nature

当前位置: Nature » 蛋白&蛋白质组学 » 正文

苏氨酸蛋白激酶Akt由磷酸化介导的活化

摘要 : 哈佛医学院的研究人员在新研究中表明,Akt S477/T479磷酸化是Akt激活机制的一个重要层面,其调控了Akt的生理功能,由此揭示出了癌症中联系异常细胞周期进程与Akt过度激活的一个新机制。相关文章发表于2014年4月9日的《Nature》杂志上。

细胞增殖分裂是细胞最基本的生理活动,生长因子、激素及癌基因产物等均可诱导细胞的增殖或抑制细胞的增殖,归根到底均是影响细胞周期的运行。研究表明,细胞周期调控异常与细胞癌变密切相关。失控性的细胞生长与分裂是癌症的一个重要标志。

Akt,亦被称作为Akt蛋白激酶B(PKB),是在如葡萄糖代谢、凋亡、细胞增殖转录及细胞迁移等多种细胞过程中起到重要作用的一种丝氨酸/苏氨酸特异性蛋白激酶。Akt过度激活可导致包括癌症在内的许多病理状况,与癌症不良预后以及化疗或放疗耐受密切相关。以往的研究证实S473和T308位点磷酸化可以激活Akt。目前尚不清楚是否还有进一步的机制导致了Akt完全激活,Akt过度激活是否与细胞周期进程失控之间是否存在直接关联。

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。

通过在小鼠嗅球中删除cyclin A2等位基因,研究人员发现其可导致S477/T479磷酸化减少,细胞凋亡增加。值得注意的是,S477D/T479E-Akt1可部分恢复小鼠胚胎干细胞中cyclin A2删除诱导的细胞凋亡,这表明cyclin A2在控制Akt激活中发挥了重要的生理学作用。

通过另外的一些实验,研究人员还证实Akt尾部磷酸化触动Akt激活促进了Akt的致癌功能。除了稳定Akt,Akt尾部磷酸化有可能通过改变Akt激酶动力学加速了激酶反应。此外,Akt尾部磷酸化激活Akt,还可提高Skp2或FOXO磷酸化,分别进一步促进细胞周期进程,或是导致了化疗耐受。

这些研究结果表明,Akt S477/T479磷酸化是Akt激活机制的一个重要层面,其调控了Akt的生理功能,由此揭示出了癌症中联系异常细胞周期进程与Akt过度激活的一个新机制。

原文摘要:

Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus

Pengda Liu, Michael Begley, Wojciech Michowski, Hiroyuki Inuzuka, Miriam Ginzberg,Daming Gao, Peiling Tsou, Wenjian Gan, Antonella Papa, Byeong Mo Kim, Lixin Wan, Amrik Singh, Bo Zhai, Min Yuan, Zhiwei Wang, Steven P. Gygi, Tae Ho Lee, Kun-Ping Lu, Alex Toker, Pier Paolo Pandolfi, John M. Asara, Marc W. Kirschner, Piotr Sicinski, Lewis Cantley& Wenyi Wei

Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and me-tabolism. 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 1inked to misregulated cell cycle progression, another cancer hallmark7. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expressi0n. 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 1ink between aberrant cell cycle progression and Akt hyperactivation in cancer.

对应Nature杂志: 2014年4月24日Nature杂志精选

来源: Nature 浏览次数:115

热门文章TOP

RSS订阅 - 填写您的邮件地址,订阅我们的精彩内容: - 网站地图
网站联系电话:020-87540820 备案号:粤ICP备11050685号-8 增值电信业务经营许可证:粤B2-20120479
©2011-2015 生物帮 All rights reserved.