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Dissociation of raptor from mTOR is a mechanism of rapamycin‐induced inhibition of mTOR function
Author(s) -
Oshiro Noriko,
Yoshino Kenichi,
Hidayat Sujuti,
Tokunaga Chiharu,
Hara Kenta,
Eguchi Satoshi,
Avruch Joseph,
Yonezawa Kazuyoshi
Publication year - 2004
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1356-9597.2004.00727.x
Subject(s) - pi3k/akt/mtor pathway , rptor , biology , phosphorylation , microbiology and biotechnology , sirolimus , kinase , mtorc2 , autophosphorylation , mechanistic target of rapamycin , signal transduction , protein kinase a , biochemistry , mtorc1
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.