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MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation....

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Autores principales: An, Liwei, Nie, Pingping, Chen, Min, Tang, Yang, Zhang, Hui, Guan, Jingmin, Cao, Zhifa, Hou, Chun, Wang, Wenjia, Zhao, Yun, Xu, Huixiong, Jiao, Shi, Zhou, Zhaocai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971137/
https://www.ncbi.nlm.nih.gov/pubmed/32271880
http://dx.doi.org/10.1084/jem.20191817
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author An, Liwei
Nie, Pingping
Chen, Min
Tang, Yang
Zhang, Hui
Guan, Jingmin
Cao, Zhifa
Hou, Chun
Wang, Wenjia
Zhao, Yun
Xu, Huixiong
Jiao, Shi
Zhou, Zhaocai
author_facet An, Liwei
Nie, Pingping
Chen, Min
Tang, Yang
Zhang, Hui
Guan, Jingmin
Cao, Zhifa
Hou, Chun
Wang, Wenjia
Zhao, Yun
Xu, Huixiong
Jiao, Shi
Zhou, Zhaocai
author_sort An, Liwei
collection PubMed
description Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4–YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4–YAP signaling axis essential for suppressing gastric tumorigenesis.
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spelling pubmed-79711372021-03-26 MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway An, Liwei Nie, Pingping Chen, Min Tang, Yang Zhang, Hui Guan, Jingmin Cao, Zhifa Hou, Chun Wang, Wenjia Zhao, Yun Xu, Huixiong Jiao, Shi Zhou, Zhaocai J Exp Med Article Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4–YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4–YAP signaling axis essential for suppressing gastric tumorigenesis. Rockefeller University Press 2020-04-09 /pmc/articles/PMC7971137/ /pubmed/32271880 http://dx.doi.org/10.1084/jem.20191817 Text en © 2020 An et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
An, Liwei
Nie, Pingping
Chen, Min
Tang, Yang
Zhang, Hui
Guan, Jingmin
Cao, Zhifa
Hou, Chun
Wang, Wenjia
Zhao, Yun
Xu, Huixiong
Jiao, Shi
Zhou, Zhaocai
MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway
title MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway
title_full MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway
title_fullStr MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway
title_full_unstemmed MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway
title_short MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway
title_sort mst4 kinase suppresses gastric tumorigenesis by limiting yap activation via a non-canonical pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971137/
https://www.ncbi.nlm.nih.gov/pubmed/32271880
http://dx.doi.org/10.1084/jem.20191817
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