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Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus

Nature volume 508, pages 541–545 (2014)Cite this article

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Abstract

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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Figure 1: Akt activity fluctuated during the cell cycle and mirrored the periodic cyclin A expression pattern.
Figure 2: Cdk2/cyclin A2 functioned as a physiological kinase phosphorylating Akt1 at both S477 and T479.
Figure 3: Akt1-S477/T479 phosphorylation triggered Akt1-S473 phosphorylation and enhanced Akt1 activation.
Figure 4: Akt tail phosphorylation triggered Akt activation to promote Akt oncogenic functions.

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Acknowledgements

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).

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Author notes

  1. Zhiwei Wang & Lewis Cantley

    Present address: Present addresses: The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, China (Z.W.); Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital, New York, New York 10065, USA (L.C.).,

Authors and Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Pengda Liu, Hiroyuki Inuzuka, Daming Gao, Wenjian Gan, Antonella Papa, Lixin Wan, Zhiwei Wang, Alex Toker, Pier Paolo Pandolfi & Wenyi Wei

  2. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA

    Michael Begley, Peiling Tsou, Antonella Papa, Min Yuan, Kun-Ping Lu, Pier Paolo Pandolfi, John M. Asara & Lewis Cantley

  3. Department of Systems Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Michael Begley, Peiling Tsou, Marc W. Kirschner & Lewis Cantley

  4. Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Wojciech Michowski & Piotr Sicinski

  5. Department of Cell Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Miriam Ginzberg, Bo Zhai & Steven P. Gygi

  6. Cancer Genetics Program and Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02115, Massachusetts, USA

    Antonella Papa & Pier Paolo Pandolfi

  7. Cell Signaling Technology, Danvers, 01923, Massachusetts, USA

    Amrik Singh

  8. Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA

    Byeong Mo Kim & Tae Ho Lee

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Contributions

P.L., M.B., W.M., H.I., A.P., M.G., D.G., P.T. and W.G. performed most of the experiments with assistance from B.K., L.W., A.S., B.Z. and M.Y. W.W., P.S., P.P.P., L.C. and P.L. designed the experiments. W.W., L.C., P.S., P.P.P., M.W.K. and A.T. supervised the study. P.L. and W.W. wrote the manuscript. All authors commented on the manuscript.

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Correspondence to Wenyi Wei.

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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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