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Originally published In Press as doi:10.1074/jbc.M010786200 on April 5, 2001

J. Biol. Chem., Vol. 276, Issue 26, 23421-23429, June 29, 2001
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Probing Fibroblast Growth Factor Dimerization and Role of Heparin-like Glycosaminoglycans in Modulating Dimerization and Signaling*

Chi-Pong KwanDagger , Ganesh Venkataraman§, Zachary ShriverDagger , Rahul RamanDagger , Dongfang LiuDagger , Yiwei QiDagger , Lyuba Varticovski, and Ram SasisekharanDagger §||**

From the Dagger  Division of Bioengineering and Environmental Health, the § Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, and the || Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and the  Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135

For a number of growth factors and cytokines, ligand dimerization is believed to be central to the formation of an active signaling complex. In the case of fibroblast growth factor-2 (FGF2) signaling, heparin/heparan sulfate-like glycosaminoglycans (HLGAGs) are involved through interaction with both FGF2 and its receptors (FGFRs) in assembling a tertiary complex and modulating FGF2 activity. Biochemical data have suggested different modes of HLGAG-induced FGF2 dimerization involving specific protein-protein contacts. In addition, several recent x-ray crystallography studies of FGF·FGFR and FGF·FGFR·HLGAG complexes have revealed other modes of molecular assemblage, with no FGF-FGF contacts. All these different biochemical and structural findings have clarified less and in fact raised more questions as to which mode of FGF2 dimerization, if any, is essential for signaling. In this study, we address the issue of FGF2 dimerization in signaling using a combination of biochemical, biophysical, and site-directed mutagenesis approaches. Our findings presented here provide direct evidence of FGF2 dimerization in mediating FGF2 signaling.


* This work was supported in part by the National Institutes of Health Grant RO1HL59966 (to R. S.), the Burroughs Wellcome Foundation (to R. S.), the CapCure Foundation (to R. S.), a Merck fellowship (to Z. S.), and a Whitaker Health Sciences Fund fellowship (to Z. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Center for Biomedical Engineering, MIT, 77 Massachusetts Ave., Bldg. 16-561, Cambridge, MA 02139. Tel.: 617-258-9494; Fax: 617-258-9409; E-mail: rams@mit.edu.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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