PMID- 15899889
OWN - NLM
STAT- MEDLINE
DCOM- 20050816
LR  - 20220410
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 280
IP  - 27
DP  - 2005 Jul 8
TI  - Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated 
      by p70S6 kinase.
PG  - 25485-90
AB  - The mammalian target of rapamycin (mTOR) coordinates cell growth with the growth 
      factor and nutrient/energy status of the cell. The phosphatidylinositol 
      3-kinase-AKT pathway is centrally involved in the transmission of mitogenic 
      signals to mTOR. Previous studies have shown that mTOR is a direct substrate for 
      the AKT kinase and identified Ser-2448 as the AKT target site in mTOR. In this 
      study, we demonstrate that rapamycin, a specific inhibitor of mTOR function, 
      blocks serum-stimulated Ser-2448 phosphorylation and that this drug effect is not 
      explained by the inhibition of AKT. Furthermore, the phosphorylation of Ser-2448 
      was dependent on mTOR kinase activity, suggesting that mTOR itself or a protein 
      kinase downstream from mTOR was responsible for the modification of Ser-2448. 
      Here we show that p70S6 kinase phosphorylates mTOR at Ser-2448 in vitro and that 
      ectopic expression of rapamycin-resistant p70S6 kinase restores Ser-2448 
      phosphorylation in rapamycin-treated cells. In addition, we show that cellular 
      amino acid status, which modulates p70S6 kinase (S6K1) activity via the TSC/Rheb 
      pathway, regulates Ser-2448 phosphorylation. Finally, small interfering 
      RNA-mediated depletion of p70S6 kinase reduces Ser-2448 phosphorylation in cells. 
      Taken together, these results suggest that p70S6 kinase is a major effector of 
      mTOR phosphorylation at Ser-2448 in response to both mitogen- and 
      nutrient-derived stimuli.
FAU - Chiang, Gary G
AU  - Chiang GG
AD  - Program in Signal Transduction Research, The Burnham Institute, La Jolla, 
      California 92037, USA. gchiang@burnham.org
FAU - Abraham, Robert T
AU  - Abraham RT
LA  - eng
GR  - CA52995/CA/NCI NIH HHS/United States
GR  - CA76193/CA/NCI NIH HHS/United States
GR  - F32 CA099354/CA/NCI 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 - 20050516
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Blood Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Anti-Bacterial Agents/pharmacology
MH  - Blood Proteins/pharmacology
MH  - Breast Neoplasms
MH  - Drug Resistance
MH  - HeLa Cells
MH  - Humans
MH  - In Vitro Techniques
MH  - Kidney/cytology
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*metabolism
MH  - RNA, Small Interfering
MH  - Ribosomal Protein S6 Kinases, 70-kDa/genetics/*metabolism
MH  - Serine/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2005/05/19 09:00
MHDA- 2005/08/17 09:00
CRDT- 2005/05/19 09:00
PHST- 2005/05/19 09:00 [pubmed]
PHST- 2005/08/17 09:00 [medline]
PHST- 2005/05/19 09:00 [entrez]
AID - S0021-9258(20)61357-6 [pii]
AID - 10.1074/jbc.M501707200 [doi]
PST - ppublish
SO  - J Biol Chem. 2005 Jul 8;280(27):25485-90. doi: 10.1074/jbc.M501707200. Epub 2005 
      May 16.