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The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis

Oncogene volume 34, pages 986–995 (2015)Cite this article

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Abstract

The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.

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Acknowledgements

We thank Dr Laurent Lessard (J. Wayne Cancer Institute) for his technical help. Dr Kalle Gehring, biochemistry department, McGill University for helpful discussion and colleagues at the Goodman Cancer Research Centre Drs Jose Teodoro and Jerry Pelletier for their constructive comments on the manuscript. MLT is a Jeanne and Jean-Louis Lévesque chair in Cancer Research. DPL is a recipient of Canadian Institute of Health Research (CIHR) Frederick Banting and Charles Best Doctoral Research award and of CIHR/Fonds de recherche du Quebec–Sante Training Grant in Cancer Research FRN53888 the McGill Integrated Cancer Research Training Program. This research is supported by an operating grant from the Quebec Breast Cancer Foundation and the Canadian Breast Cancer Research Alliance to MLT.

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Authors and Affiliations

  1. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada,

    S Hardy, N Uetani, N Wong, E Kostantin, D P Labbé & M L Tremblay

  2. Department of Biochemistry, McGill University, Montreal, QC, Canada

    N Wong, E Kostantin & M L Tremblay

  3. Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada

    D P Labbé & M L Tremblay

  4. Service d'anatomopathologie, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada

    L R Bégin

  5. Institut du cancer de Montréal and Département de Médecine, Centre de recherche du CHUM (CR-CHUM), Université de Montréal, Montreal, QC, Canada

    A Mes-Masson

  6. World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan

    D Miranda-Saavedra

  7. Fibrosis Laboratories, Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK

    D Miranda-Saavedra

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  1. S Hardy
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Hardy, S., Uetani, N., Wong, N. et al. The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis. Oncogene 34, 986–995 (2015). https://doi.org/10.1038/onc.2014.33

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