Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers1,2,3, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance4. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark7. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.
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We thank J. Guo, J.J. Liu, A.W. Lau, S. Shaik, A. Tron, X. Dai and K. Xu for reading the manuscript, S.B. Breitkopf for help with mass spectrometry experiments, Y. Geng, L. Liu, K. Ran, R. Chin and S. Elloul for providing reagents, and members of the Wei, Toker, Sicinski, Pandolfi and Cantley laboratories for discussions. W.W. is an American Cancer Society and a Leukemia & Lymphoma Society research scholar. P.L. is supported by 5T32HL007893. This work was supported in part by National Institutes of Health grants to W.W. (GM089763, GM094777 and CA177910), J.M.A. (2P01CA120964) and P.S. (R01CA132740).
The authors declare no competing financial interests.
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Liu, P., Begley, M., Michowski, W. et al. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 508, 541–545 (2014). https://doi.org/10.1038/nature13079
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