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Papers In Press, published online ahead of print February 18, 2003
Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53792-8550
Corresponding Author: afriedl{at}facstaff.wisc.edu
Fibroblast growth factor-2 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 to glioma angiogenesis. Here we show that all brain endothelial cell heparan sulfate proteoglycans carry heparan sulfate chains similarly capable of forming a ternary complex with fibroblast growth factor-2 and fibroblast growth factor receptor-1c and of promoting a mitogenic signal. Immunohistochemical analysis reveals that glypican-1 is overexpressed in glioma vessel endothelial cells, whereas this cell surface heparan sulfate proteoglycan is consistently undetectable in normal brain vessels. To determine the effect of increased glypican-1 expression on fibroblast growth factor-2 signaling, we transfected normal brain endothelial cells, which express low baseline levels of glypican-1 with this proteoglycan. Glypican-1 expression enhances growth of brain endothelial cells and sensitizes them to fibroblast growth factor-2-induced mitogenesis despite the fact that glypican-1 remains a minor proteoglycan. In contrast, overexpression of syndecan-1 has no effect on growth or fibroblast growth factor-2 sensitivity. We conclude that the glypican-1 core protein has a specific role in fibroblast growth factor-2 signaling. Glypican-1 overexpression may contribute to angiogenesis and radiation resistance characteristic for this malignancy.
J. Biol. Chem, 10.1074/jbc.M211259200
Submitted on November 4, 2002
Revised on February 17, 2003
Accepted on February 18, 2003
Heparan sulfate proteoglycans as regulators of FGF2 signaling in brain endothelial cells - specific role for glypican-1 in glioma angiogenesis
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