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Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

Authors
 Youngeun Kim  ;  Wantae Kim  ;  Yonghee Song  ;  Jeong-Rae Kim  ;  Kyungjoo Cho  ;  Hyuk Moon  ;  Simon Weonsang Ro  ;  Eunjeong Seo  ;  Yeon-Mi Ryu  ;  Seung-Jae Myung  ;  Eek-Hoon Jho 
Citation
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.114(18) : 4691-4696, 2017 
Journal Title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN
 0027-8424 
Issue Date
2017
Keywords
Hippo signaling ; ITCH ; YOD1 ; cell density ; deubiquitinase
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.
Full Text
http://www.pnas.org/content/114/18/4691.long
DOI
10.1073/pnas.1620306114
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
Yonsei Authors
Ro, Simon Weonsang(노원상) ORCID logo https://orcid.org/0000-0003-2187-3698
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154446
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