Department of Biochemistry and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada.
Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
J Biol Chem. 2020 Aug 14;295(33):11682-11692. doi: 10.1074/jbc.RA120.014464. Epub 2020 Jun 22.
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 fact -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.
肝再生磷酸酶（PRLs）是癌症的标志物，可促进肿瘤生长。它们已被涉及多种生化途径，但磷酸酶活性的生理相关靶点仍逃避了 20 年的研究。在这里，我们表明，在转移的小鼠模型中，PRL3 的催化活性不是必需的。PRL3 与 CNNM4 结合并抑制其活性，CNNM4 是一种与镁转运相关的膜蛋白。对 CNNM 结合或磷酸酶活性有缺陷的 PRL3 突变体的分析表明，CNNM 结合是促进肿瘤转移所必需且充分的。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，这会阻止 CNNM 结合，并可能发挥调节作用。我们表明，PRL 半胱氨酸磷酸化水平会根据培养条件和不同组织而变化。对相关蛋白磷酸酶的检查表明，磷酸半胱氨酸的稳定性是 PRL 独特且进化上保守的特性。PRL3 作为伪磷酸酶的功能的证明对癌症的 PRL 抑制剂的设计具有重要意义。
