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Suppression of tumor growth and metastasis in Mgat5-deficient mice

Nature Medicine volume 6, pages 306–312 (2000)Cite this article

Abstract

Golgi β1,6N-acetylglucosaminyltransferase V (MGAT5) is required in the biosynthesis of β1,6GlcNAc-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.

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Figure 1: MGAT5 in N-glycan biosynthesis, and overexpression of its products in human cancers.
Figure 2: Targeted mutation of the Mgat5 locus in mice.
Figure 3: Mouse embryo at embryonic day 7.5.
Figure 4: PyMT-dependent tumor growth is suppresses in Mgat5−/− mice.
Figure 5: Mammary fat pads and tumors.
Figure 6: Suppression of membrane ruffling, actin filament turnover and PKB phosphoprotein in PyMT Mgat5−/− tumor cells.

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Acknowledgements

The authors thank C. Warren, S. Kulkarni and P. Cheung for suggestions. This research was supported by grants from National Cancer Institute of Canada, the Mizutani Foundation, the National Science and Engineering Research Council of Canada, and GlycoDesign (Toronto, Canada). W.J.M. is supported by a Medical Research Council Scientist Award.

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Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave. R988, Toronto, M5G 1X5, Ontario, Canada

    Maria Granovsky, Judy Pawling & James W. Dennis

  2. Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada

    Maria Granovsky & James W. Dennis

  3. Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, 620 University Ave., Toronto, M5G 2C1, Ontario, Canada

    Jimmie Fata & Rama Khokha

  4. Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, L8S 4K1, Ontario, Canada

    William J. Muller

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Correspondence to James W. Dennis.

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Granovsky, M., Fata, J., Pawling, J. et al. Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat Med 6, 306–312 (2000). https://doi.org/10.1038/73163

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