Vézina, C., Kudelski, A. & Sehgal, S. N.
Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot.
28, 721–726 (1975).
Martel, R. R., Klicius, J. & Galet, S.
Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can. J. Physiol. Pharmacol.
55, 48–51 (1977).
Houchens, D. P., Ovejera, A. A., Riblet, S. M. & Slagel, D. E.
Human brain tumor xenografts in nude mice as a chemotherapy model. Eur. J. Cancer Clin. Oncol.
19, 799–805 (1983).
Heitman, J., Movva, N. R. & Hall, M. N.
Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science
253, 905–909 (1991). The discovery of TOR by genetic selection in yeast. This study not only discovered the cellular target of rapamycin but also elucidated its mode of action via binding to the FPR1 gene product (the yeast homologue of mammalian FKBP12).
Zoncu, R., Efeyan, A. & Sabatini, D. M.
mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol.
12, 21–35 (2011).
Sarbassov, D. D.
et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell
22, 159–168 (2006).
Wullschleger, S., Loewith, R. & Hall, M. N.
TOR signaling in growth and metabolism. Cell
124, 471–484 (2006).
Fingar, D. C., Salama, S., Tsou, C., Harlow, E. & Blenis, J.
Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev.
16, 1472–1487 (2002).
Noda, T. & Ohsumi, Y.
Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem.
273, 3963–3966 (1998).
Jung, C. H., Ro, S. H., Cao, J., Otto, N. M. & Kim, D. H.
mTOR regulation of autophagy. FEBS Lett.
584, 1287–1295 (2010).
Schmidt, A., Kunz, J. & Hall, M. N.
TOR2 is required for organization of the actin cytoskeleton in yeast. Proc. Natl Acad. Sci. USA
93, 13780–13785 (1996).
et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell
10, 457–468 (2002). The discovery of the two TOR complexes TORC1 and TORC2.
et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol.
6, 1122–1128 (2004).
Sarbassov, D. D.
et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol.
14, 1296–1302 (2004).
Zhou, H. & Huang, S.
Role of mTOR signaling in tumor cell motility, invasion and metastasis. Curr. Protein Pept. Sci.
12, 30–42 (2011).
Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M.
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science
307, 1098–1101 (2005). The demonstration that mTORC2 is the long-sought-after PDK2. AKT is a major oncogene that is mutated in many cancers. The kinase responsible for phosphorylation of AKT at Ser473 to fully activate AKT signalling was a subject of intense study, and the identification of TORC2 as the responsible kinase was influential in directing interest in the field towards cancer research.
García-Martínez, J. M. & Alessi, D. R.
mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J.
416, 375–385 (2008).
Ikenoue, T., Inoki, K., Yang, Q., Zhou, X. & Guan, K. L.
Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J.
27, 1919–1931 (2008).
Zinzalla, V., Stracka, D., Oppliger, W. & Hall, M. N.
Activation of mTORC2 by association with the ribosome. Cell
144, 757–768 (2011).
Oh, W. J.
et al. mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J.
29, 3939–3951 (2010).
Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M.
mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature
468, 1100–1104 (2010).
Gu, Y., Lindner, J., Kumar. A., Yuan, W. & Magnuson, M. A.
Rictor/mTORC2 is essential for maintaining a balance between β-cell proliferation and cell size. Diabetes
60, 827–837 (2011).
Bentzinger, C. F.
et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab.
8, 411–424 (2008).
et al. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J. Cell Biol.
187, 859–874 (2009).
et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab.
8, 399–410 (2008).
Cybulski, N., Polak, P., Auwerx, J., Rüegg, M. A. & Hall, M. N.
mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc. Natl Acad. Sci. USA
106, 9902–9907 (2009).
Blouet, C., Ono, H. & Schwartz, G. J.
Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab.
8, 459–467 (2008).
Shah, O. J., Wang, Z. & Hunter, T.
Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol.
14, 1650–1656 (2004).
Harrington, L. S.
et al. The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol.
166, 213–223 (2004). References 28 and 29 describe the negative-feedback loop in the mTORC1 pathway in which mTORC1-activated S6K dampens insulin receptor signalling by negatively regulating IRS1.
Um, S. H.
et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature
431, 200–205 (2004). This paper showed the first evidence of the negative-feedback loop in an animal model.
Gangloff, Y. G.
et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol. Cell. Biol.
24, 9508–9516 (2004).
et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol. Cell. Biol.
24, 6710–6718 (2004).
et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest.
121, 2197–2209 (2011).
et al. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation
123, 1073–1082 (2011).
Guertin, D. A.
et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell
15, 148–159 (2009).
et al. Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Sci. Signal.
2, ra2 (2009).
et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell
39, 171–183 (2010).
et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science
310, 1193–1196 (2005).
et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol.
14, 885–890 (2004).
Harrison, D. E.
et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature
460, 392–395 (2009). The first pharmacological extension of lifespan in mammals. Strikingly, the effect of rapamycin was obtained even though treatment commenced when the mice had already reached adulthood.
et al. Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin. Am. J. Pathol.
171, 1733–1742 (2007).
et al. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci. Transl. Med.
3, 89ra58 (2011).
Andoh, T. F., Burdmann, E. A., Fransechini, N., Houghton, D. C. & Bennett, W. M.
Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int.
50, 1110–1117 (1996).
Thompson, C. A.
First drug-eluting coronary stent approved. Am. J. Health Syst. Pharm.
60, 1210–1212 (2003).
Rini, B. I.
Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin. Cancer Res.
14, 1286–1290 (2008).
Gabardi, S. & Baroletti, S. A.
Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology. Pharmacotherapy
30, 1044–1056 (2010).
Mita, M., Sankhala, K., Abdel-Karim, I., Mita, A. & Giles, F.
Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opin. Investig. Drugs
17, 1947–1954 (2008).
et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med.
356, 2271–2281 (2007).
Motzer, R. J.
et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet
372, 449–456 (2008).
et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J. Clin. Oncol.
27, 3822–3829 (2009).
Yao, J. C.
et al. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med.
364, 514–523 (2011).
Bissler, J. J.
et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med.
358, 140–151 (2008).
O'Reilly, K. E.
et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res.
66, 1500–1508 (2006).
et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J. Clin. Oncol.
26, 1603–1610 (2008).
Choo, A. Y., Yoon, S. O., Kim, S. G., Roux, P. P. & Blenis, J.
Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl Acad. Sci. USA
105, 17414–17419 (2008).
Feldman, M. E.
et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol.
7, e38 (2009).
Thoreen, C. C.
et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem.
284, 8023–8032 (2009).
Dowling, R. J.
et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science
328, 1172–1176 (2010).
Baumann, P., Hagemeier, H., Mandl-Weber, S., Franke, D. & Schmidmaier, R.
Myeloma cell growth inhibition is augmented by synchronous inhibition of the insulin-like growth factor-1 receptor by NVP-AEW541 and inhibition of mammalian target of rapamycin by Rad001. Anticancer Drugs
20, 259–266 (2009).
Rao, R. D.
et al. Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. Neoplasia
7, 921–929 (2005).
et al. Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. Leuk. Res.
31, 673–682 (2007).
et al. Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates. J. Med. Chem.
53, 452–459 (2010).
et al. Dual inhibition of Akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol. Cancer Ther.
9, 963–975 (2010).
et al. Rapamycin-mediated FOXO1 inactivation reduces the anticancer efficacy of rapamycin. Anticancer Res.
30, 799–804 (2010).
Ballou, L. M. & Lin, R. Z.
Rapamycin and mTOR kinase inhibitors. J. Chem. Biol.
1, 27–36 (2008).
Knight, Z. A.
et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell
125, 733–747 (2006). The first description, together with the paper below, of a dual mTOR/PI3K inhibitor. The lead compound, PI103, has served as a model for further development.
Fan, Q. W.
et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell
9, 341–349 (2006).
Raynaud, F. I.
et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol. Cancer Ther.
8, 1725–1738 (2009).
Zhang, Y. J., Duan, Y. & Zheng, X. F.
Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov. Today
16, 325–331 (2011).
Baumann, P., Mandl-Weber, S., Oduncu, F. & Schmidmaier, R.
The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp. Cell Res.
315, 485–497 (2009).
Manara, M. C.
et al. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin. Cancer Res.
16, 530–540 (2010).
Engelman, J. A.
et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med.
14, 1351–1356 (2008).
Aziz, S. A.
et al. Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma. Clin. Cancer Res.
16, 6029–6039 (2010).
Molckovsky, A. & Siu, L. L.
First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American Society of Clinical Oncology meeting. J. Hematol. Oncol.
1, 20 (2008).
Garlich, J. R.
et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res.
68, 206–215 (2008).
et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nature Chem. Biol.
4, 691–699 (2008). The first description of a pan-mTOR inhibitor targeting TORC1 and TORC2 activity. The lead compound PP242 potently suppressed TORC1 and TORC2 activity with reduced efficacy against the related PIKK kinases DNA-PK and PI3K. A more potent and drug-like derivative, INK128, is currently in clinical trials for patients with advanced solid tumours and multiple myeloma.
Hsieh, A. C.
et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell
17, 249–261 (2010).
Janes, M. R.
et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nature Med.
16, 205–213 (2010).
Hsieh, A. C. & Ruggero, D.
Targeting eukaryotic translation initiation factor 4E (eIF4E) in cancer. Clin. Cancer Res.
16, 4914–4920 (2010).
Chresta, C. M.
et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res.
70, 288–298 (2010).
et al. Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055. Biochem. Soc. Trans.
39, 456–459 (2011).
Sini, P., James, D., Chresta, C. & Guichard, S.
Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy
6, 553–554 (2010).
Holt, S. V.
et al. The mTOR kinase inhibitor AZD8055 induces cell death in Her2+ tumors partially or intrinsically resistant to ErbB2 inhibitors. In 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (Berlin, Germany; 16–19 Nov.) Abstr. 157 (2010).
et al. The combination of AZD8055 and selumetinib (AZD6244, ARRY-142886) is synergistic in a subset of non small cell lung cancer cell lines with co-dependency to the MEK and mTOR pathways. In
NCRI Conference (Liverpool, UK; 7–10 Nov.) Abstr. LB144 (2010).
et al. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc. Natl Acad. Sci. USA
107, 12469–12474 (2010).
Tan, D. S.
et al. First-in-human phase I study exploring three schedules of OSI-027, a novel small molecule TORC1/TORC2 inhibitor, in patients with advanced solid tumors and lymphoma. J. Clin. Oncol.
28 (Suppl. 15), Abstr. 3006 (2010).
et al. INK128 is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity. Mol. Cancer Ther.
8 (Suppl. 12), Abstr. B148 (2009).
et al. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res.
68, 9551–9557 (2008).
Lewis, G. P.
et al. Muller cell reactivity and photoreceptor cell death are reduced after experimental retinal detachment using an inhibitor of the Akt/mTOR pathway. Invest. Ophthalmol. Vis. Sci.
50, 4429–4435 (2009).
et al. Targeting the Akt/mTOR pathway in Brca1-deficient cancers. Oncogene
30, 2443–2450 (2011).
Gravina, G. L.
et al. The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone refractory prostate cancer cells. Endocr. Relat. Cancer
18, 385–400 (2011).
et al. The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. Br. J. Cancer.
100, 932–940 (2009).
et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res.
69, 6232–6240 (2009).
et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res.
70, 621–631 (2010).
et al. Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J. Med. Chem.
54, 1473–1480 (2011).
García-Martínez, J. M.
et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem. J.
421, 29–42 (2009).
et al. WJD008, a dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin inhibitor, prevents PI3K signaling and inhibits the proliferation of transformed cells with oncogenic PI3K mutant. J. Pharmacol. Exp. Ther.
334, 830–838 (2010).
et al. Antitumor efficacy profile of PKI-402, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor. Mol. Cancer Ther.
9, 976–984 (2010).
et al. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol. Cancer Res.
7, 601–613 (2009).
Falcon, B. L.
et al. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Res.
71, 1573–1583 (2011).
Zask, A., Verheijen, J. C. & Richard, D. J.
Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review. Expert Opin. Ther. Pat.
21, 1109–1127 (2011).
Choi, J., Chen, J., Schreiber, S. L. & Clardy, J.
Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science
273, 239–242 (1996).
Liang, J., Choi, J. & Clardy, J.
Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2 Å resolution. Acta Crystallogr. D Biol. Crystallogr.
55, 736–744 (1999).
et al. The FRB domain of mTOR: NMR solution structure and inhibitor design. Biochemistry
45, 10294–10302 (2006).
Dames, S. A., Mulet, J. M., Rathgeb-Szabo, K., Hall, M. N. & Grzesiek, S.
The solution structure of the FATC domain of the protein kinase target of rapamycin suggests a role for redox-dependent structural and cellular stability. J. Biol. Chem.
280, 20558–20564 (2005).
Knutson, B. A.
Insights into the domain and repeat architecture of target of rapamycin. J. Struct. Biol.
170, 354–363 (2010).
Yip, C. K., Murata, K., Walz, T., Sabatini, D. M. & Kang, S. A.
Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell
38, 768–774 (2010).
Sturgill, T. W. & Hall, M. N.
Activating mutations in TOR are in similar structures as oncogenic mutations in PI3KCα. ACS Chem. Biol.
4, 999–1015 (2009).
Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A. & Chen, J.
Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science
294, 1942–1945 (2001).
et al. Structural characterization of the interaction of mTOR with phosphatidic acid and a novel class of inhibitor: compelling evidence for a central role of the FRB domain in small molecule-mediated regulation of mTOR. Oncogene
27, 585–595 (2008).
et al. Phospholipase D regulates myogenic differentiation through the activation of both mTORC1 and mTORC2 complexes. J. Biol. Chem.
286, 22609–22621 (2011).
Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M, Alessi, D. R. & Morris, A. D.
Metformin and reduced risk of cancer in diabetic patients. BMJ
330, 1304–1305 (2005).
et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care
32, 1620–1625 (2009).
Shaw, R. J.
et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell
6, 91–99 (2004).
Gwinn, D. M.
et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell
30, 214–226 (2008).
et al. Metformin, independent of AMPK, inhibits mTORC1 in a Rag GTPase-dependent manner. Cell Metab.
11, 390–401 (2010).
Chong, C. R. & Chabner, B. A.
Mysterious metformin. Oncologist
14, 1178–1181 (2009).
Currie, C. J., Poole, C. D. & Gale, E. A.
The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia
52, 1766–1777 (2009).
Li, D., Yeung, S. C., Hassan, M. M., Konopleva, M. & Abbruzzese, J. L.
Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology
137, 482–488 (2009).
Wright, J. L. & Stanford, J. L.
Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control
20, 1617–1622 (2009).
et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol.
27, 3297–3302 (2009).
Secchiero, P., Bosco, R., Celeghini, C. & Zauli, G.
Recent advances in the therapeutic perspectives of Nutlin-3. Curr. Pharm. Des.
17, 569–577 (2011).
et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res.
68, 3421–3428 (2008).
Wullschleger, S., Loewith, R., Oppliger, W. & Hall, M. N.
Molecular organization of target of rapamycin complex 2. J. Biol. Chem.
280, 30697–30704 (2005).
Zhang, Y., Billington, C. J. Jr, Pan, D. & Neufeld, T. P.
Drosophila target of rapamycin kinase functions as a multimer. Genetics
172, 355–362 (2006).
McMahon, L. P., Yue, W., Santen, R. J. & Lawrence, J. C. Jr.
Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex. Mol. Endocrinol.
19, 175–183 (2005).
et al. GCN2 protein kinase is required to activate amino acid deprivation responses in mice treated with the anti-cancer agent L-asparaginase. J. Biol. Chem.
284, 32742–32749 (2009).
et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science
320, 1496–1501 (2008).
et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell
141, 290–303 (2010).
et al. The rapamycin-sensitive phosphoproteome reveals that TOR controls protein kinase A toward some but not all substrates. Mol. Biol. Cell
21, 3475–3486 (2010).
et al. Characterization of the rapamycin-sensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis. Genes Dev.
23, 1929–1943 (2009).
Hsu, P. P.
et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science
332, 1317–1322 (2011).
et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science
332, 1322–1326 (2011).
et al. Genome-wide shRNA screen reveals increased mitochondrial dependence upon mTORC2 addiction. Oncogene
30, 1551–1565 (2011).
Chong, Z. Z., Shang, Y. C., Zhang, L., Wang, S. & Maiese, K.
Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. Oxid. Med. Cell. Longev.
3, 374–391 (2010).
et al. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell
73, 585–596 (1993).
Brown, E. J.
et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature
369, 756–758 (1994).
Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H.
RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell
78, 35–43 (1994).
Chiu, M. I., Katz, H. & Berlin, V.
RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc. Natl Acad. Sci. USA
91, 12574–12578 (1994).
Sabers, C. J.
et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem.
270, 815–822 (1995).
Barbet, N. C.
et al. TOR controls translation initiation and early G1 progression in yeast. Mol. Biol. Cell
7, 25–42 (1996).
Beretta, L., Gingras, A. C., Svitkin, Y. V., Hall, M. N. & Sonenberg, N.
Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J.
15, 658–664 (1996).
et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem.
272, 26457–26463 (1997).
Brunn, G. J.
et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science
277, 99–101 (1997).
Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H. & Sabatini, D. M.
RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl Acad. Sci. USA
95, 1432–1437 (1998).
et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem.
273, 14484–14494 (1998).
Wang, X., Campbell, L. E., Miller, C. M. & Proud, C. G.
Amino acid availability regulates p70 S6 kinase and multiple translation factors. Biochem. J.
334, 261–267 (1998).
Schmelzle, T. & Hall, M. N.
TOR, a central controller of cell growth. Cell
103, 253–262 (2000).
Potter, C. J., Pedraza, L. G. & Xu, T.
Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol.
4, 658–665 (2002).
Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L.
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol.
4, 648–657 (2002).
et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nature Cell Biol.
4, 699–704 (2002).
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C.
Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell
10, 151–162 (2002).
Kwiatkowski, D. J.
et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet.
11, 525–534 (2002).
Inoki, K., Li, Y., Xu, T. & Guan, K. L.
Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev.
17, 1829–1834 (2003).
Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J.
Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol.
13, 1259–1268 (2003).
et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell
11, 1457–1466 (2003).
Castro, A. F., Rebhun, J. F., Clark, G. J. & Quilliam, L. A.
Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J. Biol. Chem.
278, 32493–32496 (2003).
et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol.
5, 578–581 (2003).
Inoki, K., Zhu, T. & Guan, K. L.
TSC2 mediates cellular energy response to control cell growth and survival. Cell
115, 577–590 (2003).
Kim, D. H.
et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell
110, 163–175 (2002).
et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell
110, 177–189 (2002).
et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature
426, 620 (2003).
Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L.
Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biol.
10, 935–945 (2008).