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.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Pengda
authors.initials: P
authors.lastname: Liu
authors.forename: Wenjian
authors.initials: W
authors.lastname: Gan
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.forename: Adam S
authors.initials: AS
authors.lastname: Lazorchak
authors.forename: Daming
authors.initials: D
authors.lastname: Gao
authors.forename: Omotooke
authors.initials: O
authors.lastname: Arojo
authors.forename: Dou
authors.initials: D
authors.lastname: Liu
authors.forename: Lixin
authors.initials: L
authors.lastname: Wan
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.forename: Min
authors.initials: M
authors.lastname: Yuan
authors.forename: Byeong Mo
authors.initials: BM
authors.lastname: Kim
authors.forename: Shavali
authors.initials: S
authors.lastname: Shaik
authors.forename: Suchithra
authors.initials: S
authors.lastname: Menon
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Tae Ho
authors.initials: TH
authors.lastname: Lee
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493277:MAPKAP1 protein, human; D046912:Multiprotein Complexes; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases