Regulation of FGF-1 mitogenic activity by heparan sulfate oligosaccharidesis 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 h eparin) with FGF-1 is a requirement for enabling the growth factor to activ ate its cell surface tyrosine kinase receptor. However, little is known abo ut the regulatory role of naturally occurring cell surface us in FGF-1 acti vation. We have addressed this issue by utilizing a library of us oligosacc harides, which are defined in both length and sulfate content. Mitogenic ac tivation assays using these oligosaccharides showed that us contained both FGF-1 activatory and inhibitory sugar sequences. Further analysis of these oligosaccharides showed a clear correlation between FGF-1 promoting activit y and their 6-O-sulfate content. The results, in particular with the dodeca saccharide sequences, suggested that specific positioning of 6-O-sulfate gr oups may be required for the promotion of FGF-1 mitogenic activity. This ma y also be true for 2-O-sulfate groups though the evidence was not as conclu sive. Differential activation of FGF-1 and FGF-2 was also observed and foun d to be mediated by both oligosaccharide length and sulfation pattern, with different specific O-sulfate positioning being implicated for the promotio n of different growth factors. These results suggest that variation and tig ht control of the fine structure of us may allow cells to not only control their positive/negative responses to individual FGEs but also to change spe cificity towards promotion of different members of the FGF family.