PMID- 18411301
OWN - NLM
STAT- MEDLINE
DCOM- 20080708
LR  - 20220309
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 28
IP  - 12
DP  - 2008 Jun
TI  - The TSC1-TSC2 complex is required for proper activation of mTOR complex 2.
PG  - 4104-15
LID - 10.1128/MCB.00289-08 [doi]
AB  - The mammalian target of rapamycin (mTOR) is a protein kinase that forms two 
      functionally distinct complexes important for nutrient and growth factor 
      signaling. Both complexes phosphorylate a hydrophobic motif on downstream protein 
      kinases, which contributes to the activation of these kinases. mTOR complex 1 
      (mTORC1) phosphorylates S6K1, while mTORC2 phosphorylates Akt. The TSC1-TSC2 
      complex is a critical negative regulator of mTORC1. However, how mTORC2 is 
      regulated and whether the TSC1-TSC2 complex is involved are unknown. We find that 
      mTORC2 isolated from a variety of cells lacking a functional TSC1-TSC2 complex is 
      impaired in its kinase activity toward Akt. Importantly, the defect in mTORC2 
      activity in these cells can be separated from effects on mTORC1 signaling and 
      known feedback mechanisms affecting insulin receptor substrate-1 and 
      phosphatidylinositol 3-kinase. Our data also suggest that the TSC1-TSC2 complex 
      positively regulates mTORC2 in a manner independent of its GTPase-activating 
      protein activity toward Rheb. Finally, we find that the TSC1-TSC2 complex can 
      physically associate with mTORC2 but not mTORC1. These data demonstrate that the 
      TSC1-TSC2 complex inhibits mTORC1 and activates mTORC2, which through different 
      mechanisms promotes Akt activation.
FAU - Huang, Jingxiang
AU  - Huang J
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 
      Boston, Massachusetts 02115, USA.
FAU - Dibble, Christian C
AU  - Dibble CC
FAU - Matsuzaki, Mika
AU  - Matsuzaki M
FAU - Manning, Brendan D
AU  - Manning BD
LA  - eng
GR  - P01 CA120964/CA/NCI NIH HHS/United States
GR  - T32 ES07155/ES/NIEHS NIH HHS/United States
GR  - R01 CA122617/CA/NCI NIH HHS/United States
GR  - R01-CA122617/CA/NCI NIH HHS/United States
GR  - P01-CA120964/CA/NCI NIH HHS/United States
GR  - T32 ES007155/ES/NIEHS NIH HHS/United States
GR  - R01 CA122617-03/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080414
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Fibroblasts/metabolism
MH  - *Gene Expression Regulation
MH  - HeLa Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Models, Biological
MH  - Multiprotein Complexes
MH  - Protein Kinases/*metabolism
MH  - Proteins
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/metabolism/*physiology
PMC - PMC2423120
EDAT- 2008/04/16 09:00
MHDA- 2008/07/09 09:00
PMCR- 2008/10/01
CRDT- 2008/04/16 09:00
PHST- 2008/04/16 09:00 [pubmed]
PHST- 2008/07/09 09:00 [medline]
PHST- 2008/04/16 09:00 [entrez]
PHST- 2008/10/01 00:00 [pmc-release]
AID - MCB.00289-08 [pii]
AID - 0289-08 [pii]
AID - 10.1128/MCB.00289-08 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2008 Jun;28(12):4104-15. doi: 10.1128/MCB.00289-08. Epub 2008 Apr 
      14.