Akt plays important roles in cell proliferation, survival, and metabolism. Akt hyperactivation contributes to tumorigenesis and is associated with poor prognosis and resistance to chemotherapy and radiotherapy. It is known that activation of Akt results from phosphorylation at S473 and T308, but it is unclear whether other mechanisms are involved in full Akt activation. It is also unclear whether Akt hyperactivation is associated with dysregulated cell-cycle progression, which is also involved in tumorigenesis.
In a study reported in Nature, Liu and colleagues found that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. They showed that phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2 promoted Akt activation by facilitating or functionally compensating for S473 phosphorylation. Deletion of the cyclin A2 allele in the mouse olfactory bulb resulted in reduced S477/T479 phosphorylation and increased apoptosis. Cellular apoptosis in mouse embryonic stem cells induced by cyclin A2 deletion was partly inhibited by S477D/T479E-Akt1, supporting a physiologic role for cyclin A2 in controlling Akt activation.
The investigators concluded, “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.” ■
Liu P, et al: Nature 508:541-545, 2014.
