PMID- 24161930
OWN - NLM
STAT- MEDLINE
DCOM- 20140115
LR  - 20211203
IS  - 1476-4679 (Electronic)
IS  - 1465-7392 (Print)
IS  - 1465-7392 (Linking)
VI  - 15
IP  - 11
DP  - 2013 Nov
TI  - Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt 
      signalling to suppress tumorigenesis.
PG  - 1340-50
LID - 10.1038/ncb2860 [doi]
AB  - 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.
FAU - Liu, Pengda
AU  - Liu P
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, Massachusetts 02215, USA.
FAU - Gan, Wenjian
AU  - Gan W
FAU - Inuzuka, Hiroyuki
AU  - Inuzuka H
FAU - Lazorchak, Adam S
AU  - Lazorchak AS
FAU - Gao, Daming
AU  - Gao D
FAU - Arojo, Omotooke
AU  - Arojo O
FAU - Liu, Dou
AU  - Liu D
FAU - Wan, Lixin
AU  - Wan L
FAU - Zhai, Bo
AU  - Zhai B
FAU - Yu, Yonghao
AU  - Yu Y
FAU - Yuan, Min
AU  - Yuan M
FAU - Kim, Byeong Mo
AU  - Kim BM
FAU - Shaik, Shavali
AU  - Shaik S
FAU - Menon, Suchithra
AU  - Menon S
FAU - Gygi, Steven P
AU  - Gygi SP
FAU - Lee, Tae Ho
AU  - Lee TH
FAU - Asara, John M
AU  - Asara JM
FAU - Manning, Brendan D
AU  - Manning BD
FAU - Blenis, John
AU  - Blenis J
FAU - Su, Bing
AU  - Su B
FAU - Wei, Wenyi
AU  - Wei W
LA  - eng
GR  - AI063348/AI/NIAID NIH HHS/United States
GR  - PR093728/PR/OCPHP CDC HHS/United States
GR  - R01 AI063348/AI/NIAID NIH HHS/United States
GR  - T32 HL007893/HL/NHLBI NIH HHS/United States
GR  - 5T32HL007893/HL/NHLBI NIH HHS/United States
GR  - GM094777/GM/NIGMS NIH HHS/United States
GR  - R01 GM094777/GM/NIGMS NIH HHS/United States
GR  - K01 AG041218/AG/NIA NIH HHS/United States
GR  - R01 GM051405/GM/NIGMS NIH HHS/United States
GR  - GM089763/GM/NIGMS NIH HHS/United States
GR  - CA177910/CA/NCI NIH HHS/United States
GR  - R01 CA177910/CA/NCI NIH HHS/United States
GR  - R01 CA122617/CA/NCI NIH HHS/United States
GR  - R01 GM089763/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131027
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (MAPKAP1 protein, human)
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Nat Cell Biol. 2013 Nov;15(11):1263-5. PMID: 24189516
EIN - Nat Cell Biol. 2019 May;21(5):662-663. PMID: 30783264
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - *Carcinogenesis
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Multiprotein Complexes/*metabolism
MH  - Mutation
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3827117
MID - NIHMS525963
COIS- Competing Financial Interests The authors declare no competing financial 
      interests.
EDAT- 2013/10/29 06:00
MHDA- 2014/01/16 06:00
PMCR- 2014/05/01
CRDT- 2013/10/29 06:00
PHST- 2013/07/14 00:00 [received]
PHST- 2013/09/18 00:00 [accepted]
PHST- 2013/10/29 06:00 [entrez]
PHST- 2013/10/29 06:00 [pubmed]
PHST- 2014/01/16 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - ncb2860 [pii]
AID - 10.1038/ncb2860 [doi]
PST - ppublish
SO  - Nat Cell Biol. 2013 Nov;15(11):1340-50. doi: 10.1038/ncb2860. Epub 2013 Oct 27.