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

Details

• Alternative Title:
  Nat Cell Biol
• Personal Author:
  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
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• Description:
  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.
• Subjects:
  • Adaptor Proteins, Signal Transducing
  • Carcinogenesis
  • Humans
  • Mechanistic Target of Rapamycin Complex 2
  • Multiprotein Complexes
  • Mutation
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • TOR Serine-Threonine Kinases
• Source:
  Nat Cell Biol. 15(11):1340-1350
• Pubmed ID:
  24161930
• Pubmed Central ID:
  PMC3827117
• Document Type:
  Journal Article
• Funding:
  AI063348/AI/NIAID NIH HHSUnited States/ ; PR093728/PR/OCPHP CDC HHSUnited States/ ; R01 AI063348/AI/NIAID NIH HHSUnited States/ ; T32 HL007893/HL/NHLBI NIH HHSUnited States/ ; 5T32HL007893/HL/NHLBI NIH HHSUnited States/ ; GM094777/GM/NIGMS NIH HHSUnited States/ ; R01 GM094777/GM/NIGMS NIH HHSUnited States/ ; K01 AG041218/AG/NIA NIH HHSUnited States/ ; R01 GM051405/GM/NIGMS NIH HHSUnited States/ ; GM089763/GM/NIGMS NIH HHSUnited States/ ; CA177910/CA/NCI NIH HHSUnited States/ ; R01 CA177910/CA/NCI NIH HHSUnited States/ ; R01 CA122617/CA/NCI NIH HHSUnited States/ ; R01 GM089763/GM/NIGMS NIH HHSUnited States/
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• Volume:
  15
• Issue:
  11
• Download URL:
  https://stacks.cdc.gov/view/cdc/23115/cdc_23115_DS1.pdf
• File Type:
  [PDF - 1.69 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:c045f8f73de74e6c8231fb224a562f07836417e43ca3f63d21fdb60140bddb01