The Chaperone-assisted E3 Ligase C Terminus of Hsc70-interacting Protein (CHIP) Targets PTEN for Proteasomal Degradation
The Chaperone-assisted E3 Ligase C Terminus of Hsc70-interacting Protein (CHIP) Targets PTEN for Proteasomal Degradation
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DOI：
10.1074/jbc.m111.321083
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发表时间：
2012-05-04
影响因子：
4.8
通讯作者：
Ghosh, Mrinal K.
中科院分区：
文献类型：
--
作者：
Ahmed, Syed Feroj;Deb, Satamita;Ghosh, Mrinal K.
作为肿瘤抑制因子，PTEN 是调节多种细胞过程的关键，使其成为受到严格监管的主要候选者。 PTEN 水平主要通过泛素-蛋白酶体系统 (UPS) 介导的 E3 连接酶降解来控制。 Nedd 4-1、XIAP 和 WWP2 已被证明可以维持 PTEN 营业额。在此，我们报道 CHIP（分子伴侣相关 E3 连接酶）诱导泛素化并调节 PTEN 的蛋白酶体周转。从我们的发现中可以明显看出，PTEN 短暂地与分子伴侣结合，从而通过与 CHIP 的相互作用转向降解途径。 CHIP 的 TPR 结构域和 PTEN 的部分 N 端结构域是它们相互作用所必需的。 CHIP 的过度表达会导致内源性 PTEN 泛素化升高和半衰期缩短。另一方面，内源性 CHIP 的消耗可以稳定 PTEN。 CHIP 还显示可能通过下调 PTEN 依赖性转录来调节 PTEN 依赖性转录。 PTEN 与人类前列腺癌患者样本中的 CHIP 呈负相关，从而引发了癌症中更复杂的 PTEN 调控模式的前景。
The tumor suppressor, PTEN is key to the regulation of diverse cellular processes, making it a prime candidate to be tightly regulated. The PTEN level is controlled in a major way by E3 ligase-mediated degradation through the Ubiquitin-Proteasome System (UPS). Nedd 4-1, XIAP, and WWP2 have been shown to maintain PTEN turnover. Here, we report that CHIP, the chaperone-associated E3 ligase, induces ubiquitination and regulates the proteasomal turnover of PTEN. It was apparent from our findings that PTEN transiently associates with the molecular chaperones and thereby gets diverted to the degradation pathway through its interaction with CHIP. The TPR domain of CHIP and parts of the N-terminal domain of PTEN are required for their interaction. Overexpression of CHIP leads to elevated ubiquitination and a shortened half-life of endogenous PTEN. On the other hand, depletion of endogenous CHIP stabilizes PTEN. CHIP is also shown to regulate PTEN-dependent transcription presumably through its down-regulation. PTEN shared an inverse correlation with CHIP in human prostate cancer patient samples, thereby triggering the prospects of a more complex mode of PTEN regulation in cancer.