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

Pengda Liu, Michael Begley, Wojciech Michowski, Hiroyuki Inuzuka, Miriam Ginzberg, Daming Gao, Peiling Tsou, Wenjian Gan, Antonella Papa, Byeong Mo Kim, Lixin Wan, Amrik Singh, Bo Zhai, Min Yuan, Zhiwei Wang, Steven P. Gygi, Tae Ho Lee, Kun Ping Lu, Alex Toker, Pier Paolo PandolfiJohn M. Asara, Marc W. Kirschner, Piotr Sicinski, Lewis C Cantley, Wenyi Wei

Research output: Contribution to journalArticleResearchpeer-review

181 Citations (Scopus)

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 cancers, and is closely associated with poor prognosis and chemo-or radiotherapeutic resistance. 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 hallmark. 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.

Original languageEnglish
Pages (from-to)541-545
Number of pages5
JournalNature
Volume508
DOIs
Publication statusPublished - 24 Apr 2014
Externally publishedYes

Keywords

  • growth factor signalling
  • kinases
  • oncogenes
  • phosphorylation

Cite this

Liu, P., Begley, M., Michowski, W., Inuzuka, H., Ginzberg, M., Gao, D., Tsou, P., Gan, W., Papa, A., Kim, B. M., Wan, L., Singh, A., Zhai, B., Yuan, M., Wang, Z., Gygi, S. P., Lee, T. H., Lu, K. P., Toker, A., ... Wei, W. (2014). Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature, 508, 541-545. https://doi.org/10.1038/nature13079