The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C
The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C
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DOI：
10.1038/emboj.2008.120
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发表时间：
2008-07-23
期刊：
影响因子：
11.4
通讯作者：
Jacinto, Estela
中科院分区：
文献类型：
--
作者：
Facchinetti, Valeria;Ouyang, Weiming;Jacinto, Estela
雷帕霉素靶标(TOR)是雷帕霉素敏感的TOR复合体1(TORC1)的一部分，调节蛋白质合成的各个方面。TOR是否作为TORC2的一部分在这一过程中发挥作用仍有待阐明。在这里，我们证明了哺乳动物(M)TORC2的mTOR、SIN1和Rictor是Akt和TURN Motif(TM)位点的常规蛋白激酶C(PKC)磷酸化所必需的。这种TORC2功能是不依赖于生长因子的，从酵母到哺乳动物都是保守的。TM位点的磷酸化促进了羧基末端的折叠，并通过与激酶结构域中保守的碱性残基相互作用来稳定新合成的Akt和PKC。如果没有TM位点的磷酸化，Akt就会受到分子伴侣Hsp90的保护，免受泛素化介导的蛋白酶体降解。最后，我们证明了mTORC2在体内独立控制Akt TM和HM位点，并在体外直接磷酸化这两个位点。我们的研究揭示了TOR途径在调节蛋白质折叠和稳定性方面的一个新功能，这一过程很可能与TOR在蛋白质合成中的功能有关。
The target of rapamycin (TOR), as part of the rapamycin-sensitive TOR complex 1 (TORC1), regulates various aspects of protein synthesis. Whether TOR functions in this process as part of TORC2 remains to be elucidated. Here, we demonstrate that mTOR, SIN1 and rictor, components of mammalian (m) TORC2, are required for phosphorylation of Akt and conventional protein kinase C (PKC) at the turn motif (TM) site. This TORC2 function is growth factor independent and conserved from yeast to mammals. TM site phosphorylation facilitates carboxyl-terminal folding and stabilizes newly synthesized Akt and PKC by interacting with conserved basic residues in the kinase domain. Without TM site phosphorylation, Akt becomes protected by the molecular chaperone Hsp90 from ubiquitination-mediated proteasome degradation. Finally, we demonstrate that mTORC2 independently controls the Akt TM and HM sites in vivo and can directly phosphorylate both sites in vitro. Our studies uncover a novel function of the TOR pathway in regulating protein folding and stability, processes that are most likely linked to the functions of TOR in protein synthesis.