Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis

Pengda Liu, Wenjian Gan, Hiroyuki Inuzuka, Adam S. Lazorchak, Daming Gao, Omotooke Arojo, Dou Liu, Lixin Wan, Bo Zhai, Yonghao Yu, Min Yuan, Byeong Mo Kim, Shavali Shaik, Suchithra Menon, Steven P. Gygi, Tae Ho Lee, John M. Asara, Brendan D. Manning, John Blenis, Bing SuWenyi Wei

Research output: Contribution to journalArticle

144 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1340-1350
Number of pages11
JournalNature Cell Biology
Volume15
Issue number11
DOIs
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Cell Biology

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    Liu, P., Gan, W., Inuzuka, H., Lazorchak, A. S., Gao, D., Arojo, O., Liu, D., Wan, L., Zhai, B., Yu, Y., Yuan, M., Kim, B. M., Shaik, S., Menon, S., Gygi, S. P., Lee, T. H., Asara, J. M., Manning, B. D., Blenis, J., ... Wei, W. (2013). Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nature Cell Biology, 15(11), 1340-1350. https://doi.org/10.1038/ncb2860