes.
Heparan sulfates (HS) play an important role in the control of cell growth and differentiation by virtue of their ability to modulate the activities of heparin-binding growth factors, an issue that is particularly well studied for fibroblast growth factors (FGFs). HS/heparin co-ordinate the interaction of FGFs with their receptors (FGFRs) and are thought to play a critical role in receptor dimerization. Biochemical and crystallographic studies, conducted mainly with FGF-2 or FGF-1 and FGF receptors 1 and 2, suggests that an octasaccharide is the minimal length required for FGF- and FGFR-induced dimerization and subsequent activation. In addition, 6-O-sulfate groups are thought to be essential for binding of HS to FGFR and for receptor dimerization. We show here that oligosaccharides shorter than 8 sugar units support activation of FGFR2 IIIb by FGF-1 and interaction of FGFR4 with FGF-1. In contrast, only relatively long oligosaccharides supported receptor binding and activation in the FGF-1.FGFR1 or FGF-7.FGFR2 IIIb setting. In addition, both 6-O- and 2-O-desulfated heparin activated FGF-1 signaling via FGFR2 IIIb, whereas neither one stimulated FGF-1 signaling via FGFR1 or FGF-7 via FGFR2 IIIb. These findings indicate that the structure of HS required for activating FGFs is dictated by the specific FGF and FGFR combination. These different requirements may reflect the differences in the mode by which a given FGFR interacts with the various FGFs.
Ostrovsky
Olga
O
Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Berman
Bluma
B
Gallagher
John
J
Mulloy
Barbara
B
Fernig
David G
DG
Delehedde
Maryse
M
Ron
Dina
D
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002455:Cell Division; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000737:chemistry* / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000378:metabolism; D051379:Mice; D009844:Oligosaccharides / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D013997:Time Factors
D003432:Cross-Linking Reagents; C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; C496455:Fgf7 protein, rat; D009844:Oligosaccharides; D017468:Receptors, Fibroblast Growth Factor; D016220:Fibroblast Growth Factor 1; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006493:Heparin; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496349:Fgfr1 protein, mouse; C496350:Fgfr1 protein, rat; C496354:Fgfr2 protein, mouse; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2