RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation
RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation
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DOI：
10.1038/cr.2013.27
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发表时间：
2013-04-01
期刊：
影响因子：
44.1
通讯作者：
Gu, Wei
中科院分区：
文献类型：
--
作者：
Lee, James T.;Shan, Jing;Gu, Wei
PTEN肿瘤抑制因子是一种脂质磷酸酶，在调节磷脂酰肌醇-3-激酶（PI 3 K）信号转导级联中发挥重要作用。然而，PTEN活性在细胞中调节的机制需要进一步阐明。虽然以前的研究表明，泛素化的PTEN可以调节其稳定性和亚细胞定位，泛素化的作用，在最关键的方面，其磷酸酶活性的PTEN功能，尚未得到充分解决。在这里，我们确定了一种新的E3泛素连接酶的PTEN，Ret指蛋白（RFP），这是能够促进非典型的多泛素化的PTEN。这些泛素化不导致PTEN不稳定或重新定位，而是显著抑制PTEN磷酸酶活性，因此调节其调节PI 3 K信号转导级联的能力。事实上，RFP过表达减轻了PTEN介导的对AKT活化的抑制作用;相反，RNAi介导的内源性RFP敲低增强了PTEN抑制AKT活化的能力。此外，RFP介导的PTEN泛素化抑制了TRAIL表达的PTEN依赖性激活，也抑制了其诱导凋亡的能力。我们的研究结果表明，RFP介导的泛素化在控制PTEN活性的关键作用。
The PTEN tumor suppressor is a lipid phosphatase that has a central role in regulating the phosphatidylinositol-3-kinase (PI3K) signal transduction cascade. Nevertheless, the mechanism by which the PTEN activity is regulated in cells needs further elucidation. Although previous studies have shown that ubiquitination of PTEN can modulate its stability and subcellular localization, the role of ubiquitination in the most critical aspect of PTEN function, its phosphatase activity, has not been fully addressed. Here, we identify a novel E3 ubiquitin ligase of PTEN, Ret finger protein (RFP), that is able to promote atypical polyubiquitinations of PTEN. These ubiquitinations do not lead to PTEN instability or relocalization, but rather significantly inhibit PTEN phosphatase activity and therefore modulate its ability to regulate the PI3K signal transduction cascade. Indeed, RFP overexpression relieves PTEN-mediated inhibitory effects on AKT activation; in contrast, RNAi-mediated knockdown of endogenous RFP enhances the ability of PTEN to suppress AKT activation. Moreover, RFP-mediated ubiquitination of PTEN inhibits PTEN-dependent activation of TRAIL expression and also suppresses its ability to induce apoptosis. Our findings demonstrate a crucial role of RFP-mediated ubiquitination in controlling PTEN activity.