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Glycobiology Advance Access originally published online on March 2, 2009
Glycobiology 2009 19(6):644-654; doi:10.1093/glycob/cwp031
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Specific inhibition of FGF-2 signaling with 2-O-sulfated octasaccharides of heparan sulfate

Satoko Ashikari-Hada2, Hiroko Habuchi3, Noriko Sugaya2, Takashi Kobayashi2 and Koji Kimata1,3

2 Institute for Molecular Science of Medicine
3 Research Complex for the Medicine Frontiers, Aichi Medical University, Yazako, Nagakute, Aichi 480-1195, Japan

1 To whom correspondence should be addressed: Tel: +81-561-61-1898; Fax: +81-561-61-1896; e-mail: kimata{at}aichi-med-u.ac.jp

Received on June 11, 2008; revised on February 3, 2009; accepted on February 23, 2009

In fibroblast growth factor (FGF)-2 signaling, the formation of a ternary complex of FGF-2, tyrosine-kinase fibroblast growth factor receptor (FGFR)-1, and cell surface heparan sulfate (HS) proteoglycan is known to be critical for the activation of FGFR-1 and downstream signal transduction. Exogenous heparin polymer and some octasaccharides inhibited FGF-2-induced phosphorylation both of FGFR-1 and of extracellular signal-regulated kinase (ERK1/2) in Chinese hamster ovary (CHO)-K1 cells transfected with FGFR-1, which present HS on their cell surface. The inhibitory effect of octasaccharide was dependent on the number of 2-O-sulfate groups within a molecule but independent of the number of 6-O-sulfate groups. Sulfation at the 2-O-position was a prerequisite not only for the binding of HS to FGF-2 but also for regulation of FGF-2 signaling and competitive inhibition with endogenous HS. Interestingly, FGF-4-induced phosphorylation was impeded only by specific octasaccharides containing both 2-O- and 6-O-sulfated groups, which were necessary for binding FGF-4. In CHO-677 cells deficient in HS biosynthesis, heparin enhanced FGF-2-induced phosphorylation of ERK1/2. On the other hand, an FGF-2-binding octasaccharide inhibited the phosphorylation. Our data suggest that the activity of particular heparin-binding factors can be inhibited by distinctive oligosaccharides that can bind the factors but cannot form functional signaling complexes irrespective of whether cells have a normal complement of HS or lack HS.

Key words: fibroblast growth factor / fibroblast growth factor receptor / heparan sulfate / oligosaccharide / phosphorylation


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