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Tumor Suppressor Function of Laminin-Binding α-Dystroglycan Requires a Distinct β3-N-Acetylglucosaminyltransferase
Xingfeng Bao, Motohiro Kobayashi, Shingo Hatakeyama, Kiyohiko Angata, Donald Gullberg, Jun Nakayama, Michiko N. Fukuda, Minoru Fukuda and Stuart A. Kornfeld
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 29 (Jul. 21, 2009), pp. 12109-12114
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/40484090
Page Count: 6
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α-Dystroglycan (α-DG) represents a highly glycosylated cell surface molecule that is expressed in the epithelial cell-basement membrane (BM) interface and plays an essential role in epithelium development and tissue organization. The α-DG-mediated epithelial cell-BM interaction is often impaired in invasive carcinomas, yet roles and underlying mechanisms of such an impaired interaction in tumor progression remain unclear. We report here a suppressor function of laminin-binding glycans on α-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, laminin-binding glycans are dramatically decreased, although the amount of α-DG and β-dystroglycan is maintained. The decrease of lamininbinding glycans and consequent increased cell migration were associated with the decreased expression of β3-N-acetylglucosaminyltransferase-1 (β3GnT1). Forced expression of β3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. β3GnT1 was found to be required for laminin-binding glycan synthesis through formation of a complex with LARGE, thus regulating the function of LARGE. Interaction of the laminin-binding glycans with laminin and other adhesive molecules in BM attenuates tumor cell migratory potential by antagonizing ERK/AKT phosphorylation induced by the components in the ECM. These results identify a previously undescribed role of carbohydrate-dependent cell-BM interaction in tumor suppression and its control by β3GnT1 and LARGE.
Proceedings of the National Academy of Sciences of the United States of America © 2009 National Academy of Sciences