The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis
The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis
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DOI：
10.1038/onc.2014.33
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发表时间：
2015-02-19
期刊：
影响因子：
8
通讯作者：
Tremblay, M. L.
中科院分区：
文献类型：
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作者：
Hardy, S.;Uetani, N.;Tremblay, M. L.
三种PRL（再生肝磷酸酶）蛋白酪氨酸磷酸酶（PRL-1，-2和-3）已被确定为几种人类癌症转移的关键贡献者，但其促癌特性的分子基础尚不清楚。在PRL磷酸酶的亚家族中，PRL-2在乳腺癌细胞中的过表达已被证明通过仍有待揭示的机制促进肿瘤生长。在这里，我们表明，PRL-2通过与镁转运蛋白CNNM 3形成功能性异源二聚体来调节细胞内镁水平。我们进一步揭示CNNM 3不是PRL-2的磷酸化底物，并且相互作用通过CNNM 3的CBS对结构域特有的环发生，该环仅存在于具有PRL直系同源物的生物体中。支持PRL-2在细胞镁转运中的作用的是观察到PRL-2敲低导致细胞镁内流的显著减少。此外，在PRL-2敲除小鼠中，血清镁水平与对照动物相比显著升高，表明PRL-2在调节细胞镁稳态中起关键作用。虽然CNNM 3的表达水平在各种癌细胞系的镁耗竭后保持不变，但内源性PRL-2和CNNM 3之间的相互作用显著增加。重要的是，用CNNM 3和不与PRL-2相关的突变形式进行的异种移植肿瘤测定证实了CNNM 3本身是促癌的，并且PRL-2/CNNM 3相关性对于赋予转化活性是重要的。这一发现进一步从人乳腺癌组织中的数据中得到证实，该数据显示CNNM 3水平与PRL-2表达和肿瘤增殖指数正相关。总之，我们证明致癌PRL-2通过与CNNM 3镁转运蛋白结合调节细胞内镁水平来控制肿瘤生长。
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.