p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN
p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN
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DOI：
10.1038/cdd.2013.141
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发表时间：
2014-01-01
影响因子：
12.4
通讯作者：
Kim, T. W.
中科院分区：
文献类型：
--
作者：
Hong, S-W;Moon, J-H;Kim, T. W.
PTEN是人类癌症中最常见的突变或缺失的肿瘤抑制因子之一。NEDD 4 -1最近被鉴定为PTEN的E3泛素连接酶;然而，关于泛素化在调节PTEN功能中的作用以及调节PTEN泛素化的机制，仍然存在许多重要的问题。在本研究中，我们证明了p34，这被确定为NEDD 4 -1的结合伴侣，控制PTEN泛素化通过调节NEDD 4 -1蛋白的稳定性。p34与NEDD 4 -1的WW 1结构域相互作用，这种相互作用增强NEDD 4 -1稳定性。p34的表达促进PTEN多泛素化，导致PTEN蛋白降解，而p34敲低导致PTEN单泛素化。值得注意的是，在来自结肠癌患者的肿瘤样品中证实了PTEN和p34/NEDD 4 -1水平之间的负相关性。因此，p34作为NEDD 4 -1和PTEN的致癌行为的关键调节因子。
PTEN is one of the most frequently mutated or deleted tumor suppressors in human cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; however, a number of important questions remain regarding the role of ubiquitination in regulating PTEN function and the mechanisms by which PTEN ubiquitination is regulated. In the present study, we demonstrated that p34, which was identified as a binding partner of NEDD4-1, controls PTEN ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, an inverse correlation between PTEN and p34/ NEDD4-1 levels was confirmed in tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of the oncogenic behavior of NEDD4-1 and PTEN.