PMID- 10910062
OWN - NLM
STAT- MEDLINE
DCOM- 20000817
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 60
IP  - 13
DP  - 2000 Jul 1
TI  - A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and 
      the mammalian target of rapamycin in mitogen-stimulated and transformed cells.
PG  - 3504-13
AB  - The microbially derived antiproliferative agent rapamycin inhibits cell growth by 
      interfering with the signaling functions of the mammalian target of rapamycin 
      (mTOR). In this study, we demonstrate that interleukin-3 stimulation induces a 
      wortmannin-sensitive increase in mTOR kinase activity in a myeloid progenitor 
      cell line. The involvement of phosphoinositide 3'-kinase (PI3K) in the regulation 
      of mTOR activity was further suggested by findings that mTOR was phosphorylated 
      in vitro and in vivo by the PI3K-regulated protein kinase, AKT/PKB. Although AKT 
      phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, 
      Ser2448 was the major phosphorylation site in insulin-stimulated or -activated 
      AKT-expressing human embryonic kidney cells. Transient transfection assays with 
      mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that 
      AKT-dependent mTOR phosphorylation was not essential for either PHAS-I 
      phosphorylation or p70S6K activation in HEK cells. However, a deletion of amino 
      acids 2430-2450 in mTOR, which includes the potential AKT phosphorylation sites, 
      significantly increased both the basal protein kinase activity and in vivo 
      signaling functions of mTOR. These results demonstrate that mTOR is a direct 
      target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that 
      the identified AKT phosphorylation sites are nested within a "repressor domain" 
      that negatively regulates the catalytic activity of mTOR. Furthermore, the 
      activation status of the PI3K-AKT pathway in cancer cells may be an important 
      determinant of cellular sensitivity to the cytostatic effect of rapamycin.
FAU - Sekulic, A
AU  - Sekulic A
AD  - Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
FAU - Hudson, C C
AU  - Hudson CC
FAU - Homme, J L
AU  - Homme JL
FAU - Yin, P
AU  - Yin P
FAU - Otterness, D M
AU  - Otterness DM
FAU - Karnitz, L M
AU  - Karnitz LM
FAU - Abraham, R T
AU  - Abraham RT
LA  - eng
GR  - CA 52995/CA/NCI NIH HHS/United States
GR  - CA 76193/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Androstadienes)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Interleukin-3)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (AKT1 protein, human)
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  - Androstadienes/pharmacology
MH  - Animals
MH  - Cell Line
MH  - Cell Line, Transformed
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Interleukin-3/pharmacology
MH  - Kidney
MH  - Kinetics
MH  - Mammals
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - *Protein Kinases
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Recombinant Proteins/metabolism/pharmacology
MH  - Signal Transduction/drug effects/*physiology
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
MH  - Wortmannin
EDAT- 2000/07/26 11:00
MHDA- 2000/08/19 11:00
CRDT- 2000/07/26 11:00
PHST- 2000/07/26 11:00 [pubmed]
PHST- 2000/08/19 11:00 [medline]
PHST- 2000/07/26 11:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2000 Jul 1;60(13):3504-13.