Nature2014-06-18 6:05 PM

Akt由磷酸化介导的活化 Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus

论文摘要 

丝氨酸/苏氨酸蛋白激酶Akt是一种重要的细胞信号作用分子,在如细胞增殖、存活和代谢等一系列过程中发挥功能。它的活化已知受两个关键的磷酸化点控制——一个在催化域中,另一个在一个憎水主题内。在这项研究中,Wenyi Wei及同事发现,Akt的活性在整个细胞周期中波动,在靠近该分子的羧基端的两个点上被Cdk2/cyclin A 或mTORC2磷酸化能促进其在截然不同生理条件下的完全活化。这些新颖的磷酸化事件在Akt的包括癌症、糖尿病和神经疾病在内的病理活动中似乎也是重要的。

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 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 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-Akt, 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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