PMID- 16027121
OWN - NLM
STAT- MEDLINE
DCOM- 20051020
LR  - 20220309
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 280
IP  - 37
DP  - 2005 Sep 16
TI  - Akt activates the mammalian target of rapamycin by regulating cellular ATP level 
      and AMPK activity.
PG  - 32081-9
AB  - The serine/threonine kinase Akt is an upstream positive regulator of the 
      mammalian target of rapamycin (mTOR). However, the mechanism by which Akt 
      activates mTOR is not fully understood. The known pathway by which Akt activates 
      mTOR is via direct phosphorylation and inhibition of tuberous sclerosis complex 2 
      (TSC2), which is a negative regulator of mTOR. Here we establish an additional 
      pathway by which Akt inhibits TSC2 and activates mTOR. We provide for the first 
      time genetic evidence that Akt regulates intracellular ATP level and demonstrate 
      that Akt is a negative regulator of the AMP-activated protein kinase (AMPK), 
      which is an activator of TSC2. We show that in Akt1/Akt2 DKO cells AMP/ATP ratio 
      is markedly elevated with concomitant increase in AMPK activity, whereas in cells 
      expressing activated Akt there is a dramatic decrease in AMP/ATP ratio and a 
      decline in AMPK activity. Currently, the Akt-mediated phosphorylation of TSC2 and 
      the inhibition of AMPK-mediated phosphorylation of TSC2 are viewed as two 
      separate pathways, which activate mTOR. Our results demonstrate that Akt lies 
      upstream of these two pathways and induces full inhibition of TSC2 and activation 
      of mTOR both through direct phosphorylation and by inhibition of AMPK-mediated 
      phosphorylation of TSC2. We propose that the activation of mTOR by Akt-mediated 
      cellular energy and inhibition of AMPK is the predominant pathway by which Akt 
      activates mTOR in vivo.
FAU - Hahn-Windgassen, Annett
AU  - Hahn-Windgassen A
AD  - Department of Biochemistry and Molecular Genetics, University of Illinois at 
      Chicago, 60607, USA.
FAU - Nogueira, Veronique
AU  - Nogueira V
FAU - Chen, Chia-Chen
AU  - Chen CC
FAU - Skeen, Jennifer E
AU  - Skeen JE
FAU - Sonenberg, Nahum
AU  - Sonenberg N
FAU - Hay, Nissim
AU  - Hay N
LA  - eng
GR  - AG016927/AG/NIA NIH HHS/United States
GR  - CA090764/CA/NCI NIH HHS/United States
GR  - T32DK007739/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050715
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Repressor Proteins)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tsc2 protein, rat)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
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 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (AKT2 protein, human)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Akt2 protein, mouse)
RN  - EC 2.7.11.1 (Akt2 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.4.3 (Adenylate Kinase)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/chemistry
MH  - Adenosine Triphosphate/chemistry/*metabolism
MH  - Adenylate Kinase/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - *Gene Expression Regulation
MH  - *Gene Expression Regulation, Enzymologic
MH  - Humans
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Mice
MH  - Models, Biological
MH  - Phosphorylation
MH  - Plasmids/metabolism
MH  - Protein Biosynthesis
MH  - Protein Kinases/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Repressor Proteins/*metabolism
MH  - Retroviridae/genetics
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - Transfection
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/*metabolism
EDAT- 2005/07/20 09:00
MHDA- 2005/10/21 09:00
CRDT- 2005/07/20 09:00
PHST- 2005/07/20 09:00 [pubmed]
PHST- 2005/10/21 09:00 [medline]
PHST- 2005/07/20 09:00 [entrez]
AID - S0021-9258(20)79179-9 [pii]
AID - 10.1074/jbc.M502876200 [doi]
PST - ppublish
SO  - J Biol Chem. 2005 Sep 16;280(37):32081-9. doi: 10.1074/jbc.M502876200. Epub 2005 
      Jul 15.