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