Nature Medicine
6, 306 - 312 (2000)
doi:10.1038/73163
Suppression of tumor growth and metastasis in Mgat5-deficient miceMaria Granovsky1, 2, Jimmie Fata3, Judy Pawling1, William J. Muller4, Rama Khokha3
& James W. Dennis1, 21
Samuel Lunenfeld Research Institute, Mount Sinai Hospital 600 University Ave. R988, Toronto, Ontario, Canada M5G 1X5
2
Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada
3
Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, 620 University Ave., Toronto, Ontario, Canada M5G 2C1
4
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada L8S 4K1
Correspondence should be addressed to James W. Dennis Dennis@mshri.on.caGolgi  1,6N-acetylglucosaminyltransferase V (MGAT5) is required in the biosynthesis of 1,6GlcNAc-branched N-linked glycans attached to cell surface and secreted glycoproteins. Amounts of MGAT5 glycan products are commonly increased in malignancies, and correlate with disease progression. To study the functions of these N-glycans in development and disease, we generated mice deficient in Mgat5 by targeted gene mutation. These Mgat5
-/- mice lacked Mgat5 products and appeared normal, but differed in their responses to certain extrinsic conditions. Mammary tumor growth and metastases induced by the polyomavirus middle T oncogene was considerably less in Mgat5
-/- mice than in transgenic littermates expressing Mgat5. Furthermore, Mgat5 glycan products stimulated membrane ruffling and phosphatidylinositol 3 kinase−protein kinase B activation, fueling a positive feedback loop that amplified oncogene signaling and tumor growth in vivo. Our results indicate that inhibitors of MGAT5 might be useful in the treatment of malignancies by targeting their dependency on focal adhesion signaling for growth and metastasis.
|
