Abstract
The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1inhibitor 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.
| Original language | English |
|---|---|
| Pages (from-to) | 8023-8032 |
| Number of pages | 10 |
| Journal | Journal of Biological Chemistry |
| Volume | 284 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2009 Mar 20 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. / Thoreen, Carson C.; Kang, Seong A.; Chang, Jae Won; Liu, Qingsong; Zhang, Jianming; Gao, Yi; Reichling, Laurie J.; Sim, Taebo; Sabatini, David M.; Gray, Nathaniel S.
In: Journal of Biological Chemistry, Vol. 284, No. 12, 20.03.2009, p. 8023-8032.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1
AU - Thoreen, Carson C.
AU - Kang, Seong A.
AU - Chang, Jae Won
AU - Liu, Qingsong
AU - Zhang, Jianming
AU - Gao, Yi
AU - Reichling, Laurie J.
AU - Sim, Taebo
AU - Sabatini, David M.
AU - Gray, Nathaniel S.
PY - 2009/3/20
Y1 - 2009/3/20
N2 - The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1inhibitor 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.
AB - The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1inhibitor 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=65549145048&partnerID=8YFLogxK
U2 - 10.1074/jbc.M900301200
DO - 10.1074/jbc.M900301200
M3 - Article
C2 - 19150980
AN - SCOPUS:65549145048
VL - 284
SP - 8023
EP - 8032
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 12
ER -