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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Bibliographic Details
Published in:Science advances 2021-11, Vol.7 (46), p.eabi6439
Main Authors: Cai, Qinbo, Zhou, Wolong, Wang, Wei, Dong, Bingning, Han, Dong, Shen, Tao, Creighton, Chad J, Moore, David D, Yang, Feng
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Cancer
Cell Biology
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abi6439