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J. Biol. Chem., Vol. 283, Issue 36, 24848-24859, September 5, 2008

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The Proteoglycan Brevican Binds to Fibronectin after Proteolytic Cleavage and Promotes Glioma Cell Motility^*

Bin Hu, Leopold L. Kong, Russell T. Matthews^¶, and Mariano S. Viapiano^||1

From the Center for Molecular Neurobiology and the ^||Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio 43210, the Department of Neurobiology, Yale University College of Medicine, New Haven, Connecticut 06510, and the ^¶Department of Physiology and Neuroscience, State University of New York Medical School, Syracuse, New York 13210

The adult neural parenchyma contains a distinctive extracellular matrix that acts as a barrier to cell and neurite motility. Nonneural tumors that metastasize to the central nervous system almost never infiltrate it and instead displace the neural tissue as they grow. In contrast, invasive gliomas disrupt the extracellular matrix and disperse within the neural tissue. A major inhibitory component of the neural matrix is the lectican family of chondroitin sulfate proteoglycans, of which brevican is the most abundant member in the adult brain. Interestingly, brevican is also highly up-regulated in gliomas and promotes glioma dispersion by unknown mechanisms. Here we show that brevican secreted by glioma cells enhances cell adhesion and motility only after proteolytic cleavage. At the molecular level, brevican promotes epidermal growth factor receptor activation, increases the expression of cell adhesion molecules, and promotes the secretion of fibronectin and accumulation of fibronectin microfibrils on the cell surface. Moreover, the N-terminal cleavage product of brevican, but not the full-length protein, associates with fibronectin in cultured cells and in surgical samples of glioma. Taken together, our results provide the first evidence of the cellular and molecular mechanisms that may underlie the motility-promoting role of brevican in primary brain tumors. In addition, these results underscore the important functional implications of brevican processing in glioma progression.

Received for publication, February 21, 2008 , and in revised form, June 9, 2008.

^* This work was supported by research grants from the Accelerate Brain Cancer Cure Foundation (to R. T. M.), the American Brain Tumor Association (Butler Family Foundation Fellowship to M. S. V. and Joel A. Gringras J. Fellowship to B. H.) and the Dardinger Center Fund for Neuro-Oncology Research at the Ohio State University Medical Center (to M. S. V.). 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: Center for Molecular Neurobiology, The Ohio State University, 226B Rightmire Hall, 1060 Carmack Rd., Columbus, OH 43210. Tel.: 614-292-4362; Fax: 614-292-5379; E-mail: viapiano.1{at}osu.edu.

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