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Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function.

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.

Pubmed ID: 15066126

Authors

  • Oshiro N
  • Yoshino K
  • Hidayat S
  • Tokunaga C
  • Hara K
  • Eguchi S
  • Avruch J
  • Yonezawa K

Journal

Genes to cells : devoted to molecular & cellular mechanisms

Publication Data

April 6, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA73818
  • Agency: NIDDK NIH HHS, Id: DK17776

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Dose-Response Relationship, Drug
  • Humans
  • Phosphorylation
  • Protein Kinases
  • Proteins
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • Tacrolimus Binding Protein 1A