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O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

Authors
 Eunah Kim  ;  Jeong Gu Kang  ;  Min Jueng Kang  ;  Jae Hyung Park  ;  Yeon Jung Kim  ;  Tae Hyun Kweon  ;  Han-Woong Lee  ;  Eek-Hoon Jho  ;  Yong-Ho Lee  ;  Seung-Il Kim  ;  Eugene C Yi  ;  Hyun Woo Park  ;  Won Ho Yang  ;  Jin Won Cho 
Citation
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.117(25) : 14259-14269, 2020-06 
Journal Title
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 
ISSN
 0027-8424 
Issue Date
2020-06
MeSH
Adaptor Proteins, Signal Transducing / metabolism ; Apoptosis ; Cell Proliferation ; HEK293 Cells ; Homeostasis ; Humans ; Phosphorylation ; Protein-Serine-Threonine Kinases / metabolism* ; Tumor Suppressor Proteins / metabolism*
Keywords
Hippo pathway ; LATS2 ; MOB1 ; O-GlcNAcylation ; cancer
Abstract
The Hippo pathway controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis. The LATS-mediated negative feedback loop prevents excessive activation of the effectors YAP/TAZ, maintaining homeostasis of the Hippo pathway. YAP and TAZ are hyperactivated in various cancer cells which lead to tumor growth. Aberrantly increased O-GlcNAcylation has recently emerged as a cause of hyperactivation of YAP in cancer cells. However, the mechanism, which induces hyperactivation of TAZ and blocks LATS-mediated negative feedback, remains to be elucidated in cancer cells. This study found that in breast cancer cells, abnormally increased O-GlcNAcylation hyperactivates YAP/TAZ and inhibits LATS2, a direct negative regulator of YAP/TAZ. LATS2 is one of the newly identified O-GlcNAcylated components in the MST-LATS kinase cascade. Here, we found that O-GlcNAcylation at LATS2 Thr436 interrupted its interaction with the MOB1 adaptor protein, which connects MST to LATS2, leading to activation of YAP/TAZ by suppressing LATS2 kinase activity. LATS2 is a core component in the LATS-mediated negative feedback loop. Thus, this study suggests that LATS2 O-GlcNAcylation is deeply involved in tumor growth by playing a critical role in dysregulation of the Hippo pathway in cancer cells.
Files in This Item:
T202003698.pdf Download
DOI
10.1073/pnas.1913469117
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seung Il(김승일)
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/180032
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