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Proc Natl Acad Sci U S A. 2017 May 2;114(18):4691-4696. doi: 10.1073/pnas.1620306114. Epub 2017 Apr 17.

Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability.

Author information

1
Department of Life Science, University of Seoul, Seoul 130-743, Republic of Korea.
2
Department of Mathematics, University of Seoul, Seoul 130-743, Republic of Korea.
3
Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
4
Department of Gastroenterology and Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea.
5
Department of Life Science, University of Seoul, Seoul 130-743, Republic of Korea; ej70@uos.ac.kr.

Abstract

Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination-deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.

KEYWORDS:

Hippo signaling; ITCH; YOD1; cell density; deubiquitinase

PMID:
28416659
PMCID:
PMC5422760
DOI:
10.1073/pnas.1620306114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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