PMID- 24481632
OWN - NLM
STAT- MEDLINE
DCOM- 20141116
LR  - 20211203
IS  - 1674-8018 (Electronic)
IS  - 1674-800X (Print)
IS  - 1674-800X (Linking)
VI  - 5
IP  - 3
DP  - 2014 Mar
TI  - Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex 
      integrity and activity.
PG  - 171-7
LID - 10.1007/s13238-014-0021-8 [doi]
AB  - Mammalian target of rapamycin (mTOR) plays essential roles in cell proliferation, 
      survival and metabolism by forming at least two functional distinct multi-protein 
      complexes, mTORC1 and mTORC2. External growth signals can be received and 
      interpreted by mTORC2 and further transduced to mTORC1. On the other hand, mTORC1 
      can sense inner-cellular physiological cues such as amino acids and energy states 
      and can indirectly suppress mTORC2 activity in part through phosphorylation of 
      its upstream adaptors, IRS-1 or Grb10, under insulin or IGF-1 stimulation 
      conditions. To date, upstream signaling pathways governing mTORC1 activation have 
      been studied extensively, while the mechanisms modulating mTORC2 activity remain 
      largely elusive. We recently reported that Sin1, an essential mTORC2 subunit, was 
      phosphorylated by either Akt or S6K in a cellular context-dependent manner. More 
      importantly, phosphorylation of Sin1 at T86 and T398 led to a dissociation of 
      Sin1 from the functional mTORC2 holo-enzyme, resulting in reduced Akt activity 
      and sensitizing cells to various apoptotic challenges. Notably, an ovarian cancer 
      patient-derived Sin1-R81T mutation abolished Sin1-T86 phosphorylation by 
      disrupting the canonical S6K-phoshorylation motif, thereby bypassing 
      Sin1-phosphorylation-mediated suppression of mTORC2 and leading to sustained Akt 
      signaling to promote tumorigenesis. Our work therefore provided physiological and 
      pathological evidence to reveal the biological significance of Sin1 
      phosphorylation-mediated suppression of the mTOR/Akt oncogenic signaling, and 
      further suggested that misregulation of this process might contribute to Akt 
      hyper-activation that is frequently observed in human cancers.
FAU - Liu, Pengda
AU  - Liu P
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA, 02115, USA.
FAU - Guo, Jianping
AU  - Guo J
FAU - Gan, Wenjian
AU  - Gan W
FAU - Wei, Wenyi
AU  - Wei W
LA  - eng
GR  - R01 GM094777/GM/NIGMS NIH HHS/United States
GR  - GM089763/GM/NIGMS NIH HHS/United States
GR  - T32 HL007893/HL/NHLBI NIH HHS/United States
GR  - R01 GM089763/GM/NIGMS NIH HHS/United States
GR  - 5T32HL007893/HL/NHLBI NIH HHS/United States
GR  - GM094777/GM/NIGMS NIH HHS/United States
GR  - CA177910/CA/NCI NIH HHS/United States
GR  - R01 CA177910/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - Germany
TA  - Protein Cell
JT  - Protein & cell
JID - 101532368
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Multiprotein Complexes)
RN  - 1114-81-4 (Phosphothreonine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Animals
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Models, Biological
MH  - Multiprotein Complexes/*metabolism
MH  - Phosphorylation
MH  - Phosphothreonine/*metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3967077
EDAT- 2014/02/01 06:00
MHDA- 2014/11/17 06:00
PMCR- 2014/01/31
CRDT- 2014/02/01 06:00
PHST- 2014/02/01 06:00 [entrez]
PHST- 2014/02/01 06:00 [pubmed]
PHST- 2014/11/17 06:00 [medline]
PHST- 2014/01/31 00:00 [pmc-release]
AID - 21 [pii]
AID - 10.1007/s13238-014-0021-8 [doi]
PST - ppublish
SO  - Protein Cell. 2014 Mar;5(3):171-7. doi: 10.1007/s13238-014-0021-8.