Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway
Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway
复制标题
去泛素化酶 USP9X 通过稳定 Hippo 通路中的大肿瘤抑制激酶 2 (LATS2) 来抑制肿瘤发生
DOI：
10.1074/jbc.ra117.000392
复制
发表时间：
2018-01-26
影响因子：
4.8
通讯作者：
Zhao, Bin
中科院分区：
文献类型：
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作者：
Zhu, Chu;Ji, Xinyan;Zhao, Bin
Hippo通路通过大肿瘤抑制激酶1/2 （LATS1/2）介导的YAP/TAZ转录共激活子磷酸化，在控制器官大小和抑制肿瘤发生中发挥重要作用。LATS1/2的激酶活性受细胞外信号的磷酸化调控。此外，在缺氧等条件下，泛素-蛋白酶体系统会抑制LATS2蛋白水平。然而，从LATS2去除泛素修饰从而稳定该蛋白的机制尚不清楚。在这里，使用串联亲和纯化（TAP），我们发现后期促进复合物/环体（APC/C），一个泛素连接酶复合物，和USP9X，一个去泛素化酶，特异性地与LATS2相互作用。我们还发现，尽管APC1与LATS2共同定位于细胞内囊泡结构，但它不调节LATS2蛋白水平和活性。相比之下，USP9X消融术显著降低了LATS2蛋白水平。我们进一步证明了USP9X去泛素化LATS2，从而阻止了蛋白酶体对LATS2的降解。此外，在胰腺癌细胞中，USP9X的缺失激活了YAP，增强了细胞的致癌潜能。此外，USP9X消融术诱导的肿瘤发生不仅依赖于LATS2抑制，还依赖于YAP/TAZ活性。我们得出结论，USP9X是Hippo通路激酶LATS2的去泛素酶，Hippo通路作为下游信号级联，介导USP9X的肿瘤抑制活性。
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.