Regulation of FGF-1 mitogenic activity by heparan sulfate oligosaccharides is dependent on specific structural features: differential requirements for the modulation of FGF-1 and FGF-2.
The interaction of heparan sulfate (HS) (and the closely related molecule heparin) with FGF-1 is a requirement for enabling the growth factor to activate its cell surface tyrosine kinase receptor. However, little is known about the regulatory role of naturally occurring cell surface HS in FGF-1 activation. We have addressed this issue by utilizing a library of HS oligosaccharides, which are defined in both length and sulfate content. Mitogenic activation assays using these oligosaccharides showed that HS contained both FGF-1 activatory and inhibitory sugar sequences. Further analysis of these oligosaccharides showed a clear correlation between FGF-1 promoting activity and their 6-O-sulfate content. The results, in particular with the dodecasaccharide sequences, suggested that specific positioning of 6-O-sulfate groups may be required for the promotion of FGF-1 mitogenic activity. This may also be true for 2-O-sulfate groups though the evidence was not as conclusive. Differential activation of FGF-1 and FGF-2 was also observed and found to be mediated by both oligosaccharide length and sulfation pattern, with different specific O-sulfate positioning being implicated for the promotion of different growth factors. These results suggest that variation and tight control of the fine structure of HS may allow cells to not only control their positive/negative responses to individual FGFs but also to change specificity towards promotion of different members of the FGF family.
Pye
D A
DA
CRC Department of Drug Development and CRC and University of Manchester Department of Medical Oncology, PICR, Christie Hospital, Manchester M20 4BX, UK.
Vivès
R R
RR
Hyde
P
P
Gallagher
J T
JT
D000818:Animals; D002240:Carbohydrate Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D008934:Mitogens; D009844:Oligosaccharides