Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis
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Lazorchak, Adam S
Gao, Daming
Arojo, Omotooke
Liu, Dou
Zhai, Bo
Yu, Yonghao
Kim, Byeong Mo
Menon, Suchithra
Lee, Tae Ho
Su, Bing
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ncb2860Metadata
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Liu, P., W. Gan, H. Inuzuka, A. S. Lazorchak, D. Gao, O. Arojo, D. Liu, et al. 2013. “Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis.” Nature cell biology 15 (11): 10.1038/ncb2860. doi:10.1038/ncb2860. http://dx.doi.org/10.1038/ncb2860.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 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827117/pdf/Terms of Use
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