Cell-cycle-regulated Activation of Akt Kinase by Phosphorylation at Its Carboxyl Terminus

Nature. 2014 Apr 24;508(7497):541-5. doi: 10.1038/nature13079. Epub 2014 Mar 9.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Cycle / physiology*
  • Cell Proliferation
  • Cyclin A2 / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Enzyme Activation
  • Male
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Multiprotein Complexes / metabolism
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Olfactory Bulb / cytology
  • Olfactory Bulb / enzymology
  • Olfactory Bulb / metabolism
  • Oncogene Protein v-akt / chemistry
  • Oncogene Protein v-akt / metabolism
  • Phosphorylation
  • Phosphoserine / metabolism
  • Phosphothreonine / metabolism
  • Proto-Oncogene Proteins c-akt / chemistry*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Cyclin A2
  • Multiprotein Complexes
  • Phosphothreonine
  • Phosphoserine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Oncogene Protein v-akt
  • Proto-Oncogene Proteins c-akt
  • Cyclin-Dependent Kinase 2