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J. Biol. Chem., Vol. 281, Issue 37, 26884-26892, September 15, 2006

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Heparan Sulfate-related Oligosaccharides in Ternary Complex Formation with Fibroblast Growth Factors 1 and 2 and Their Receptors^*

Nadja Jastrebova, Maarten Vanwildemeersch, Alan C. Rapraeger, Guillermo Giménez-Gallego^¶, Ulf Lindahl, and Dorothe Spillmann¹

From the Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden, the Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, and ^¶Centro de Investigaciones Biológicas, 28040 Madrid, Spain

Biosynthesis of heparan sulfate (HS) is strictly regulated to yield products with cell/tissue-specific composition. Interactions between HS and a variety of proteins, including growth factors and morphogens, are essential for embryonic development and for homeostasis in the adult. Fibroblast growth factors (FGFs) and their various receptors (FRs) form ternary complexes with HS, as required for receptor signaling. Libraries of HS-related, radiolabeled oligosaccharides were generated by chemo-enzymatic modification of heparin and tested for affinity to immobilized FR ectodomains in the presence of FGF1 or FGF2. Experiments were designed to enable assessment of N-sulfated 8and 10-mers with defined numbers of iduronic acid 2-O-sulfate and glucosamine 6-O-sulfate groups. FGF1 and FGF2 were found to require similar oligosaccharides in complex formation with FR1c–3c, FGF2 affording somewhat more efficient oligosaccharide recruitment than FGF1. FR4, contrary to FR1c–3c, bound oligosaccharides at physiological ionic conditions even in the absence of FGFs, and this interaction was further promoted by FGF1 but not by FGF2. In all systems studied, the stability of FGF-oligosaccharide-FR complexes correlated with the overall level of saccharide O-sulfation rather than on the precise distribution of sulfate groups.

Received for publication, January 26, 2006 , and in revised form, June 27, 2006.

^* This study was supported by grants from the Swedish Research Council (Grant 15023), the Swedish Cancer Society, the Swedish Foundation for Strategic Research (Grant A303:156e), and Polysackaridforskning AB. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medical Biochemistry and Microbiology, The Biomedical Centre, Uppsala University, P. O. Box 582, SE-75123 Uppsala, Sweden. Tel.: 46-18-471-4367; Fax: 46-4714209; E-mail: Dorothe.Spillmann{at}imbim.uu.se.

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