An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1
Open accessAbstract
The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an immunosuppressant and anti-cancer agent. Here we find that Torin1, a highly potent and selective ATP-competitive mTOR inhibitor that directly inhibits both complexes, impairs cell growth and proliferation to a far greater degree than rapamycin. Surprisingly, these effects are independent of mTORC2 inhibition and are instead because of suppression of rapamycin-resistant functions of mTORC1 that are necessary for cap-dependent translation and suppression of autophagy. These effects are at least partly mediated by mTORC1-dependent and rapamycin-resistant phosphorylation of 4E-BP1. Our findings challenge the assumption that rapamycin completely inhibits mTORC1 and indicate that direct inhibitors of mTORC1 kinase activity may be more successful than rapamycin at inhibiting tumors that depend on mTORC1. The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an immunosuppressant and anti-cancer agent. Here we find that Torin1, a highly potent and selective ATP-competitive mTOR inhibitor that directly inhibits both complexes, impairs cell growth and proliferation to a far greater degree than rapamycin. Surprisingly, these effects are independent of mTORC2 inhibition and are instead because of suppression of rapamycin-resistant functions of mTORC1 that are necessary for cap-dependent translation and suppression of autophagy. These effects are at least partly mediated by mTORC1-dependent and rapamycin-resistant phosphorylation of 4E-BP1. Our findings challenge the assumption that rapamycin completely inhibits mTORC1 and indicate that direct inhibitors of mTORC1 kinase activity may be more successful than rapamycin at inhibiting tumors that depend on mTORC1. Correction: An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.Journal of Biological ChemistryVol. 295Issue 9PreviewVOLUME 284 (2009) PAGES 8023–8032 Full-Text PDF Open Access The mammalian target of rapamycin (mTOR) 3The abbreviations used are: mTOR, mammalian target of rapamycin; Raptor, regulatory associated protein of mTOR; Rictor, rapamycin-insensitive companion of mTOR; PI3K, phosphatidylinositol 3-kinase; LC3, light chain 3; 4E-BP1, eIF4E-binding protein 1; eIF4E, eukaryotic initiation factor 4E; GβL, G-β subunit-like; MEF, mouse embryonic fibroblast; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; HEK, human embryonic kidney; DMSO, dimethyl sulfoxide; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; ATM, ataxia telangiectasia, mutated; PI, phosphatidylinositol; BSA, bovine serum albumin; PBS, phosphate-buffered saline; shRNA, short hairpin RNA. pathway is considered a major regulator of cell growth. The mTOR serine/threonine kinase is the founding component of the pathway and the catalytic subunit of two functionally distinct protein complexes, mTORC1 and mTORC2. mTORC1 contains the large protein Raptor, as well as mLST8/GβL and PRAS40, whereas mTORC2 is defined by the protein Rictor and also includes Sin1, Protor, and mLST8/GβL (1Guertin D.A. Sabatini D.M. Cancer Cell. 2007; 12: 9-22Abstract Full Text Full Text PDF PubMed Scopus (2433) Google Scholar). Growth factors, such as insulin and IGF, activate both complexes, and they are important downstream effectors of the PI3K/PTEN signaling network (2Manning B.D. Cantley L.C. Cell. 2007; 129: 1261-1274Abstract Full Text Full Text PDF PubMed Scopus (4763) Google Scholar). Additionally, the availability of nutrients, like amino acids and glucose, regulates mTORC1. Many insights into mTOR signaling have come from investigations into the mechanism of action of rapamycin, a bacterially produced macrolide inhibitor of mTOR that has diverse clinical applications as an anti-fungal, immunosuppressant, and anti-cancer drug (3Sehgal S.N. Transplant. Proc. 2003; 35: S7-S14Crossref PubMed Scopus (600) Google Scholar). Rapamycin acts through an unusual allosteric mechanism that requires binding to its intracellular receptor, FKBP12, for inhibition of its target. Under acute treatment, rapamycin is thought to selectively inhibit mTORC1, which is often referred to as the rapamycin-sensitive complex. Conversely, mTORC2 is considered rapamycin-insensitive, although its assembly can be inhibited by prolonged rapamycin treatment in some cell types (4Sarbassov D.D. Ali S.M. Sengupta S. Sheen J.H. Hsu P.P. Bagley A.F. Markhard A.L. Sabatini D.M. Mol. Cell. 2006; 22: 159-168Abstract Full Text Full Text PDF PubMed Scopus (2207) Google Scholar). Because of its
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Torin 1 inhibited the serine phosphorylation induced by HyIL-6 in both STAT1 and STAT3, without affecting their tyrosine phosphorylation.
“only Torin 1, an mTOR inhibitor targeting both mTORC1 and mTORC2 complexes (Thoreen et al., 2009), inhibited the Ser phosphorylation induced by HyIL-6 in both STAT1 and STAT3, without affecting their Tyr phosphorylation”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Thoreen et al., 2009
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- Authors
- Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., & Gray, N. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Corresponding author
- Sabatini, David M.
- Gray, Nathanael S.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 284
- Issue
- 12
- Pages
- 8023-8032
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2658096
- OpenAlex
- W2098912234
- Cited by
- 1,803
- References
- 6
- Citations by year
- 2026: 67 · 2025: 62 · 2024: 63 · 2023: 78 · 2022: 79 · 2021: 96 · 2020: 111 · 2019: 104 · 2018: 104 · 2017: 100 · 2016: 126 · 2015: 132 · 2014: 114 · 2013: 159 · 2012: 115
- FWCI
- 57.10
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-02-28)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH)
- American Cancer Society
- W. M. Keck Foundation
- Damon Runyon Cancer Research Foundation
- Massachusetts Institute of Technology
- Barr Foundation
- National Institutes of Health (W81XWH, AI47389, R01 AI47389)
- National Cancer Institute (R01CA103866, R01CA129105)
- National Institute of Allergy and Infectious Diseases (R01 AI47389, R01AI047389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTOR, mTORC1, mTORC2, Torin1, rapamycin resistance, ATP-competitive kinase inhibitors, cap-dependent translation, 4E-BP1 phosphorylation, autophagy, cell growth and proliferation, cancer therapy, allosteric inhibition, immunosuppression
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Adenosine Triphosphate, Animals, Antibiotics, Antineoplastic, Autophagy, Carrier Proteins, Cell Survival, Cells, Cultured, Immunosuppressive Agents, Multienzyme Complexes, Phosphoproteins, Phosphorylation, Proteins, RNA Caps, Transcription Factors, Protein Biosynthesis, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, Cell Cycle Proteins, Drug Resistance, Neoplasm, Sirolimus, Eukaryotic Initiation Factors, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, TOR Serine-Threonine Kinases
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