The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance

Fei Han, Chien-Feng Li, Zhen Cai, Xian Zhang, Guoxiang Jin, Wei-Na Zhang, Chuan Xu, Chi-Yun Wang, John Morrow, Shuxing Zhang, Dazhi Xu (), Guihua Wang () and Hui-Kuan Lin ()
Additional contact information
Fei Han: Wake Forest School of Medicine
Chien-Feng Li: Chi-Mei Foundational Medical Center
Zhen Cai: Wake Forest School of Medicine
Xian Zhang: Wake Forest School of Medicine
Guoxiang Jin: Wake Forest School of Medicine
Wei-Na Zhang: Wake Forest School of Medicine
Chuan Xu: Wake Forest School of Medicine
Chi-Yun Wang: Wake Forest School of Medicine
John Morrow: The University of Texas MD Anderson Cancer Center
Shuxing Zhang: The University of Texas MD Anderson Cancer Center
Dazhi Xu: The University of Texas MD Anderson Cancer Center
Guihua Wang: Wake Forest School of Medicine
Hui-Kuan Lin: Wake Forest School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-07188-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07188-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-07188-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().