PMID- 19720745
OWN - NLM
STAT- MEDLINE
DCOM- 20091113
LR  - 20211020
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 29
IP  - 21
DP  - 2009 Nov
TI  - Characterization of Rictor phosphorylation sites reveals direct regulation of 
      mTOR complex 2 by S6K1.
PG  - 5657-70
LID - 10.1128/MCB.00735-09 [doi]
AB  - The mammalian target of rapamycin (mTOR) functions within two distinct complexes 
      (mTORC1 and mTORC2) to control cell growth, proliferation, survival, and 
      metabolism. While there has been great progress in our understanding of mTORC1 
      regulation, the signaling mechanisms that regulate mTORC2 have not been defined. 
      In this study, we use liquid chromatography-tandem mass spectrometry analyses to 
      identify 21 phosphorylation sites on the core mTORC2 component Rictor. We find 
      that one site, T1135, undergoes growth factor-responsive phosphorylation that is 
      acutely sensitive to rapamycin and is phosphorylated downstream of mTORC1. We 
      find that Rictor-T1135 is directly phosphorylated by the mTORC1-dependent kinase 
      S6K1. Although this phosphorylation event does not affect mTORC2 integrity or in 
      vitro kinase activity, expression of a phosphorylation site mutant of Rictor 
      (T1135A) in either wild-type or Rictor null cells causes an increase in the 
      mTORC2-dependent phosphorylation of Akt on S473. However, Rictor-T1135 
      phosphorylation does not appear to regulate mTORC2-mediated effects on SGK1 or 
      PKC alpha. While the precise molecular mechanism affecting Akt is unknown, 
      phosphorylation of T1135 stimulates binding of Rictor to 14-3-3 proteins. We 
      provide evidence that Rictor-T1135 phosphorylation acts in parallel with other 
      mTORC1-dependent feedback mechanisms, such as those affecting IRS-1 signaling to 
      PI3K, to regulate the response of Akt to insulin.
FAU - Dibble, Christian C
AU  - Dibble CC
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 
      Huntington Ave., SPH2-117, Boston, MA 02115, USA.
FAU - Asara, John M
AU  - Asara JM
FAU - Manning, Brendan D
AU  - Manning BD
LA  - eng
GR  - R01 CA122617-04/CA/NCI NIH HHS/United States
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
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090831
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (14-3-3 Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Insulin)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (rictor protein, mouse)
RN  - 1114-81-4 (Phosphothreonine)
RN  - 17885-08-4 (Phosphoserine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (Rps6ka1 protein, mouse)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - 14-3-3 Proteins/metabolism
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution/drug effects
MH  - Animals
MH  - Binding Sites
MH  - Carrier Proteins/chemistry/*metabolism
MH  - Chromatography, Liquid
MH  - Conserved Sequence
MH  - HeLa Cells
MH  - Humans
MH  - Insulin/pharmacology
MH  - Intercellular Signaling Peptides and Proteins/pharmacology
MH  - Mass Spectrometry
MH  - Mice
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Phosphorylation/drug effects
MH  - Phosphoserine/metabolism
MH  - Phosphothreonine/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Ribosomal Protein S6 Kinases, 90-kDa/*metabolism
MH  - Sirolimus/pharmacology
MH  - Vertebrates/metabolism
PMC - PMC2772744
EDAT- 2009/09/02 06:00
MHDA- 2009/11/17 06:00
PMCR- 2010/05/01
CRDT- 2009/09/02 09:00
PHST- 2009/09/02 09:00 [entrez]
PHST- 2009/09/02 06:00 [pubmed]
PHST- 2009/11/17 06:00 [medline]
PHST- 2010/05/01 00:00 [pmc-release]
AID - MCB.00735-09 [pii]
AID - 0735-09 [pii]
AID - 10.1128/MCB.00735-09 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2009 Nov;29(21):5657-70. doi: 10.1128/MCB.00735-09. Epub 2009 Aug 
      31.