PMID- 15066126
OWN - NLM
STAT- MEDLINE
DCOM- 20041122
LR  - 20220225
IS  - 1356-9597 (Print)
IS  - 1356-9597 (Linking)
VI  - 9
IP  - 4
DP  - 2004 Apr
TI  - Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition 
      of mTOR function.
PG  - 359-66
AB  - The mammalian target of rapamycin (mTOR) is a Ser/Thr protein kinase that plays a 
      crucial role in a nutrient-sensitive signalling pathway that regulates cell 
      growth. TOR signalling is potently inhibited by rapamycin, through the direct 
      binding of a FK506-binding protein 12 (FKBP12)/rapamycin complex to the TOR FRB 
      domain, a segment amino terminal to the kinase catalytic domain. The molecular 
      basis for the inhibitory action of FKBP12/rapamycin remains uncertain. Raptor 
      (regulatory associated protein of mTOR) is a recently identified mTOR binding 
      partner that is essential for mTOR signalling in vivo, and whose binding to mTOR 
      is critical for mTOR-catalysed substrate phosphorylation in vitro. Here we 
      investigated the stability of endogenous mTOR/raptor complex in response to 
      rapamycin in vivo, and to the direct addition of a FKBP12/rapamycin complex in 
      vitro. Rapamycin diminished the recovery of endogenous raptor with endogenous or 
      recombinant mTOR in vivo; this inhibition required the ability of mTOR to bind 
      the FKBP12/rapamycin complex, but was independent of mTOR kinase activity. 
      Rapamycin, in the presence of FKBP12, inhibited the association of raptor with 
      mTOR directly in vitro, and concomitantly reduced the mTOR-catalysed 
      phosphorylation of raptor-dependent, but not raptor-independent substrates; mTOR 
      autophosphorylation was unaltered. These observations indicate that rapamycin 
      inhibits mTOR function, at least in part, by inhibiting the interaction of raptor 
      with mTOR; this action uncouples mTOR from its substrates, and inhibits mTOR 
      signalling without altering mTOR's intrinsic catalytic activity.
FAU - Oshiro, Noriko
AU  - Oshiro N
AD  - Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
FAU - Yoshino, Ken-ichi
AU  - Yoshino K
FAU - Hidayat, Sujuti
AU  - Hidayat S
FAU - Tokunaga, Chiharu
AU  - Tokunaga C
FAU - Hara, Kenta
AU  - Hara K
FAU - Eguchi, Satoshi
AU  - Eguchi S
FAU - Avruch, Joseph
AU  - Avruch J
FAU - Yonezawa, Kazuyoshi
AU  - Yonezawa K
LA  - eng
GR  - CA73818/CA/NCI NIH HHS/United States
GR  - DK17776/DK/NIDDK 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  - England
TA  - Genes Cells
JT  - Genes to cells : devoted to molecular & cellular mechanisms
JID - 9607379
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Proteins)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Regulatory-Associated Protein of mTOR)
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  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
EIN - Genes Cells. 2004 May;9(5):497
MH  - Adaptor Proteins, Signal Transducing
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Proteins/*metabolism
MH  - Regulatory-Associated Protein of mTOR
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Sirolimus/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Tacrolimus Binding Protein 1A/antagonists & inhibitors
EDAT- 2004/04/07 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/04/07 05:00
PHST- 2004/04/07 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/04/07 05:00 [entrez]
AID - GTC727 [pii]
AID - 10.1111/j.1356-9597.2004.00727.x [doi]
PST - ppublish
SO  - Genes Cells. 2004 Apr;9(4):359-66. doi: 10.1111/j.1356-9597.2004.00727.x.