PMID- 10567225
OWN - NLM
STAT- MEDLINE
DCOM- 20000211
LR  - 20230815
IS  - 0264-6021 (Print)
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 344 Pt 2
IP  - Pt 2
DP  - 1999 Dec 1
TI  - Mammalian target of rapamycin is a direct target for protein kinase B: 
      identification of a convergence point for opposing effects of insulin and 
      amino-acid deficiency on protein translation.
PG  - 427-31
AB  - Growth factor induced activation of phosphoinositide 3-kinase and protein kinase 
      B (PKB) leads to increased activity of the mammalian target of rapamycin (mTOR). 
      This subsequently leads to increased phosphorylation of eIF4E binding protein-1 
      (4EBP1) and activation of p70 ribosomal S6 protein kinase (p70(S6K)), both of 
      which are important steps in the stimulation of protein translation. The 
      stimulation of translation is attenuated in cells deprived of amino acids and 
      this is associated with the attenuation of 4EBP1 phosphorylation and p70(S6K) 
      activation. It has been suggested that PKB regulates mTOR function by 
      phosphorylation although direct phosphorylation of mTOR by PKB has not been 
      demonstrated previously. In the present work, we have found that PKB directly 
      phosphorylates mTOR and, using phosphospecific antibodies, we have shown this 
      phosphorylation occurs at Ser(2448). Insulin also induces phosphorylation on 
      Ser(2448) and this effect is blocked by wortmannin but not rapamycin, consistent 
      with the effect being mediated by PKB. Amino-acid starvation rapidly attenuated 
      the reactivity of the Ser(2448) phosphospecific antibody with mTOR and this could 
      not be restored by either insulin stimulation of cells or incubation with PKB in 
      vitro. Our findings demonstrate that mTOR is a direct target for PKB and support 
      the conclusion that regulation of phosphorylation of Ser(2448) is a point of 
      convergence for the counteracting regulatory effects of growth factors and amino 
      acid levels.
FAU - Nave, B T
AU  - Nave BT
AD  - Department of Biochemistry, University College London, Gower St, London WC1E 6BT, 
      U.K.
FAU - Ouwens, M
AU  - Ouwens M
FAU - Withers, D J
AU  - Withers DJ
FAU - Alessi, D R
AU  - Alessi DR
FAU - Shepherd, P R
AU  - Shepherd PR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Amino Acids)
RN  - 0 (Androstadienes)
RN  - 0 (Insulin)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
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  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Amino Acids/*deficiency
MH  - Androstadienes/pharmacology
MH  - Insulin/*pharmacology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - *Protein Biosynthesis
MH  - *Protein Kinases
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Wortmannin
PMC - PMC1220660
EDAT- 1999/11/24 09:00
MHDA- 2000/02/19 09:00
PMCR- 2000/06/01
CRDT- 1999/11/24 09:00
PHST- 1999/11/24 09:00 [pubmed]
PHST- 2000/02/19 09:00 [medline]
PHST- 1999/11/24 09:00 [entrez]
PHST- 2000/06/01 00:00 [pmc-release]
PST - ppublish
SO  - Biochem J. 1999 Dec 1;344 Pt 2(Pt 2):427-31.