Journal article
Liu Liu, Xiaoming Dai, Shasha Yin, Pengda Liu, Elizabeth G. Hill, Wenyi Wei, W. Gan
Science Signaling, 2022
Science Signaling, 2022
Semantic Scholar
DOI
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APA
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Liu, L., Dai, X., Yin, S., Liu, P., Hill, E. G., Wei, W., & Gan, W. (2022). DNA-PK promotes activation of the survival kinase AKT in response to DNA damage through an mTORC2-ECT2 pathway. Science Signaling.
Chicago/Turabian
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Liu, Liu, Xiaoming Dai, Shasha Yin, Pengda Liu, Elizabeth G. Hill, Wenyi Wei, and W. Gan. “DNA-PK Promotes Activation of the Survival Kinase AKT in Response to DNA Damage through an mTORC2-ECT2 Pathway.” Science Signaling (2022).
MLA
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Liu, Liu, et al. “DNA-PK Promotes Activation of the Survival Kinase AKT in Response to DNA Damage through an mTORC2-ECT2 Pathway.” Science Signaling, 2022.
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@article{liu2022a,
title = {DNA-PK promotes activation of the survival kinase AKT in response to DNA damage through an mTORC2-ECT2 pathway},
year = {2022},
journal = {Science Signaling},
author = {Liu, Liu and Dai, Xiaoming and Yin, Shasha and Liu, Pengda and Hill, Elizabeth G. and Wei, Wenyi and Gan, W.}
}
Abstract
Description How the DNA damage response promotes cell survival through the kinase DNA-PK is revealed. DNA-PK’s double duty The kinase DNA-PK is a coordinator of the DNA damage response (DDR). DNA-PK also promotes cell survival and resistance to chemotherapy through activation of the kinase AKT. Liu et al. found that DNA-PK mediated a phosphorylation event that activated AKT in a manner dependent on mTOR complex 2 and the guanine nucleotide exchange factor ECT2. Disrupting this mechanism increased the toxicity of DNA-damaging agents in cultured cells. The findings elucidate a pathway linking the DDR to cell survival and may lead to new ways to overcome tumor resistance to DNA damage–associated therapies (see also the Focus by Shin et al.). The kinase AKT (also known as protein kinase B) is a key regulator of cell proliferation, survival, and metabolism. In addition to being activated by growth factors, AKT is activated in response to DNA damage. Here, we found that the DNA damage response kinase DNA-PK sustains cell survival through a phosphorylation event that leads to increased AKT activity. In various cancer and noncancer cells in culture, DNA damage caused by ionizing radiation or topoisomerase inhibitors triggered DNA-PK–dependent phosphorylation of the mTOR complex 2 (mTORC2) subunit Sin1, which enabled its interaction with the guanine nucleotide exchange factor ECT2. Depleting Sin1 or ECT2 or disrupting the protein interaction or catalytic function of ECT2 attenuated DNA damage–induced AKT activation, thereby enhancing cellular sensitivity to DNA-damaging agents. Our findings elucidate a mechanism mediating DNA damage–induced AKT activation and cell survival.
