PMID- 15767663
OWN - NLM
STAT- MEDLINE
DCOM- 20050419
LR  - 20220225
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 25
IP  - 7
DP  - 2005 Apr
TI  - Distinct signaling events downstream of mTOR cooperate to mediate the effects of 
      amino acids and insulin on initiation factor 4E-binding proteins.
PG  - 2558-72
AB  - Signaling through the mammalian target of rapamycin (mTOR) controls cell size and 
      growth as well as other functions, and it is a potential therapeutic target for 
      graft rejection, certain cancers, and disorders characterized by inappropriate 
      cell or tissue growth. mTOR signaling is positively regulated by hormones or 
      growth factors and amino acids. mTOR signaling regulates the phosphorylation of 
      several proteins, the best characterized being ones that control mRNA 
      translation. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) undergoes 
      phosphorylation at multiple sites. Here we show that amino acids regulate the 
      N-terminal phosphorylation sites in 4E-BP1 through the RAIP motif in a 
      rapamycin-insensitive manner. Several criteria indicate this reflects a 
      rapamycin-insensitive output from mTOR. In contrast, the insulin-stimulated 
      phosphorylation of the C-terminal site Ser64/65 is generally sensitive to 
      rapamycin, as is phosphorylation of another well-characterized target for mTOR 
      signaling, S6K1. Our data imply that it is unlikely that mTOR directly 
      phosphorylates Thr69/70 in 4E-BP1. Although 4E-BP1 and S6K1 bind the mTOR 
      partner, raptor, our data indicate that the outputs from mTOR to 4E-BP1 and S6K1 
      are distinct. In cells, efficient phosphorylation of 4E-BP1 requires it to be 
      able to bind to eIF4E, whereas phosphorylation of 4E-BP1 by mTOR in vitro shows 
      no such preference. These data have important implications for understanding 
      signaling downstream of mTOR and the development of new strategies to impair mTOR 
      signaling.
FAU - Wang, Xuemin
AU  - Wang X
AD  - Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, 
      Dow St., Dundee DD1 5EH, United Kingdom.
FAU - Beugnet, Anne
AU  - Beugnet A
FAU - Murakami, Mirei
AU  - Murakami M
FAU - Yamanaka, Shinya
AU  - Yamanaka S
FAU - Proud, Christopher G
AU  - Proud CG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Amino Acids)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Chromones)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Insulin)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoproteins)
RN  - 2ZD004190S (Threonine)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Amino Acid Sequence
MH  - Amino Acids/*pharmacology
MH  - Animals
MH  - Carrier Proteins/chemistry/genetics/*metabolism
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Chromones/pharmacology
MH  - Cricetinae
MH  - Eukaryotic Initiation Factor-4E/*metabolism
MH  - Humans
MH  - Insulin/*pharmacology
MH  - Intracellular Signaling Peptides and Proteins
MH  - Molecular Sequence Data
MH  - Morpholines/pharmacology
MH  - Phosphoproteins/chemistry/genetics/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Binding
MH  - Protein Kinases/genetics/*metabolism
MH  - Rats
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Sequence Alignment
MH  - Serine/genetics/metabolism
MH  - *Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Threonine/genetics/metabolism
PMC - PMC1061630
EDAT- 2005/03/16 09:00
MHDA- 2005/04/20 09:00
PMCR- 2005/04/01
CRDT- 2005/03/16 09:00
PHST- 2005/03/16 09:00 [pubmed]
PHST- 2005/04/20 09:00 [medline]
PHST- 2005/03/16 09:00 [entrez]
PHST- 2005/04/01 00:00 [pmc-release]
AID - 25/7/2558 [pii]
AID - 0978-04 [pii]
AID - 10.1128/MCB.25.7.2558-2572.2005 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2005 Apr;25(7):2558-72. doi: 10.1128/MCB.25.7.2558-2572.2005.