The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2
Open accessAbstract
The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
Kim, D.-H., Sarbassov, D. D., Ali, S. M., King, J. E., Latek, R. R., Erdjument-Bromage, H., Tempst, P., & Sabatini, D. M. (2002) · Cell · doi:10.1016/s0092-8674(02)00808-5 · Cited by 2,986
Defining the role of mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.008 · Cited by 2,833
Sarbassov, D. D., Ali, S. M., Kim, D.-H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., Tempst, P., & Sabatini, D. M. (2004) · Current Biology · doi:10.1016/j.cub.2004.06.054 · Cited by 2,665
mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
O'Reilly, K. E., Rojo, F., She, Q.-B., Solit, D., Mills, G. B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2925 · Cited by 2,561
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.029 · Cited by 2,365
Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive
Jacinto, E., Loewith, R., Schmidt, A., Lin, S., Rüegg, M. A., Hall, A., & Hall, M. N. (2004) · Nature Cell Biology · doi:10.1038/ncb1183 · Cited by 2,114
Self-citationLoewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J. L., Bonenfant, D., Oppliger, W., Jenoe, P., & Hall, M. N. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00636-6 · Cited by 1,886
Self-citationRaptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR Action
Hara, K., Maruki, Y., Long, X., Yoshino, K.-I., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., & Yonezawa, K. (2002) · Cell · doi:10.1016/s0092-8674(02)00833-4 · Cited by 1,810
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. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900301200 · Cited by 1,803
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., et al. (2004) · Nature · doi:10.1038/nature02866 · Cited by 1,677
Guertin, D. A., Stevens, D. M., Thoreen, C. C., Burds, A. A., Kalaany, N. Y., Moffat, J., Brown, M., Fitzgerald, K. J., & Sabatini, D. M. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.10.007 · Cited by 1,415
Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S. Y., Huang, Q., Qin, J., & Su, B. (2006) · Cell · doi:10.1016/j.cell.2006.08.033 · Cited by 1,410
Translational control of gene expression
Sonenberg, N., Hershey, J. W. B., & Mathews, M. B. (2000) · Cold Spring Harbor Laboratory eBooks · Cited by 1,379
Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism
Gingras, A.-C., Gygi, S. P., Raught, B., Polakiewicz, R. D., Abraham, R. T., Hoekstra, M. F., Aebersold, R., & Sonenberg, N. (1999) · Genes & Development · doi:10.1101/gad.13.11.1422 · Cited by 1,343
mTOR and cancer: insights into a complex relationship
Sabatini, D. M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1974 · Cited by 1,322
Translational control of gene expression
Hannig, E. M. (2001) · BioEssays · doi:10.1002/bies.1108 · Cited by 1,189
A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling
Knight, Z. A., Gonzalez, B., Feldman, M. E., Zunder, E. R., Goldenberg, D. D., Williams, O., Loewith, R., Stokoe, D., Balla, A., Toth, B., et al. (2006) · Cell · doi:10.1016/j.cell.2006.03.035 · Cited by 1,174
Self-citationRole of Translocation in the Activation and Function of Protein Kinase B
Andjelkovic, M., Alessi, D. R., Meier, R., Fernandez, A., Lamb, N. J. C., Frech, M., Cron, P., Cohen, P., Lucocq, J. M., & Hemmings, B. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.50.31515 · Cited by 1,051
Current development of mTOR inhibitors as anticancer agents
Faivre, S., Kroemer, G., & Raymond, E. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2062 · Cited by 1,000
García-Martínez, J. M., & Alessi, D. R. (2008) · Biochemical Journal · doi:10.1042/bj20081668 · Cited by 907
Hierarchical phosphorylation of the translation inhibitor 4E-BP1
Gingras, A.-C., Raught, B., Gygi, S. P., Niedzwiecka, A., Miron, M., Burley, S. K., Polakiewicz, R. D., Wyslouch-Cieszynska, A., Aebersold, R., & Sonenberg, N. (2001) · Genes & Development · doi:10.1101/gad.912401 · Cited by 883
Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism
Wan, X., Harkavy, B., Shen, N., Grohar, P., & Helman, L. J. (2007) · Oncogene · doi:10.1038/sj.onc.1209990 · Cited by 755
Brunn, G. J., Williams, J., Sabers, C., Wiederrecht, G., Lawrence, J. C., & Abraham, R. T. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00911.x · Cited by 723
mTOR·RICTOR Is the Ser473 Kinase for Akt/Protein Kinase B in 3T3-L1 Adipocytes
Hresko, R. C., & Mueckler, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508361200 · Cited by 635
Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling
Ikenoue, T., Inoki, K., Yang, Q., Zhou, X., & Guan, K. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.119 · Cited by 610
The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis
Ruggero, D., Montanaro, L., Ma, L., Xu, W., Londei, P., Cordon-Cardo, C., & Pandolfi, P. P. (2004) · Nature Medicine · doi:10.1038/nm1042 · Cited by 586
Self-citationAllosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors
Lindsley, C. W., Zhao, Z., Leister, W. H., Robinson, R. G., Barnett, S. F., Defeo-Jones, D., Jones, R. E., Hartman, G. D., Huff, J. R., Huber, H. E., et al. (2005) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2004.11.011 · Cited by 503
Regulation of Protein Kinase B/Akt-Serine 473 Phosphorylation by Integrin-linked Kinase
Persad, S., Attwell, S., Gray, V., Mawji, N., Deng, J. T., Leung, D., Yan, J., Sanghera, J., Walsh, M. P., & Dedhar, S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102940200 · Cited by 497
Identification of a PKB/Akt Hydrophobic Motif Ser-473 Kinase as DNA-dependent Protein Kinase
Feng, J., Park, J., Cron, P., Hess, D., & Hemmings, B. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406731200 · Cited by 488
Exploring the specificity of the PI3K family inhibitor LY294002
Gharbi, S. I., Zvelebil, M. J., Shuttleworth, S. J., Hancox, T., Saghir, N., Timms, J. F., & Waterfield, M. D. (2007) · Biochemical Journal · doi:10.1042/bj20061489 · Cited by 462
Easton, J. B., & Houghton, P. J. (2006) · Oncogene · doi:10.1038/sj.onc.1209886 · Cited by 459
Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases
Apsel, B., Blair, J. A., Gonzalez, B., Nazif, T. M., Feldman, M. E., Aizenstein, B., Hoffman, R., Williams, R. L., Shokat, K. M., & Knight, Z. A. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.117 · Cited by 440
Self-citationDyskeratosis Congenita and Cancer in Mice Deficient in Ribosomal RNA Modification
Ruggero, D., Grisendi, S., Piazza, F., Rego, E., Mari, F., Rao, P. H., Cordon-Cardo, C., & Pandolfi, P. P. (2003) · Science · doi:10.1126/science.1079447 · Cited by 435
Self-citationImpaired Control of IRES-Mediated Translation in X-Linked Dyskeratosis Congenita
Yoon, A., Peng, G., Brandenburg, Y., Zollo, O., Xu, W., Rego, E., & Ruggero, D. (2006) · Science · doi:10.1126/science.1123835 · Cited by 424
Self-citationShiota, C., Woo, J.-T., Lindner, J., Shelton, K. D., & Magnuson, M. A. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.08.013 · Cited by 389
PKBα/Akt1 Acts Downstream of DNA-PK in the DNA Double-Strand Break Response and Promotes Survival
Bozulic, L., Surucu, B., Hynx, D., & Hemmings, B. A. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.02.024 · Cited by 386
The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor
Fox, C. J., Hammerman, P. S., Cinalli, R. M., Master, S. R., Chodosh, L. A., & Thompson, C. B. (2003) · Genes & Development · doi:10.1101/gad.1105003 · Cited by 336
Targeting the mTOR signaling network in cancer
Chiang, G. G., & Abraham, R. T. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.08.001 · Cited by 327
Chemical Genetics: Where Genetics and Pharmacology Meet
Knight, Z. A., & Shokat, K. M. (2007) · Cell · doi:10.1016/j.cell.2007.01.021 · Cited by 243
Self-citationNovel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1
Feldman, R. I., Wu, J. M., Polokoff, M. A., Kochanny, M. J., Dinter, H., Zhu, D., Biroc, S. L., Alicke, B., Bryant, J., Yuan, S., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501367200 · Cited by 228
Rictor and Integrin-Linked Kinase Interact and Regulate Akt Phosphorylation and Cancer Cell Survival
McDonald, P. C., Oloumi, A., Mills, J., Dobreva, I., Maidan, M., Gray, V., Wederell, E. D., Bally, M. B., Foster, L. J., & Dedhar, S. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5869 · Cited by 224
Kumar, A., Harris, T. E., Keller, S. R., Choi, K. M., Magnuson, M. A., & Lawrence, J. C. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01405-07 · Cited by 216
Wang, X., Beugnet, A., Murakami, M., Yamanaka, S., & Proud, C. G. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.7.2558-2572.2005 · Cited by 205
When translation meets transformation: the mTOR story
Averous, J., & Proud, C. G. (2006) · Oncogene · doi:10.1038/sj.onc.1209887 · Cited by 197
The Akt of translational control
Ruggero, D., & Sonenberg, N. (2005) · Oncogene · doi:10.1038/sj.onc.1209098 · Cited by 196
Self-citationFadden, P., Haystead, T. A. J., & Lawrence, J. C. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.15.10240 · Cited by 195
Pim-1 Ligand-bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by LY294002
Jacobs, M. D., Black, J., Futer, O., Swenson, L., Hare, B., Fleming, M., & Saxena, K. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413155200 · Cited by 192
Mothe‐Satney, I., Yang, D., Fadden, P., Haystead, T., & Lawrence, J. C. (2000) · Molecular and Cellular Biology · doi:10.1128/.20.10.3558-3567.2000 · Cited by 187
Mothe‐Satney, I., Brunn, G. J., McMahon, L. P., Capaldo, C., Abraham, R. T., & Lawrence, J. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006005200 · Cited by 130
The Rapamycin-Binding Domain Governs Substrate Selectivity by the Mammalian Target of Rapamycin
McMahon, L. P., Choi, K. M., Lin, T.-A., Abraham, R. T., & Lawrence, J. C. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.21.7428-7438.2002 · Cited by 113
Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKB-pathway
Stauffer, F., Maira, S.-M., Furet, P., & Garcı́a-Echeverrı́a, C. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.12.018 · Cited by 87
Karim, M. M., Hughes, J. M. X., Warwicker, J., Scheper, G. C., Proud, C. G., & McCarthy, J. E. G. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011068200 · Cited by 74
Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells
Tamgüney, T., Zhang, C., Fiedler, D., Shokat, K. M., & Stokoe, D. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.04.006 · Cited by 33
Self-citationSer-64 and Ser-111 in PHAS-I Are Dispensable for Insulin-stimulated Dissociation from eIF4E
Ferguson, G., Mothe‐Satney, I., & Lawrence, J. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307949200 · Cited by 30
Cited by
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509
mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497
Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996
Metadata
- Authors
- Feldman, M. E., Apsel, B., Uotila, A., Loewith, R., Knight, Z. A., Ruggero, D., & Shokat, K. M.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-02-10
- Volume
- 7
- Issue
- 2
- Pages
- e1000038
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- OpenAlex
- W2035521247
- Cited by
- 1,082
- References
- 55
- FWCI
- 43.57
- Type
- journal article
- Language
- en
- Open access
- gold
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
