title: The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis.
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.
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Hardy
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Uetani
authors.affiliation: 1] Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada [2] Department of Biochemistry, McGill University, Montreal, QC, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Wong
authors.affiliation: 1] Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada [2] Department of Biochemistry, McGill University, Montreal, QC, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Kostantin
authors.affiliation: 1] Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada [2] Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
authors.forename: D P
authors.initials: DP
authors.lastname: Labbé
authors.affiliation: Service d'anatomopathologie, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.
authors.forename: L R
authors.initials: LR
authors.lastname: Bégin
authors.affiliation: Centre de recherche du CHUM (CR-CHUM), Institut du cancer de Montréal and Département de Médecine, Université de Montréal, Montreal, QC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Mes-Masson
authors.affiliation: 1] World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan [2] Fibrosis Laboratories, Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK.
authors.forename: D
authors.initials: D
authors.lastname: Miranda-Saavedra
authors.affiliation: 1] Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada [2] Department of Biochemistry, McGill University, Montreal, QC, Canada [3] Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
authors.forename: M L
authors.initials: ML
authors.lastname: Tremblay
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
chemical_list: C000597250:CNNM3 protein, human; C000597249:CNNM3 protein, mouse; D027682:Cation Transport Proteins; D016213:Cyclins; D017874:Immediate-Early Proteins; D017027:Protein Tyrosine Phosphatases; C111533:Ptp4a2 protein, mouse; D008274:Magnesium