Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.
Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.
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Akt也称为蛋白激酶B，在细胞增殖、存活和代谢中起关键作用。Akt过度激活会导致许多病理生理状况，包括人类癌症，并且与预后不良以及化疗或放疗耐药性密切相关。Akt在S473和T308处的磷酸化激活Akt。然而，目前还不清楚是否有进一步的机制解释Akt的完全激活，以及Akt的过度激活是否与另一个癌症标志--细胞周期进程失调有关。在这里，我们报告Akt活性在整个细胞周期波动，反映细胞周期蛋白A的表达。在不同的生理条件下，细胞周期蛋白依赖性激酶2（Cdk 2）/细胞周期蛋白A或mTORC 2在Akt末端羧基端磷酸化S477和T479，通过促进或功能性补偿S473磷酸化促进Akt活化。此外，小鼠嗅球中细胞周期蛋白A2等位基因的缺失导致S477/T479磷酸化减少和细胞凋亡增加。值得注意的是，在小鼠胚胎干细胞中，细胞周期蛋白A2缺失诱导的细胞凋亡部分被S477 D/T479 E-Akt 1挽救，支持细胞周期蛋白A2在调控Akt激活中的生理作用。总之，我们的研究结果表明Akt S477/T479磷酸化是Akt激活机制的一个重要层，以调节其生理功能，从而在癌症中异常细胞周期进展和Akt过度激活之间提供了新的机制联系。
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 radio-therapeutic resistance. Phosphorylation of Akt at S473 and T308 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.
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影响因子：
10.7
作者：
Liu, Pengda;Kenney, John M.;Greenleaf, Arno L.
通讯作者：
Greenleaf, Arno L.
DOI：
10.1083/jcb.60.2.523
发表时间：
1974-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dean PN;Jett JH
通讯作者：
Jett JH
影响因子：
2.7
作者：
Otero, Jose Javier;Kalaszczynska, Ilona;Michowski, Wojciech;Wong, Michael;Gygli, Patrick Edwin;Gokozan, Hamza Numan;Griveau, Amelie;Odajima, Junko;Czeisler, Catherine;Catacutan, Fay Patsy;Murnen, Alice;Schueller, Ulrich;Sicinski, Piotr;Rowitch, David
通讯作者：
Rowitch, David
DOI：
10.1083/jcb.153.1.137
发表时间：
2001-04-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Geley S;Kramer E;Gieffers C;Gannon J;Peters JM;Hunt T
通讯作者：
Hunt T
影响因子：
50.3
作者：
Inuzuka H;Tseng A;Gao D;Zhai B;Zhang Q;Shaik S;Wan L;Ang XL;Mock C;Yin H;Stommel JM;Gygi S;Lahav G;Asara J;Xiao ZX;Kaelin WG Jr;Harper JW;Wei W
通讯作者：
Wei W