WWP2 is a physiological ubiquitin ligase for phosphatase and tensin homolog (PTEN) in mice
WWP2 is a physiological ubiquitin ligase for phosphatase and tensin homolog (PTEN) in mice
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WWP2 是小鼠磷酸酶和张力蛋白同源物 (PTEN) 的生理性泛素连接酶
DOI：
10.1074/jbc.ra117.001060
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发表时间：
2018-06-08
影响因子：
4.8
通讯作者：
Zhang, Lingqiang
中科院分区：
文献类型：
--
作者：
Li, Hongchang;Zhang, Pengfei;Zhang, Lingqiang
肿瘤抑制性磷酸酶和张力蛋白同源物（PTEN）在调节磷脂酰肌醇3-激酶（PI 3 K）信号传导中起核心作用，并且其基因在各种人类癌症中非常频繁地突变。大量研究表明，PTEN水平受到转录和翻译后修饰的严格调控，尤其是泛素化显著调节PTEN蛋白水平。虽然已经报道了几种泛素连接酶在体外介导PTEN泛素化，但促进体内PTEN降解的泛素连接酶尚未报道。在这里，我们利用特定的基因敲除小鼠模型，以证明WW结构域的E3泛素蛋白连接酶2（WWP 2）促进PTEN降解在生理条件下，而另一种泛素连接酶，热休克蛋白70相互作用蛋白（CHIP）的羧基末端，没有这样的效果。WWP 2敲除小鼠表现出减小的体型、升高的PTEN蛋白水平以及降低的丝氨酸/苏氨酸激酶和PTEN靶AKT的磷酸化水平。相反，我们观察到在CHIP敲除组织和小鼠胚胎成纤维细胞中没有PTEN蛋白水平升高。此外，CHIP/WWP 2双敲除小鼠中的PTEN蛋白水平与WWP 2单敲除小鼠中的那些非常相似，并且显著高于WT和CHIP敲除小鼠。我们的结果表明，WWP 2而不是CHIP是一种促进体内PTEN降解的遍在蛋白连接酶。考虑到PTEN在肿瘤发展中的重要作用，我们认为WWP 2可能是抗癌治疗中微调PTEN水平的潜在靶点。
The tumor suppressor phosphatase and tensin homolog (PTEN) plays a central role in regulating phosphatidylinositol 3-kinase (PI3K) signaling, and its gene is very frequently mutated in various human cancers. Numerous studies have revealed that PTEN levels are tightly regulated by both transcriptional and posttranslational modifications, with especially ubiquitylation significantly regulating PTEN protein levels. Although several ubiquitin ligases have been reported to mediate PTEN ubiquitylation in vitro, the ubiquitin ligase that promotes PTEN degradation in vivo has not been reported. Here we took advantage of specific knockout mouse models to demonstrate that WW domain–containing E3 ubiquitin protein ligase 2 (WWP2) promotes PTEN degradation under physiological conditions, whereas another ubiquitin ligase, carboxyl terminus of Hsp70-interacting protein (CHIP), had no such effect. WWP2 knockout mice exhibited reduced body size, elevated PTEN protein levels, and reduced phosphorylation levels of the serine/threonine kinase and PTEN target AKT. In contrast, we observed no elevation of PTEN protein levels in CHIP knockout tissues and mouse embryonic fibroblasts. Furthermore, PTEN protein levels in CHIP/WWP2 double knockout mice were very similar to those in WWP2 single knockout mice and significantly higher than in WT and CHIP knockout mice. Our results demonstrate that WWP2, rather than CHIP, is an ubiquitin ligase that promotes PTEN degradation in vivo. Considering PTEN's significant role in tumor development, we propose that WWP2 may be a potential target for fine-tuning PTEN levels in anticancer therapies.