PMID- 14970221
OWN - NLM
STAT- MEDLINE
DCOM- 20040722
LR  - 20220228
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 16
DP  - 2004 Apr 16
TI  - Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site 
      regulated by nutrient status.
PG  - 15719-22
AB  - The mammalian target of rapamycin (mTOR) is a key regulator of protein 
      translation. Signaling via mTOR is increased by growth factors but decreased 
      during nutrient deprivation. Previous studies have identified Ser2448 as a 
      nutrient-regulated phosphorylation site located in the mTOR catalytic domain, 
      insulin stimulates Ser2448 phosphorylation via protein kinase B (PKB), while 
      Ser2448 phosphorylation is attenuated with amino acid starvation. Here we have 
      identified Thr2446 as a novel nutrient-regulated phosphorylation site on mTOR. 
      Thr2446 becomes phosphorylated when CHO-IR cells are nutrient-deprived, but 
      phosphorylation is reduced by insulin stimulation. Nutrient deprivation activates 
      AMP-activated protein kinase (AMPK). To test whether this could be involved in 
      regulating phoshorylation of mTOR, we treated cultured murine myotubes with 
      5'-aminoimidazole-4-carboxamide ribonucleoside (AICAR) or dinitrophenol (DNP). 
      Both treatments activated AMPK and also caused a concomitant increase in 
      phosphorylation of Thr2446 and a parallel decrease in insulin's ability to 
      phosphorylate p70 S6 kinase. In vitro kinase assays using peptides based on the 
      sequence in amino acids 2440-2551 of mTOR found that PKB and AMPK are capable of 
      phosphorylating sites in this region. However, phosphorylation by PKB is 
      restricted when Thr2446 is mutated to an acidic residue mimicking 
      phosphorylation. Conversely, AMP-kinase-induced phosphorylation is reduced when 
      Ser2448 is phosphorylated. These data suggest differential phosphorylation 
      Thr2446 and Ser2448 could act as a switch mechanism to integrate signals from 
      nutrient status and growth factors to control the regulation of protein 
      translation.
FAU - Cheng, Susan W Y
AU  - Cheng SW
AD  - Department of Biochemistry and Molecular Biology, University College London, 
      Gower Street, London WC1E 6BT, United Kingdom.
FAU - Fryer, Lee G D
AU  - Fryer LG
FAU - Carling, David
AU  - Carling D
FAU - Shepherd, Peter R
AU  - Shepherd PR
LA  - eng
GR  - MC_U120027537/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040217
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Dinitrophenols)
RN  - 0 (Insulin)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Ribonucleotides)
RN  - 2ZD004190S (Threonine)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
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 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - F0X88YW0YK (AICA ribonucleotide)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - AMP-Activated Protein Kinases
MH  - Aminoimidazole Carboxamide/*analogs & derivatives/pharmacology
MH  - Animals
MH  - CHO Cells
MH  - Cricetinae
MH  - Dinitrophenols/pharmacology
MH  - Enzyme Activation/drug effects
MH  - Humans
MH  - Insulin/metabolism
MH  - Mice
MH  - Multienzyme Complexes/metabolism
MH  - Phosphorylation
MH  - Protein Biosynthesis
MH  - Protein Kinases/genetics/*metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Ribonucleotides/pharmacology
MH  - *Signal Transduction
MH  - Sirolimus/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Threonine/metabolism
EDAT- 2004/02/19 05:00
MHDA- 2004/07/23 05:00
CRDT- 2004/02/19 05:00
PHST- 2004/02/19 05:00 [pubmed]
PHST- 2004/07/23 05:00 [medline]
PHST- 2004/02/19 05:00 [entrez]
AID - S0021-9258(20)88283-0 [pii]
AID - 10.1074/jbc.C300534200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 Apr 16;279(16):15719-22. doi: 10.1074/jbc.C300534200. Epub 2004 
      Feb 17.