DNA-PK promotes activation of the survival kinase AKT in response to DNA damage through an mTORC2-ECT2 pathway.
DNA-PK promotes activation of the survival kinase AKT in response to DNA damage through an mTORC2-ECT2 pathway.
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DOI：
10.1126/scisignal.abh2290
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发表时间：
2022-01-04
影响因子：
7.3
通讯作者：
Gan W
中科院分区：
文献类型：
--
作者：
Liu L;Dai X;Yin S;Liu P;Hill EG;Wei W;Gan W
激酶AKT（也称为蛋白激酶B）是细胞增殖、存活和代谢的关键调节剂。除了被生长因子激活外，AKT还响应DNA损伤而被激活。在这里，我们发现DNA损伤反应激酶DNA-PK通过导致AKT活性增加的磷酸化事件维持细胞存活。在培养的各种癌症和非癌细胞中，由电离辐射或拓扑异构酶抑制剂引起的DNA损伤触发了mTOR复合物2（mTORC 2）亚基Sin 1的DNA-PK依赖性磷酸化，这使得能够与鸟嘌呤核苷酸交换因子ECT 2相互作用。耗尽Sin 1或ECT 2或破坏蛋白质相互作用或ECT 2的催化功能会减弱DNA损伤诱导的AKT活化，从而增强细胞对DNA损伤剂的敏感性。我们的研究结果阐明了介导DNA损伤诱导的AKT激活和细胞存活的机制。
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 non-cancer 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 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.
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