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J. Biol. Chem., Vol. 278, Issue 18, 16045-16053, May 2, 2003
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From the Department of Pathology and Laboratory Medicine,
University of Wisconsin, Madison, Wisconsin 53562-8550
Fibroblast growth factor-2 (FGF2) is a potent
angiogenic factor in gliomas. Heparan sulfate promotes ligand binding
to receptor tyrosine kinase and regulates signaling. The goal of this
study was to examine the contribution of heparan sulfate proteoglycans (HSPGs) to glioma angiogenesis. Here we show that all brain endothelial cell HSPGs carry heparan sulfate chains similarly capable of forming a
ternary complex with FGF2 and fibroblast growth factor receptor-1c and
of promoting a mitogenic signal. Immunohistochemical analysis revealed
that glypican-1 was overexpressed in glioma vessel endothelial cells,
whereas this cell-surface HSPG was consistently undetectable in normal
brain vessels. To determine the effect of increased glypican-1
expression on FGF2 signaling, we transfected normal brain endothelial
cells, which express low base-line levels of glypican-1, with this
proteoglycan. Glypican-1 expression enhanced growth of brain
endothelial cells and sensitized them to FGF2-induced mitogenesis
despite the fact that glypican-1 remained a minor proteoglycan. In
contrast, overexpression of syndecan-1 had no effect on growth or FGF2
sensitivity. We conclude that the glypican-1 core protein has a
specific role in FGF2 signaling. Glypican-1 overexpression may
contribute to angiogenesis and the radiation resistance characteristic
of this malignancy.
Heparan Sulfate Proteoglycans as Regulators of Fibroblast Growth
Factor-2 Signaling in Brain Endothelial Cells
SPECIFIC ROLE FOR GLYPICAN-1 IN GLIOMA ANGIOGENESIS*
,
*
This work was supported by American Cancer Society Research
Scholar Grant RSG-01-068-01 (to A. F.).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.
Present address: Dept. of Obstetrics and Gynecology, University of
Kiel, Michaelisstr. 16, D-24105 Kiel, Germany.
§
To whom correspondence should be addressed: Dept. of Pathology and
Laboratory Medicine, University of Wisconsin, Clinical Sciences Center
K4/850, Madison, WI 53562-8550. Tel.: 608-265-9283; Fax: 608-265-6215;
E-mail: afriedl@facstaff.wisc.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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