Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India.
Nat Cell Biol. 2011 Jun;13(6):728-33. doi: 10.1038/ncb2240. Epub 2011 May 1.
PTEN, a lipid phosphatase, is one of the most frequently mutated tumour suppressors in human cancer. Several recent studies have highlighted the importance of ubiquitylation in regulating PTEN tumour-suppressor function, but the enzymatic machinery required for PTEN ubiquitylation is not clear. In this study, by using a tandem affinity-purification approach, we have identified WWP2 (also known as atrophin-1-interacting protein 2, AIP-2) as a PTEN-interacting protein. WWP2 is an E3 ubiquitin ligase that belongs to the NEDD4-like protein family, which is involved in regulating transcription, embryonic stem-cell fate, cellular transport and T-cell activation processes. We show that WWP2 physically interacts with PTEN and mediates its degradation through a ubiquitylation-dependent pathway. Functionally, we show that WWP2 controls cellular apoptosis and is required for tumorigenicity of cells. Collectively, our results reveal a functional E3 ubiquitin ligase for PTEN that plays a vital role in tumour-cell survival.
PTEN 是一种脂质磷酸酶，是人类癌症中最常发生突变的肿瘤抑制因子之一。最近的几项研究强调了泛素化在调节 PTEN 肿瘤抑制功能中的重要性，但 PTEN 泛素化所需的酶机制尚不清楚。在这项研究中，我们通过使用串联亲和纯化方法，鉴定出 WWP2（也称为萎缩蛋白 1 相互作用蛋白 2，AIP-2）是与 PTEN 相互作用的蛋白质。WWP2 是一种 E3 泛素连接酶，属于 NEDD4 样蛋白家族，参与调节转录、胚胎干细胞命运、细胞运输和 T 细胞激活过程。我们表明 WWP2 与 PTEN 物理相互作用，并通过泛素化依赖性途径介导其降解。功能上，我们表明 WWP2 控制细胞凋亡，并且是细胞致瘤性所必需的。总的来说，我们的结果揭示了 PTEN 的一种功能性 E3 泛素连接酶，它在肿瘤细胞存活中起着至关重要的作用。
