PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth
PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth
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DOI：
10.1074/jbc.ra120.014464
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发表时间：
2020-08-14
影响因子：
4.8
通讯作者：
Gehring, Kalle
中科院分区：
文献类型：
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作者：
Kozlov, Guennadi;Funato, Yosuke;Gehring, Kalle
再生肝磷酸酶（PRLs）是肿瘤的标志物，促进肿瘤生长。它们与多种生物化学途径有关，但磷酸酶活性的生理相关靶标已经回避了20年的研究。在这里，我们发现在小鼠转移模型中不需要PRL3的催化活性。PRL3结合并抑制CNNM4，一种与镁运输相关的膜蛋白。对PRL3突变体CNNM结合或磷酸酶活性特异性缺陷的分析表明，CNNM结合是促进肿瘤转移的必要和充分条件。由于prl确实具有磷酸酶活性，因此它们实际上是伪磷酸酶。磷酸酶活性导致磷酸半胱氨酸的形成，从而阻断CNNM结合并可能发挥调节作用。我们发现PRL半胱氨酸磷酸化水平在不同的培养条件和不同的组织中有所不同。对相关蛋白磷酸酶的检测表明，磷酸半胱氨酸的稳定性是prl独特且进化保守的特性。证明PRL3作为假磷酸酶的功能对设计用于癌症的PRL抑制剂具有重要的影响。
Phosphatases of regenerating liver (PRLs) are markers of cancer and promote tumor growth. They have been implicated in a variety of biochemical pathways but the physiologically relevant target of phosphatase activity has eluded 20 years of investigation. Here, we show that PRL3 catalytic activity is not required in a mouse model of metastasis. PRL3 binds and inhibits CNNM4, a membrane protein associated with magnesium transport. Analysis of PRL3 mutants specifically defective in either CNNM-binding or phosphatase activity demonstrate that CNNM binding is necessary and sufficient to promote tumor metastasis. As PRLs do have phosphatase activity, they are in factpseudo-pseudophosphatases. Phosphatase activity leads to formation of phosphocysteine, which blocks CNNM binding and may play a regulatory role. We show levels of PRL cysteine phosphorylation vary in response to culture conditions and in different tissues. Examination of related protein phosphatases shows the stability of phosphocysteine is a unique and evolutionarily conserved property of PRLs. The demonstration that PRL3 functions as a pseudophosphatase has important ramifications for the design of PRL inhibitors for cancer.