@article{9e462000016643679f43f65e40b79200,
title = "Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis",
abstract = "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 Thr 86 and Thr 398 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- or 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. Finally, a cancer-patient-derived Sin1-R81T mutation impairs Sin1 phosphorylation, leading to hyper-activation of mTORC2 by bypassing this negative regulation. Together, our results reveal a Sin1-phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the mTORC1-S6K-Sin1 signalling axis might cause aberrant hyper-activation of the mTORC2-Akt pathway, which facilitates tumorigenesis.",
author = "Pengda Liu and Wenjian Gan and Hiroyuki Inuzuka and Lazorchak, {Adam S.} and Daming Gao and Omotooke Arojo and Dou Liu and Lixin Wan and Bo Zhai and Yonghao Yu and Min Yuan and Kim, {Byeong Mo} and Shavali Shaik and Suchithra Menon and Gygi, {Steven P.} and Lee, {Tae Ho} and Asara, {John M.} and Manning, {Brendan D.} and John Blenis and Bing Su and Wenyi Wei",
note = "Funding Information: We thank A. Toker, J. Guo, K. Xu, A. W. Lau and A. Tron for critical reading of the manuscript, S. J. Elledge (Harvard Medial School, USA), S. Ishii (University of Tsukuba, Japan), W. Hahn (Dana-Farber Cancer Institute, Harvard Medical School, USA), D. Sarbassov (UT M. D. Anderson Cancer Center, USA) K. Guan (UC San Diego, USA) and J. Dempsey (Harvard Medical School, USA) for providing valuable reagents, B. Spiegelman (Dana-Farber Cancer Institute, Harvard Medical School, USA) for providing 3T3-L1 adipocyte cells, L. Cantley and A. Toker for helpful suggestions, and members of the W.W., J.B. and B.S. laboratories for useful discussions. W.W. is an ACS research scholar and a LLS research scholar. Y. Yu is a CPRIT Scholar (CPRIT R1103) in Cancer Research and a Virginia Murchison Linthicum Scholar in Medical Research. P.L. is a NRSA T32 trainee and supported by 5T32HL007893. This work was supported in part by NIH grants (W.W., GM089763, GM094777 and CA177910; and B.S., AI063348 and PR093728).",
year = "2013",
month = nov,
doi = "10.1038/ncb2860",
language = "English",
volume = "15",
pages = "1340--1350",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "11",
}
