PMID- 19487463
OWN - NLM
STAT- MEDLINE
DCOM- 20090925
LR  - 20231121
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 29
IP  - 15
DP  - 2009 Aug
TI  - Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell 
      growth.
PG  - 4308-24
LID - 10.1128/MCB.01665-08 [doi]
AB  - The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) functions as a 
      rapamycin-sensitive environmental sensor that promotes cellular biosynthetic 
      processes in response to growth factors and nutrients. While diverse 
      physiological stimuli modulate mTORC1 signaling, the direct biochemical 
      mechanisms underlying mTORC1 regulation remain poorly defined. Indeed, while 
      three mTOR phosphorylation sites have been reported, a functional role for 
      site-specific mTOR phosphorylation has not been demonstrated. Here we identify a 
      new site of mTOR phosphorylation (S1261) by tandem mass spectrometry and 
      demonstrate that insulin-phosphatidylinositol 3-kinase signaling promotes mTOR 
      S1261 phosphorylation in both mTORC1 and mTORC2. Here we focus on mTORC1 and show 
      that TSC/Rheb signaling promotes mTOR S1261 phosphorylation in an amino 
      acid-dependent, rapamycin-insensitive, and autophosphorylation-independent 
      manner. Our data reveal a functional role for mTOR S1261 phosphorylation in 
      mTORC1 action, as S1261 phosphorylation promotes mTORC1-mediated substrate 
      phosphorylation (e.g., p70 ribosomal protein S6 kinase 1 [S6K1] and eukaryotic 
      initiation factor 4E binding protein 1) and cell growth to increased cell size. 
      Moreover, Rheb-driven mTOR S2481 autophosphorylation and S6K1 phosphorylation 
      require S1261 phosphorylation. These data provide the first evidence that 
      site-specific mTOR phosphorylation regulates mTORC1 function and suggest a model 
      whereby insulin-stimulated mTOR S1261 phosphorylation promotes mTORC1 autokinase 
      activity, substrate phosphorylation, and cell growth.
FAU - Acosta-Jaquez, Hugo A
AU  - Acosta-Jaquez HA
AD  - Department of Cell and Developmental Biology, University of Michigan Medical 
      School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
FAU - Keller, Jennifer A
AU  - Keller JA
FAU - Foster, Kathryn G
AU  - Foster KG
FAU - Ekim, Bilgen
AU  - Ekim B
FAU - Soliman, Ghada A
AU  - Soliman GA
FAU - Feener, Edward P
AU  - Feener EP
FAU - Ballif, Bryan A
AU  - Ballif BA
FAU - Fingar, Diane C
AU  - Fingar DC
LA  - eng
GR  - K01 DK060654/DK/NIDDK NIH HHS/United States
GR  - P20 RR16462/RR/NCRR NIH HHS/United States
GR  - R01 DK078135/DK/NIDDK NIH HHS/United States
GR  - 5P60 DK 20572/DK/NIDDK NIH HHS/United States
GR  - R01 DK-078135/DK/NIDDK NIH HHS/United States
GR  - P60 DK020572/DK/NIDDK NIH HHS/United States
GR  - P20 RR016462/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090601
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (Transcription Factors)
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 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - 3T3-L1 Cells
MH  - *Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Binding Sites/genetics
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - *Cell Proliferation
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Flow Cytometry
MH  - Humans
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Insulin/pharmacology
MH  - Mass Spectrometry
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - *Phosphoproteins/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/genetics/*metabolism
MH  - Proteins
MH  - Signal Transduction/drug effects/genetics/*physiology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/genetics/*metabolism
PMC - PMC2715808
EDAT- 2009/06/03 09:00
MHDA- 2009/09/26 06:00
PMCR- 2010/02/01
CRDT- 2009/06/03 09:00
PHST- 2009/06/03 09:00 [entrez]
PHST- 2009/06/03 09:00 [pubmed]
PHST- 2009/09/26 06:00 [medline]
PHST- 2010/02/01 00:00 [pmc-release]
AID - MCB.01665-08 [pii]
AID - 1665-08 [pii]
AID - 10.1128/MCB.01665-08 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2009 Aug;29(15):4308-24. doi: 10.1128/MCB.01665-08. Epub 2009 Jun 
      1.