Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between PRL (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that PRL2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. PRL2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high PRL2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative PRL2 substrate and demonstrated that PRL2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of PRL2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of PRL2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies.

在人类癌症中，经常发现抑制肿瘤的PTEN（在10号染色体上缺失的磷酸酶和张力蛋白同系物）水平降低，但是人们对PTEN的下调方式尚不完全了解。另外，尽管在PRL（再生肝的磷酸酶）2与癌症之间存在着令人信服的联系，但是该磷酸酶如何诱导肿瘤发生一直是一个谜。在这里，我们发现PRL2消融抑制PTEN杂合性诱导的肿瘤发生。PRL2缺乏症会升高PTEN并减弱AKT信号传导，从而导致肿瘤扩散减少和细胞凋亡增加。我们还发现，高PRL2表达与低PTEN水平相关，从而降低了患者的整体生存率。从机理上讲，我们将PTEN鉴定为PRL2的底物，并证明PRL2通过在Y336处使PTEN磷酸化来下调PTEN，从而增加NEDD4介导的PTEN泛素化和蛋白酶体降解。考虑到癌症对PTEN的微弱降低的敏感性，PRL2下调PTEN的能力为其致癌性提供了生化基础。结果还表明，PRL2的药理靶向可以提供一种恢复PTEN的新治疗策略，从而消除PTEN缺乏症引起的恶性肿瘤。