Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function
- PMID: 15066126
- DOI: 10.1111/j.1356-9597.2004.00727.x
Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function
Erratum in
- Genes Cells. 2004 May;9(5):497
Abstract
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.
Similar articles
-
A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis.Cancer Res. 2008 Apr 15;68(8):2934-43. doi: 10.1158/0008-5472.CAN-07-6487. Cancer Res. 2008. PMID: 18413763
-
The FRB domain of mTOR: NMR solution structure and inhibitor design.Biochemistry. 2006 Aug 29;45(34):10294-302. doi: 10.1021/bi060976+. Biochemistry. 2006. PMID: 16922504
-
Rheb binds and regulates the mTOR kinase.Curr Biol. 2005 Apr 26;15(8):702-13. doi: 10.1016/j.cub.2005.02.053. Curr Biol. 2005. PMID: 15854902
-
The rapamycin-sensitive signal transduction pathway as a target for cancer therapy.Oncogene. 2000 Dec 27;19(56):6680-6. doi: 10.1038/sj.onc.1204091. Oncogene. 2000. PMID: 11426655 Review.
-
Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase.Oncogene. 2006 Oct 16;25(48):6361-72. doi: 10.1038/sj.onc.1209882. Oncogene. 2006. PMID: 17041622 Review.
Cited by
-
Identification and characterization of TOR in Macrobrachium rosenbergii and its role in muscle protein and lipid production.Sci Rep. 2024 Jan 24;14(1):2082. doi: 10.1038/s41598-023-50300-3. Sci Rep. 2024. PMID: 38267514 Free PMC article.
-
Silibinin Downregulates Types I and III Collagen Expression via Suppression of the mTOR Signaling Pathway.Int J Mol Sci. 2023 Sep 21;24(18):14386. doi: 10.3390/ijms241814386. Int J Mol Sci. 2023. PMID: 37762688 Free PMC article.
-
Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth.JCI Insight. 2023 Jul 10;8(13):e158098. doi: 10.1172/jci.insight.158098. JCI Insight. 2023. PMID: 37427586 Free PMC article.
-
Molecular treatment trajectories within psoriatic T lymphocytes: a mini review.Front Immunol. 2023 May 12;14:1170273. doi: 10.3389/fimmu.2023.1170273. eCollection 2023. Front Immunol. 2023. PMID: 37251381 Free PMC article. Review.
-
Treatment of Rapamycin and Evaluation of an Autophagic Response in the Gut of Bactericera cockerelli (Sulč).Insects. 2023 Jan 31;14(2):142. doi: 10.3390/insects14020142. Insects. 2023. PMID: 36835711 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Miscellaneous