Phosphorylation of Akt at the C-terminal tail triggers Akt activation.

Aberrant hyper-activation of the protein kinase Akt plays a critical role in promoting tumorigenesis. Mechanistically, previous studies establish that phosphorylation of Akt at S473 and T308 by mTORC2 and PDK1, respectively, is necessary for its full activation, thereby having been used as Akt activation markers. Recently, we report that phosphorylation of S477 and T479 at the extreme C-terminus of Akt1 promotes Akt1 activation. We further demonstrate that Akt1 pS477 and pT479 events are governed by Cdk2/Cyclin A or mTORC2 under distinct cellular contexts such as cell cycle progression or growth stimulation conditions. Here, we summarize our major findings regarding the biological significance for pS477/pT479-mediated activation of Akt and also provide perspectives for future follow-up studies.