期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 4, 页码 1178-1191出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.000392
关键词
anaphase-promoting complex; LATS2; USP9X; ubiquitination; deubiquitination; protein stability; tumor suppressor gene; signal transduction; Hippo pathway
资金
- National Key R&D Program of China [2017YFA0504502]
- National Natural Science Foundation of China Key Project [81730069]
- Excellent Young Scholars Project [31422036]
- General Project [31471316]
- International Collaboration Project [31661130150]
- 111 Project [B13026]
- Qianjiang Scholar Plan of Hangzhou
- Thousand Young Talents Plan of China
- Academy of Medical Sciences (United Kingdom) Newton Advanced Fellowship
- Academy of Medical Sciences (AMS) [NAF003\\1004] Funding Source: researchfish
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据