The Phosphatases of Regenerating Liver (PRLs) are members of the protein tyrosine phosphatase (PTP) superfamily that play pro-oncogenic roles in cell proliferation, migration, and survival. We previously demonstrated that PRLs can post-translationally downregulate PTEN, a tumor suppressor frequently inactivated in human cancers, by dephosphorylating PTEN at Tyr336, which promotes the NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Here we report that PRLs can also reduce PTEN expression by upregulating MicroRNA-21 (miR-21), which is one of the most frequently overexpressed miRNAs in solid tumors. We observe a broad correlation between PRL and miR-21 levels in multiple human cancers. Mechanistically, PRL2, the most abundant and ubiquitously expressed PRL family member, promotes the JAK2/STAT3 pathway-mediated miR-21 expression by directly dephosphorylating JAK2 at Tyr570. Finally, we confirm that the PRL2-mediated miR-21 expression contributes to its oncogenic potential in breast cancer cells. Our study defines a new functional role of PRL2 in PTEN regulation through a miR-21-dependent post-transcriptional mechanism, in addition to our previously reported NEDD4-dependent post-translational PTEN regulation. Together, these studies further establish the PRLs as negative regulators of PTEN.

中文翻译：

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PRL2 磷酸酶通过激活 JAK2/STAT3 通路下调 PTEN 抑癌基因来上调 miR-21。


再生肝磷酸酶 （PRLs） 是蛋白酪氨酸磷酸酶 （PTP） 超家族的成员，在细胞增殖、迁移和存活中起促癌作用。我们之前证明，PRLs 可以通过在 Tyr336 位点去磷酸化 PTEN 来翻译后下调 PTEN，PTEN 是一种在人类癌症中经常失活的肿瘤抑制因子，这促进了 NEDD4 介导的 PTEN 泛素化和蛋白酶体降解。在这里，我们报道了 PRLs 还可以通过上调 MicroRNA-21 （miR-21） 来降低 PTEN 表达，MicroRNA-21 是实体瘤中最常过表达的 miRNA 之一。我们观察到 PRL 和 miR-21 水平在多种人类癌症中具有广泛的相关性。从机制上讲，PRL2 是最丰富和普遍表达的 PRL 家族成员，通过直接在 Tyr570 位点去磷酸化 JAK2 来促进 JAK2/STAT3 通路介导的 miR-21 表达。最后，我们证实 PRL2 介导的 miR-21 表达有助于其在乳腺癌细胞中的致癌潜力。除了我们之前报道的 NEDD4 依赖性翻译后 PTEN 调节外，我们的研究还通过 miR-21 依赖性转录后机制定义了 PRL2 在 PTEN 调节中的新功能作用。总之，这些研究进一步确立了 PRLs 是 PTEN 的负调节因子。