Gene interactions and pathways from curated databases and text-mining
Genes Cells 2004, PMID: 15066126

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

Oshiro, Noriko; Yoshino, Ken-ichi; Hidayat, Sujuti; Tokunaga, Chiharu; Hara, Kenta; Eguchi, Satoshi; Avruch, Joseph; Yonezawa, Kazuyoshi

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.

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Text Mining Data

raptor ⊣ FKBP12: " 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 "

mTOR ⊣ FKBP12: " 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 "

Manually curated Databases

  • IRef Biogrid Interaction: MLST8 — MTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RPS6KB1 — MTOR (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: RPTOR — MTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: EIF4EBP1 — MTOR (direct interaction, enzymatic study)
  • IRef Hprd Interaction: MLST8 — MTOR (in vivo)
  • IRef Hprd Interaction: RPTOR — MTOR (in vitro)
  • IRef Hprd Interaction: RPTOR — MTOR (in vivo)
  • IRef Innatedb Interaction: MLST8 — MTOR (unknown, -)
In total, 4 gene pairs are associated to this article in curated databases