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SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis

The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of...

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Autores principales: Wang, Guihua, Long, Jie, Gao, Yuan, Zhang, Weina, Han, Fei, Xu, Chuan, Sun, Li, Yang, Shun-Chin, Lan, Jingqin, Hou, Zhenlin, Cai, Zhen, Jin, Guoxiang, Hsu, Che-Chia, Wang, Yu-Hui, Hu, Junbo, Chen, Tsai-Yu, Li, Hongyu, Lee, Min Gyu, Lin, Hui-Kuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414065/
https://www.ncbi.nlm.nih.gov/pubmed/30692626
http://dx.doi.org/10.1038/s41556-018-0266-1
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author Wang, Guihua
Long, Jie
Gao, Yuan
Zhang, Weina
Han, Fei
Xu, Chuan
Sun, Li
Yang, Shun-Chin
Lan, Jingqin
Hou, Zhenlin
Cai, Zhen
Jin, Guoxiang
Hsu, Che-Chia
Wang, Yu-Hui
Hu, Junbo
Chen, Tsai-Yu
Li, Hongyu
Lee, Min Gyu
Lin, Hui-Kuan
author_facet Wang, Guihua
Long, Jie
Gao, Yuan
Zhang, Weina
Han, Fei
Xu, Chuan
Sun, Li
Yang, Shun-Chin
Lan, Jingqin
Hou, Zhenlin
Cai, Zhen
Jin, Guoxiang
Hsu, Che-Chia
Wang, Yu-Hui
Hu, Junbo
Chen, Tsai-Yu
Li, Hongyu
Lee, Min Gyu
Lin, Hui-Kuan
author_sort Wang, Guihua
collection PubMed
description The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt upon growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which recognizes Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, cancer associated Akt mutant (E17K) displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumor development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis.
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spelling pubmed-64140652019-07-28 SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis Wang, Guihua Long, Jie Gao, Yuan Zhang, Weina Han, Fei Xu, Chuan Sun, Li Yang, Shun-Chin Lan, Jingqin Hou, Zhenlin Cai, Zhen Jin, Guoxiang Hsu, Che-Chia Wang, Yu-Hui Hu, Junbo Chen, Tsai-Yu Li, Hongyu Lee, Min Gyu Lin, Hui-Kuan Nat Cell Biol Article The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt upon growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which recognizes Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, cancer associated Akt mutant (E17K) displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumor development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis. 2019-01-28 2019-02 /pmc/articles/PMC6414065/ /pubmed/30692626 http://dx.doi.org/10.1038/s41556-018-0266-1 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wang, Guihua
Long, Jie
Gao, Yuan
Zhang, Weina
Han, Fei
Xu, Chuan
Sun, Li
Yang, Shun-Chin
Lan, Jingqin
Hou, Zhenlin
Cai, Zhen
Jin, Guoxiang
Hsu, Che-Chia
Wang, Yu-Hui
Hu, Junbo
Chen, Tsai-Yu
Li, Hongyu
Lee, Min Gyu
Lin, Hui-Kuan
SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis
title SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis
title_full SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis
title_fullStr SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis
title_full_unstemmed SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis
title_short SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis
title_sort setdb1-mediated methylation of akt promotes its k63-linked ubiquitination and activation leading to tumorigenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414065/
https://www.ncbi.nlm.nih.gov/pubmed/30692626
http://dx.doi.org/10.1038/s41556-018-0266-1
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