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The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance
PI3K/Akt signaling is activated in cancers and governs tumor initiation and progression, but how Akt is activated under diverse stresses is poorly understood. Here we identify AMPK as an essential regulator for Akt activation by various stresses. Surprisingly, AMPK is also activated by growth factor...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226490/ https://www.ncbi.nlm.nih.gov/pubmed/30413706 http://dx.doi.org/10.1038/s41467-018-07188-9 |
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author | Han, Fei Li, Chien-Feng Cai, Zhen Zhang, Xian Jin, Guoxiang Zhang, Wei-Na Xu, Chuan Wang, Chi-Yun Morrow, John Zhang, Shuxing Xu, Dazhi Wang, Guihua Lin, Hui-Kuan |
author_facet | Han, Fei Li, Chien-Feng Cai, Zhen Zhang, Xian Jin, Guoxiang Zhang, Wei-Na Xu, Chuan Wang, Chi-Yun Morrow, John Zhang, Shuxing Xu, Dazhi Wang, Guihua Lin, Hui-Kuan |
author_sort | Han, Fei |
collection | PubMed |
description | PI3K/Akt signaling is activated in cancers and governs tumor initiation and progression, but how Akt is activated under diverse stresses is poorly understood. Here we identify AMPK as an essential regulator for Akt activation by various stresses. Surprisingly, AMPK is also activated by growth factor EGF through Ca2+/Calmodulin-dependent kinase and is essential for EGF-mediated Akt activation and biological functions. AMPK phosphorylates Skp2 at S256 and promotes the integrity and E3 ligase activity of Skp2 SCF complex leading to K63-linked ubiquitination and activation of Akt and subsequent oncogenic processes. Importantly, AMPK-mediated Skp2 S256 phosphorylation promotes breast cancer progression in mouse tumor models, correlates with Akt and AMPK activation in breast cancer patients, and predicts poor survival outcomes. Finally, targeting AMPK-mediated Skp2 S256 phosphorylation sensitizes cells to anti-EGF receptor targeted therapy. Our study sheds light on how stress and EGF induce Akt activation and new mechanisms for AMPK-mediated oncogenesis and drug resistance. |
format | Online Article Text |
id | pubmed-6226490 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62264902018-11-13 The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance Han, Fei Li, Chien-Feng Cai, Zhen Zhang, Xian Jin, Guoxiang Zhang, Wei-Na Xu, Chuan Wang, Chi-Yun Morrow, John Zhang, Shuxing Xu, Dazhi Wang, Guihua Lin, Hui-Kuan Nat Commun Article PI3K/Akt signaling is activated in cancers and governs tumor initiation and progression, but how Akt is activated under diverse stresses is poorly understood. Here we identify AMPK as an essential regulator for Akt activation by various stresses. Surprisingly, AMPK is also activated by growth factor EGF through Ca2+/Calmodulin-dependent kinase and is essential for EGF-mediated Akt activation and biological functions. AMPK phosphorylates Skp2 at S256 and promotes the integrity and E3 ligase activity of Skp2 SCF complex leading to K63-linked ubiquitination and activation of Akt and subsequent oncogenic processes. Importantly, AMPK-mediated Skp2 S256 phosphorylation promotes breast cancer progression in mouse tumor models, correlates with Akt and AMPK activation in breast cancer patients, and predicts poor survival outcomes. Finally, targeting AMPK-mediated Skp2 S256 phosphorylation sensitizes cells to anti-EGF receptor targeted therapy. Our study sheds light on how stress and EGF induce Akt activation and new mechanisms for AMPK-mediated oncogenesis and drug resistance. Nature Publishing Group UK 2018-11-09 /pmc/articles/PMC6226490/ /pubmed/30413706 http://dx.doi.org/10.1038/s41467-018-07188-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Han, Fei Li, Chien-Feng Cai, Zhen Zhang, Xian Jin, Guoxiang Zhang, Wei-Na Xu, Chuan Wang, Chi-Yun Morrow, John Zhang, Shuxing Xu, Dazhi Wang, Guihua Lin, Hui-Kuan The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance |
title | The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance |
title_full | The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance |
title_fullStr | The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance |
title_full_unstemmed | The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance |
title_short | The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance |
title_sort | critical role of ampk in driving akt activation under stress, tumorigenesis and drug resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226490/ https://www.ncbi.nlm.nih.gov/pubmed/30413706 http://dx.doi.org/10.1038/s41467-018-07188-9 |
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