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MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade

Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AK...

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Autores principales: Cai, Qinbo, Zhou, Wolong, Wang, Wei, Dong, Bingning, Han, Dong, Shen, Tao, Creighton, Chad J., Moore, David D., Yang, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589317/
https://www.ncbi.nlm.nih.gov/pubmed/34767444
http://dx.doi.org/10.1126/sciadv.abi6439
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author Cai, Qinbo
Zhou, Wolong
Wang, Wei
Dong, Bingning
Han, Dong
Shen, Tao
Creighton, Chad J.
Moore, David D.
Yang, Feng
author_facet Cai, Qinbo
Zhou, Wolong
Wang, Wei
Dong, Bingning
Han, Dong
Shen, Tao
Creighton, Chad J.
Moore, David D.
Yang, Feng
author_sort Cai, Qinbo
collection PubMed
description Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AKT at S473 independent of mTORC2, the major S473 kinase. mTOR kinase inhibitors have not made notable progress in the clinic. Our identified MAPK6-AKT axis may provide a major resistance pathway. Besides repressing growth, inhibiting MAPK6 sensitized cancer cells to mTOR kinase inhibitors. MAPK6 overexpression is associated with decreased overall survival and the survival of patients with lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer. MAPK6 expression also correlated with AKT phosphorylation at S473 in human cancer tissues. We conclude that MAPK6 can promote cancer by activating AKT independent of mTORC2 and targeting MAPK6, either alone or in combination with mTOR blockade, may be effective in cancers.
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spelling pubmed-85893172021-11-18 MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade Cai, Qinbo Zhou, Wolong Wang, Wei Dong, Bingning Han, Dong Shen, Tao Creighton, Chad J. Moore, David D. Yang, Feng Sci Adv Biomedicine and Life Sciences Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AKT at S473 independent of mTORC2, the major S473 kinase. mTOR kinase inhibitors have not made notable progress in the clinic. Our identified MAPK6-AKT axis may provide a major resistance pathway. Besides repressing growth, inhibiting MAPK6 sensitized cancer cells to mTOR kinase inhibitors. MAPK6 overexpression is associated with decreased overall survival and the survival of patients with lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer. MAPK6 expression also correlated with AKT phosphorylation at S473 in human cancer tissues. We conclude that MAPK6 can promote cancer by activating AKT independent of mTORC2 and targeting MAPK6, either alone or in combination with mTOR blockade, may be effective in cancers. American Association for the Advancement of Science 2021-11-12 /pmc/articles/PMC8589317/ /pubmed/34767444 http://dx.doi.org/10.1126/sciadv.abi6439 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Cai, Qinbo
Zhou, Wolong
Wang, Wei
Dong, Bingning
Han, Dong
Shen, Tao
Creighton, Chad J.
Moore, David D.
Yang, Feng
MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade
title MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade
title_full MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade
title_fullStr MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade
title_full_unstemmed MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade
title_short MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade
title_sort mapk6-akt signaling promotes tumor growth and resistance to mtor kinase blockade
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589317/
https://www.ncbi.nlm.nih.gov/pubmed/34767444
http://dx.doi.org/10.1126/sciadv.abi6439
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