Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB
Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB
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DOI：
10.1016/j.molcel.2006.03.029
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发表时间：
2006-04-21
期刊：
影响因子：
16
通讯作者：
Sabatini, DM
中科院分区：
文献类型：
--
作者：
Sarbassov, DD;Ali, SM;Sabatini, DM
药物雷帕霉素在肿瘤学、心脏病学和移植医学中有重要用途，但其临床相关的分子效应尚不清楚。当与FKBP12结合时，雷帕霉素与mTOR、mLST8和Raptor组成的多蛋白复合体(MTORC1)相互作用并抑制其激酶活性。MTOR、mLST8和Rictor的不同复合体(MTORC2)不与FKBP12-雷帕霉素相互作用，也被认为对雷帕霉素不敏感。MTORC2磷酸化并激活Akt/PKB，Akt/PKB是细胞生存的关键调节因子。在这里，我们发现雷帕霉素抑制mTORC2的组装，在许多细胞类型中，长期的雷帕霉素处理使mTORC2的水平降低到维持Akt/PKB信号所需的水平以下。在表达对雷帕霉素耐药的Akt/PKB突变体的细胞中，雷帕霉素的促凋亡和抗肿瘤作用被抑制。我们的工作描述了雷帕霉素的一种不可预见的作用机制，表明它可以用于在某些细胞类型中抑制Akt/PKB。
The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Here we show that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolonged rapamycin treatment reduces the levels of mTORC2 below those needed to maintain Akt/PKB signaling. The proapoptotic and antitumor effects of rapamycin are suppressed in cells expressing an Akt/PKB mutant that is rapamycin resistant. Our work describes an unforeseen mechanism of action for rapamycin that suggests it can be used to inhibit Akt/PKB in certain cell types.