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J. Biol. Chem., Vol. 280, Issue 9, 8332-8342, March 4, 2005

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Deletion of Mouse Embryo Fibroblast N-Acetylglucosaminyltransferase V Stimulates 51 Integrin Expression Mediated by the Protein Kinase C Signaling Pathway^*

Hua-Bei Guo, Intaek Lee, Beau T. Bryan, and Michael Pierce

From the Department of Biochemistry and Molecular Biology and Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602

An N-linked glycan often increased during oncogenic transformation contains (1,6)-linked GlcNAc, synthesized by the N-acetylglucosaminyltransferase V (GnT-V). The progression of polyoma middle T-antigen oncoprotein-induced mammary carcinomas in GnT-V null mice was significantly retarded compared with that observed in wild-type mice. The matrix adhesion of mouse embryonic fibroblasts (MEF) from GnT-V null and wild-type mice was investigated to understand the mechanism by which deletion of GnT-V could retard tumor progression. GnT-V null MEF displayed enhanced adhesion to and spreading on fibronectin-coated plates with concomitant inhibition of cell migration. GnT-V null MEF also showed increased focal adhesion kinase tyrosine phosphorylation, consistent with decreased cell motility on fibronectin-coated plates. Expression of GnT-V cDNA in the null MEF reversed these abnormal characteristics, indicating the direct involvement of N-glycosylation events in these phenotypic changes. The 51 fibronectin receptors exhibited increased clustering on the null MEF cell surfaces, consistent with previous studies that observed less integrin clustering in cells overexpressing GnT-V. Most surprisingly, GnT-V null MEF displayed increased expression levels of both 5 and 1 subunits in lysates and on the cell surface. Increased 51 expression in the null MEF was because of increased 51 transcript levels that declined after re-expression of GnT-V cDNA, confirming that increased 51 expression in null MEF was because of changes in GnT-V expression. The increased null MEF transcripts were shown to be caused at least in part by increased integrin promoter activity. Moreover, increased 51 integrin transcripts in GnT-V null MEF were not due to a differential response to fibronectin; rather, they appeared to be mediated by activation of a protein kinase C signaling pathway. These results demonstrate that deletion of MEF GnT-V resulted in enhanced integrin clustering and activation of 51 transcription by protein kinase C signaling, which in turn up-regulated levels of cell surface 51 fibronectin receptors that resulted in increased matrix adhesion and inhibition of migration.

Received for publication, December 1, 2004 , and in revised form, December 15, 2004.

^* 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.

To whom correspondence should be addressed: Complex Carbohydrate Research Center and Dept. of Biochemistry and Molecular Biology, University of Georgia, 315 Riverbend Rd., Athens, GA 30602. Tel.: 706-542-1701; Fax: 706-542-1759; E-mail: hawkeye{at}uga.edu.

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