Phosphatase of Regenerating Liver 2 (PRL2) Is Essential for Placental Development by Down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and Activating Akt Protein
Phosphatase of Regenerating Liver 2 (PRL2) Is Essential for Placental Development by Down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and Activating Akt Protein
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DOI：
10.1074/jbc.m112.393462
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发表时间：
2012-09-14
影响因子：
4.8
通讯作者：
Zhang, Zhong-Yin
中科院分区：
文献类型：
--
作者：
Dong, Yuanshu;Zhang, Lujuan;Zhang, Zhong-Yin
再生肝磷酸酶(PRL)参与控制细胞的增殖和侵袭。PRL的异常表达与多种肿瘤的进展和转移有关。然而，PRLS在体内的具体功能仍然难以捉摸。在这里，我们发现PRL2，最普遍表达的PRL家族成员的缺失，会导致胎盘发育受损和胚胎和成年阶段的生长迟缓。切除PRL2使Akt失活并阻止糖原细胞的增殖，导致胎盘中的海绵滋养层和蜕膜层减少。这些结构缺陷会导致胎盘发育不良和功能不全，导致胎儿发育迟缓。我们证明，肿瘤抑制基因PTEN在PRL2缺陷的胎盘中升高。生化分析表明，PrL2通过蛋白酶体途径下调PTEN，从而促进Akt的激活。这项研究首次证明了PRL2是胚胎外发育所必需的，并将PRL2的致癌特性与其负调控PTEN的能力相关联，从而激活了PI3K-Akt通路。
The PRL (phosphatase of regenerating liver) phosphatases are implicated in the control of cell proliferation and invasion. Aberrant PRL expression is associated with progression and metastasis of multiple cancers. However, the specific in vivo function of the PRLs remains elusive. Here we show that deletion of PRL2, the most ubiquitously expressed PRL family member, leads to impaired placental development and retarded growth at both embryonic and adult stages. Ablation of PRL2 inactivates Akt and blocks glycogen cell proliferation, resulting in reduced spongiotrophoblast and decidual layers in the placenta. These structural defects cause placental hypotrophy and insufficiency, leading to fetal growth retardation. We demonstrate that the tumor suppressor PTEN is elevated in PRL2-deficient placenta. Biochemical analyses indicate that PRL2 promotes Akt activation by down-regulating PTEN through the proteasome pathway. This study provides the first evidence that PRL2 is required for extra-embryonic development and associates the oncogenic properties of PRL2 with its ability to negatively regulate PTEN, thereby activating the PI3K-Akt pathway.