From the Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India.
J Biol Chem. 2013 Nov 29;288(48):34545-54. doi: 10.1074/jbc.M113.503383. Epub 2013 Oct 21.
PHLPP1 (PH domain leucine-rich repeat protein phosphatase 1) is a protein-serine/threonine phosphatase and a negative regulator of the PI3-kinase/Akt pathway. Although its function as a suppressor of tumor cell growth has been established, the mechanism of its regulation is not completely understood. In this study, by utilizing the tandem affinity purification approach we have identified WDR48 and USP12 as novel PHLPP1-associated proteins. The WDR48·USP12 complex deubiquitinates PHLPP1 and thereby enhances its protein stability. Similar to PHLPP1 function, WDR48 and USP12 negatively regulate Akt activation and thus promote cellular apoptosis. Functionally, we show that WDR48 and USP12 suppress proliferation of tumor cells. Importantly, we found a WDR48 somatic mutation (L580F) that is defective in stabilizing PHLPP1 in colorectal cancers, supporting a WDR48 role in tumor suppression. Together, our results reveal WDR48 and USP12 as novel PHLPP1 regulators and potential suppressors of tumor cell survival.
PHLPP1（PH 结构域亮氨酸丰富重复蛋白磷酸酶 1）是一种丝氨酸/苏氨酸磷酸酶，也是 PI3-激酶/Akt 通路的负调控因子。虽然其作为肿瘤细胞生长抑制剂的功能已经确立，但它的调控机制尚不完全清楚。在本研究中，我们利用串联亲和纯化方法鉴定出 WDR48 和 USP12 是 PHLPP1 的新的相关蛋白。WDR48·USP12 复合物可去泛素化 PHLPP1，从而增强其蛋白稳定性。与 PHLPP1 的功能相似，WDR48 和 USP12 负调控 Akt 的激活，从而促进细胞凋亡。在功能上，我们发现 WDR48 和 USP12 抑制肿瘤细胞的增殖。重要的是，我们在结直肠癌中发现了一个 WDR48 体细胞突变（L580F），其在稳定 PHLPP1 方面存在缺陷，这支持了 WDR48 在肿瘤抑制中的作用。综上所述，我们的研究结果揭示了 WDR48 和 USP12 是 PHLPP1 的新型调节因子，也是肿瘤细胞存活的潜在抑制剂。
