Journal of Biological Chemistry
Volume 293, Issue 4, 26 January 2018, Pages 1178-1191
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Protein Synthesis and Degradation
Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway

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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.

anaphase-promoting complex
LATS2
USP9X
ubiquitination
deubiquitination
protein stability
tumor suppressor gene
signal transduction
Hippo pathway

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This work was supported by National Key R&D Program of China Grant 2017YFA0504502, National Natural Science Foundation of China Key Project Grant 81730069, Excellent Young Scholars Project Grant 31422036, General Project Grant 31471316, International Collaboration Project Grant 31661130150, 111 Project Grant B13026, the Qianjiang Scholar Plan of Hangzhou, the Thousand Young Talents Plan of China, and the Academy of Medical Sciences (United Kingdom) Newton Advanced Fellowship (to B. Z.). The authors declare that they have no conflicts of interest with the contents of this article.

This article contains Figs. S1–S6.