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JBC:浙江大学赵斌研究组阐明去泛素化酶USP9X通过调控Hippo信号通路在胰腺癌中发挥抑癌作用

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摘要 : 2017年11月28日,国际知名生物化学杂志《Journal of Biological Chemistry》在线发表了赵斌教授实验室的一篇研究论文,研究论文题为“Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway”

2017年11月28日,国际知名生物化学杂志《Journal of BioLogical Chemistry》在线发表了赵斌教授实验室的一篇研究论文,研究论文题为“Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway”,博士研究生朱楚是本文第一作者,赵斌教授是通讯作者。

Hippo信号转导通路在器官大小调控、癌症发生、组织再生、以及干细胞的功能上发挥重要作用。该通路的核心部分是一个由MST1/2和LATS1/2蛋白激酶组成的激酶链。目前LATS1/2蛋白稳定性的调控调控机制还不清楚。在该研究中,赵斌课题组通过串联亲和纯化发现LATS2结合一个去泛素化酶USP9X。敲除USP9X显著降低LATS2的蛋白水平。进一步研究表明USP9X通过直接去泛素化LATS2阻止其被蛋白酶体降解。另外,已有报道USP9X是一个强烈的胰腺癌抑癌基因,但其下游机制尚不清楚。该研究发现USP9X通过稳定LATS2促进Hippo信号通路中的下游效应分子YAP的磷酸化,抑制YAP的辅转录激活因子功能,从而抑制肿瘤发生。该研究阐明了去泛素化酶对Hippo通路的调控作用,揭示了USP9X在胰腺癌中发挥抑癌作用的分子机制,为临床治疗提供了一个新的研究方向。

JBC:浙江大学赵斌研究组阐明去泛素化酶USP9X通过调控Hippo信号通路在胰腺癌中发挥抑癌作用
USP9X去泛素化LATS2,进而稳定LATS2,抑制YAP活性,抑制胰腺癌发生发展

原文链接:

Deubiquitylase USP9X suppresses tumoriGENEsis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway

原文摘要:

The Hippo pathway plays important roles in controlling organ size and in suppressing tumorigenesis through large tumor suppressor kinase 1/2 (LATS1/2)-mediated phosphorylation of YAP/TAZ transcription co-activators. The kinase activity of LATS1/2 is regulated by phosphorylation in response to extracellular signals. Moreover, LATS2 protein levels are repressed by the ubiquitin–proteasome system in conditions such as hypoxia. However, the mechanism that removes the ubiquitin modification from LATS2 and thereby stabilizes the protein is not well understood. Here, using tandem affinity purification (TAP), we found that anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase complex, and USP9X, a deubiquitylase, specifically interact with LATS2. We also found that although APC1 co-localizes with LATS2 to intracellular vesicle structures, it does not regulate LATS2 protein levels and activity. In contrast, USP9X ablation drastically diminished LATS2 protein levels. We further demonstrated that USP9X deubiquitinates LATS2 and thus prevents LATS2 degradation by the proteasome. Furthermore, in pancreatic cancer cells, USP9X loss activated YAP and enhanced the oncogenic potential of the cells. In addition, the tumorigenesis induced by the USP9X ablation depended not only on LATS2 repression, but also on YAP/TAZ activity. We conclude that USP9X is a deubiquitylase of the Hippo pathway kinase LATS2 and that the Hippo pathway functions as a downstream signaling cascade that mediates USP9X’s tumor-suppressive activity.

doi:10.1074/jbc.RA117.000392

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