Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis.
Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis.
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DOI：
10.1038/ncb2860
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发表时间：
2013-11
影响因子：
21.3
通讯作者：
Wei, Wenyi
中科院分区：
文献类型：
--
作者：
Liu, Pengda;Gan, Wenjian;Inuzuka, Hiroyuki;Lazorchak, Adam S.;Gao, Daming;Arojo, Omotooke;Liu, Dou;Wan, Lixin;Zhai, Bo;Yu, Yonghao;Yuan, Min;Kim, Byeong Mo;Shaik, Shavali;Menon, Suchithra;Gygi, Steven P.;Lee, Tae Ho;Asara, John M.;Manning, Brendan D.;Blenis, John;Su, Bing;Wei, Wenyi
雷帕霉素的机制靶点（mTOR）通过形成多组分但功能不同的复合物mTORC 1和mTORC 2，作为细胞生长和代谢的关键调节剂发挥作用。虽然mTORC 2与mTORC 1的激活有关，但对mTORC 2的调控机制知之甚少。在这里，我们报告说，磷酸化的Sin 1在T86和T398抑制mTORC 2激酶活性的解离Sin 1从mTORC 2。重要的是，S6 K或Akt以细胞环境依赖性方式触发的Sin 1磷酸化不仅抑制胰岛素/IGF-1介导的Akt磷酸化，还抑制mTORC 2诱导的PDGF或EGF诱导的Akt磷酸化，表明mTORC 2的负调控独立于IRS-1和Grb 10。最后，癌症患者来源的Sin 1-R81 T突变损害Sin 1磷酸化，通过绕过这种负调控导致超mTORC 2激活。总之，我们的工作揭示了Sin 1磷酸化依赖的mTORC 2调节，提供了一个潜在的分子机制，mTORC 1/S6 K/Sin 1信号轴的突变可能会导致mTORC 2/Akt的异常过度激活，促进肿瘤发生。
The mechanistic target of rapamycin (mTOR) functions as a critical regulator of cellular growth and metabolism by forming multi-component, yet functionally distinct complexes mTORC1 and mTORC2. Although mTORC2 has been implicated in mTORC1 activation, little is known about how mTORC2 is regulated. Here we report that phosphorylation of Sin1 at T86 and T398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2. Importantly, Sin1 phosphorylation, triggered by S6K or Akt, in a cellular context-dependent manner, inhibits not only insulin/IGF-1-mediated, but also PDGF or EGF-induced Akt phosphorylation by mTORC2, demonstrating a negative regulation of mTORC2 independent of IRS-1 and Grb10. Lastly, a cancer patient-derived Sin1-R81T mutation impairs Sin1 phosphorylation, leading to hyper-mTORC2 activation via bypassing this negative regulation. Together, our work reveals a Sin1 phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the mTORC1/S6K/Sin1 signaling axis might cause aberrant hyper-activation of mTORC2/Akt that facilitates tumorigenesis.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
DOI：
10.1016/j.bbagen.2005.04.002
发表时间：
2005-10-10
影响因子：
3
作者：
Baer, K;Lisinski, I;Al-Hasani, H
通讯作者：
Al-Hasani, H
影响因子：
7.2
作者：
Hung, Chien-Min;Garcia-Haro, Luisa;Guertin, David A.
通讯作者：
Guertin, David A.
影响因子：
14.9
作者：
Forbes, Simon A.;Tang, Gurpreet;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew