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bioRxiv · 10.1101/2021.09.17.460854

A p53-Phosphoinositide Signalosome Regulates Nuclear Akt Activation

Chen, M.·Choi, S.·Wen, T.·Chen, C.·Thapa, N.·Cryns, V. L.·Anderson, R. A.
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Abstract

The tumor suppressor p53 and the phosphoinositide 3-kinase (PI3K)-Akt pathway have fundamental roles in regulating cell growth, apoptosis and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear Akt activation by a p53-dependent mechanism that is independent from the canonical membrane-localized PI3K-Akt pathway. Upon genotoxic stress a nuclear p53-PI3,4,5P3 complex is generated in regions devoid of membranes by a nuclear PI3K, and this complex recruits all the kinases required to activate Akt and phosphorylate FOXOs, inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear Akt in an on/off fashion upon stress, whereas mutant p53 stimulates high basal Akt activity, indicating a fundamental difference. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, underscoring its therapeutic relevance. In briefp53 assembles a PI3K-Akt pathway that regulates nuclear Akt activation independent of the canonical pathway on membranes.

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Chen, M., Choi, S., Wen, T., Chen, C., Thapa, N., Cryns, V. L., Anderson, R. A.. 2021-09-18. A p53-Phosphoinositide Signalosome Regulates Nuclear Akt Activation. https://doi.org/10.1101/2021.09.17.460854

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