mTOR signaling in tumorigenesis

Vezina, 1975, Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle, J. Antibiot., 28, 721, 10.7164/antibiotics.28.721 Heitman, 1991, Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast, Science, 253, 905, 10.1126/science.1715094 Brown, 1994, A mammalian protein targeted by G1-arresting rapamycin–receptor complex, Nature, 369, 756, 10.1038/369756a0 Sabatini, 1994, RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs, Cell, 78, 35, 10.1016/0092-8674(94)90570-3 Sabers, 1995, Isolation of a protein target of the FKBP12–rapamycin complex in mammalian cells, J. Biol. Chem., 270, 815, 10.1074/jbc.270.2.815 Bakkenist, 2004, Initiating cellular stress responses, Cell, 118, 9, 10.1016/j.cell.2004.06.023 Wullschleger, 2006, TOR signaling in growth and metabolism, Cell, 124, 471, 10.1016/j.cell.2006.01.016 Inoki, 2005, Dysregulation of the TSC-mTOR pathway in human disease, Nat. Genet., 37, 19, 10.1038/ng1494 Zoncu, 2011, mTOR: from growth signal integration to cancer, diabetes and ageing, Nat. Rev. Mol. Cell Biol., 12, 21, 10.1038/nrm3025 Hara, 2002, Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action, Cell, 110, 177, 10.1016/S0092-8674(02)00833-4 Kim, 2002, mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery, Cell, 110, 163, 10.1016/S0092-8674(02)00808-5 Kim, 2003, GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR, Mol. Cell, 11, 895, 10.1016/S1097-2765(03)00114-X Jacinto, 2004, Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive, Nat. Cell Biol., 6, 1122, 10.1038/ncb1183 Sarbassov, 2004, Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton, Curr. Biol., 14, 1296, 10.1016/j.cub.2004.06.054 Frias, 2006, mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s, Curr. Biol., 16, 1865, 10.1016/j.cub.2006.08.001 Jacinto, 2006, SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity, Cell, 127, 125, 10.1016/j.cell.2006.08.033 Laplante, 2012, mTOR signaling in growth control and disease, Cell, 149, 274, 10.1016/j.cell.2012.03.017 Guertin, 2006, Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1, Dev. Cell, 11, 859, 10.1016/j.devcel.2006.10.007 Yang, 2006, Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity, Genes Dev., 20, 2820, 10.1101/gad.1461206 Liu, 2013, Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis, Nat. Cell Biol., 15, 1340, 10.1038/ncb2860 Peterson, 2009, DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival, Cell, 137, 873, 10.1016/j.cell.2009.03.046 Vander Haar, 2007, Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40, Nat. Cell Biol., 9, 316, 10.1038/ncb1547 Wang, 2007, PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding, J. Biol. Chem., 282, 20036, 10.1074/jbc.M702376200 Pearce, 2007, Identification of Protor as a novel Rictor-binding component of mTOR complex-2, Biochem. J., 405, 513, 10.1042/BJ20070540 Pearce, 2011, Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney, Biochem. J., 436, 169, 10.1042/BJ20102103 Pearce, 2010, The nuts and bolts of AGC protein kinases, Nat. Rev. Mol. Cell Biol., 11, 9, 10.1038/nrm2822 Sabatini, 2006, mTOR and cancer: insights into a complex relationship, Nat. Rev. Cancer, 6, 729, 10.1038/nrc1974 Guertin, 2007, Defining the role of mTOR in cancer, Cancer Cell, 12, 9, 10.1016/j.ccr.2007.05.008 Cantor, 2012, Cancer cell metabolism: one hallmark, many faces, Cancer Discov., 2, 881, 10.1158/2159-8290.CD-12-0345 Crino, 2006, The tuberous sclerosis complex, N. Engl. J. Med., 355, 1345, 10.1056/NEJMra055323 Hemminki, 1998, A serine/threonine kinase gene defective in Peutz–Jeghers syndrome, Nature, 391, 184, 10.1038/34432 Engelman, 2006, The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism, Nat. Rev. Genet., 7, 606, 10.1038/nrg1879 Wander, 2011, Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy, J. Clin. Invest., 121, 1231, 10.1172/JCI44145 Meric-Bernstam, 2009, Targeting the mTOR signaling network for cancer therapy, J. Clin. Oncol., 27, 2278, 10.1200/JCO.2008.20.0766 Murakami, 2004, mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells, Mol. Cell. Biol., 24, 6710, 10.1128/MCB.24.15.6710-6718.2004 Gangloff, 2004, Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development, Mol. Cell. Biol., 24, 9508, 10.1128/MCB.24.21.9508-9516.2004 Wu, 2013, Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression, Cell Rep., 4, 913, 10.1016/j.celrep.2013.07.030 Risson, 2009, Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy, J. Cell Biol., 187, 859, 10.1083/jcb.200903131 Polak, 2008, Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration, Cell Metab., 8, 399, 10.1016/j.cmet.2008.09.003 Bentzinger, 2008, Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy, Cell Metab., 8, 411, 10.1016/j.cmet.2008.10.002 Shende, 2011, Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice, Circulation, 123, 1073, 10.1161/CIRCULATIONAHA.110.977066 Cloetta, 2013, Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis, J. Neurosci., 33, 7799, 10.1523/JNEUROSCI.3294-12.2013 Sengupta, 2010, mTORC1 controls fasting-induced ketogenesis and its modulation by ageing, Nature, 468, 1100, 10.1038/nature09584 Hoshii, 2012, mTORC1 is essential for leukemia propagation but not stem cell self-renewal, J. Clin. Invest., 122, 2114, 10.1172/JCI62279 Shiota, 2006, Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability, Dev. Cell, 11, 583, 10.1016/j.devcel.2006.08.013 Kumar, 2008, Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity, Mol. Cell. Biol., 28, 61, 10.1128/MCB.01405-07 Yuan, 2012, Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2, J. Biol. Chem., 287, 29579, 10.1074/jbc.M112.386854 Kumar, 2010, Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism, Diabetes, 59, 1397, 10.2337/db09-1061 Carson, 2013, Deletion of Rictor in neural progenitor cells reveals contributions of mTORC2 signaling to tuberous sclerosis complex, Hum. Mol. Genet., 22, 140, 10.1093/hmg/dds414 Siuta, 2010, Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice, PLoS Biol., 8, e1000393, 10.1371/journal.pbio.1000393 Lamming, 2014, Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan, Aging Cell, 13, 911, 10.1111/acel.12256 Guertin, 2009, mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice, Cancer Cell, 15, 148, 10.1016/j.ccr.2008.12.017 Lazorchak, 2010, Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells, Mol. Cell, 39, 433, 10.1016/j.molcel.2010.07.031 Chang, 2012, Sin1 regulates Treg-cell development but is not required for T-cell growth and proliferation, Eur. J. Immunol., 42, 1639, 10.1002/eji.201142066 Tee, 2002, Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling, Proc. Natl. Acad. Sci. U. S. A., 99, 13571, 10.1073/pnas.202476899 Dibble, 2012, TBC1D7 is a third subunit of the TSC1–TSC2 complex upstream of mTORC1, Mol. Cell, 47, 535, 10.1016/j.molcel.2012.06.009 Inoki, 2002, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling, Nat. Cell Biol., 4, 648, 10.1038/ncb839 Ma, 2005, Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis, Cell, 121, 179, 10.1016/j.cell.2005.02.031 Roux, 2004, Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase, Proc. Natl. Acad. Sci. U. S. A., 101, 13489, 10.1073/pnas.0405659101 Menon, 2014, Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome, Cell, 156, 771, 10.1016/j.cell.2013.11.049 Inoki, 2003, TSC2 mediates cellular energy response to control cell growth and survival, Cell, 115, 577, 10.1016/S0092-8674(03)00929-2 Zoncu, 2011, mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase, Science, 334, 678, 10.1126/science.1207056 Demetriades, 2014, Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2, Cell, 156, 786, 10.1016/j.cell.2014.01.024 Jozwiak, 2008, Possible mechanisms of disease development in tuberous sclerosis, Lancet Oncol., 9, 73, 10.1016/S1470-2045(07)70411-4 Kobayashi, 2001, A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice, Proc. Natl. Acad. Sci. U. S. A., 98, 8762, 10.1073/pnas.151033798 Onda, 1999, Tsc2(+/−) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background, J. Clin. Invest., 104, 687, 10.1172/JCI7319 Wilson, 2005, A mouse model of tuberous sclerosis 1 showing background specific early post-natal mortality and metastatic renal cell carcinoma, Hum. Mol. Genet., 14, 1839, 10.1093/hmg/ddi190 Kladney, 2010, Tuberous sclerosis complex 1: an epithelial tumor suppressor essential to prevent spontaneous prostate cancer in aged mice, Cancer Res., 70, 8937, 10.1158/0008-5472.CAN-10-1646 Menon, 2012, Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice, Sci. Signal., 5, ra24, 10.1126/scisignal.2002739 Chen, 2014, Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) promotes breast cancer progression through enhancing glucose starvation-induced autophagy and Akt signaling, J. Biol. Chem., 289, 1164, 10.1074/jbc.M113.526335 Kenerson, 2013, Akt and mTORC1 have different roles during liver tumorigenesis in mice, Gastroenterology, 144, 1055, 10.1053/j.gastro.2013.01.053 Prizant, 2013, Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs, Mol. Endocrinol., 27, 1403, 10.1210/me.2013-1059 Blando, 2009, PTEN deficiency is fully penetrant for prostate adenocarcinoma in C57BL/6 mice via mTOR-dependent growth, Am. J. Pathol., 174, 1869, 10.2353/ajpath.2009.080055 Saucedo, 2003, Rheb promotes cell growth as a component of the insulin/TOR signalling network, Nat. Cell Biol., 5, 566, 10.1038/ncb996 Stocker, 2003, Rheb is an essential regulator of S6K in controlling cell growth in Drosophila, Nat. Cell Biol., 5, 559, 10.1038/ncb995 Tee, 2003, 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, 10.1016/S0960-9822(03)00506-2 Betz, 2013, Where is mTOR and what is it doing there?, J. Cell Biol., 203, 563, 10.1083/jcb.201306041 Menon, 2013, Cell signalling: nutrient sensing lost in cancer, Nature, 498, 444, 10.1038/498444a Goorden, 2011, Rheb is essential for murine development, Mol. Cell. Biol., 31, 1672, 10.1128/MCB.00985-10 Zou, 2011, Rheb1 is required for mTORC1 and myelination in postnatal brain development, Dev. Cell, 20, 97, 10.1016/j.devcel.2010.11.020 Melser, 2013, Rheb regulates mitophagy induced by mitochondrial energetic status, Cell Metab., 17, 719, 10.1016/j.cmet.2013.03.014 Mavrakis, 2008, Tumorigenic activity and therapeutic inhibition of Rheb GTPase, Genes Dev., 22, 2178, 10.1101/gad.1690808 Nardella, 2008, Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events, Genes Dev., 22, 2172, 10.1101/gad.1699608 Lu, 2010, Mammalian target of rapamycin activator RHEB is frequently overexpressed in human carcinomas and is critical and sufficient for skin epithelial carcinogenesis, Cancer Res., 70, 3287, 10.1158/0008-5472.CAN-09-3467 Sekiguchi, 2001, Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B, J. Biol. Chem., 276, 7246, 10.1074/jbc.M004389200 Kim, 2008, Regulation of TORC1 by Rag GTPases in nutrient response, Nat. Cell Biol., 10, 935, 10.1038/ncb1753 Sancak, 2008, The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1, Science, 320, 1496, 10.1126/science.1157535 Efeyan, 2013, Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival, Nature, 493, 679, 10.1038/nature11745 Efeyan, 2014, RagA, but not RagB, is essential for embryonic development and adult mice, Dev. Cell, 29, 321, 10.1016/j.devcel.2014.03.017 Kim, 2014, Rag GTPases are cardioprotective by regulating lysosomal function, Nat. Commun., 5, 4241, 10.1038/ncomms5241 Tsun, 2013, The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1, Mol. Cell, 52, 495, 10.1016/j.molcel.2013.09.016 Bar-Peled, 2013, A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1, Science, 340, 1100, 10.1126/science.1232044 Hardie, 2013, LKB1 and AMPK and the cancer-metabolism link — ten years after, BMC Biol., 11, 36, 10.1186/1741-7007-11-36 Mihaylova, 2011, The AMPK signalling pathway coordinates cell growth, autophagy and metabolism, Nat. Cell Biol., 13, 1016, 10.1038/ncb2329 Hardie, 2007, AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy, Nat. Rev. Mol. Cell Biol., 8, 774, 10.1038/nrm2249 Gwinn, 2008, AMPK phosphorylation of raptor mediates a metabolic checkpoint, Mol. Cell, 30, 214, 10.1016/j.molcel.2008.03.003 Viollet, 2009, AMPK: lessons from transgenic and knockout animals, Front. Biosci., 14, 19, 10.2741/3229 Lantier, 2010, Coordinated maintenance of muscle cell size control by AMP-activated protein kinase, FASEB J., 24, 3555, 10.1096/fj.10-155994 Viollet, 2003, The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity, J. Clin. Invest., 111, 91, 10.1172/JCI16567 Kang, 2013, Genetic deletion of catalytic subunits of AMP-activated protein kinase increases osteoclasts and reduces bone mass in young adult mice, J. Biol. Chem., 288, 12187, 10.1074/jbc.M112.430389 Barnes, 2004, The 5′-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle, J. Biol. Chem., 279, 38441, 10.1074/jbc.M405533200 O'Neill, 2011, AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise, Proc. Natl. Acad. Sci. U. S. A., 108, 16092, 10.1073/pnas.1105062108 Zhou, 2001, Role of AMP-activated protein kinase in mechanism of metformin action, J. Clin. Invest., 108, 1167, 10.1172/JCI13505 Evans, 2005, Metformin and reduced risk of cancer in diabetic patients, BMJ, 330, 1304, 10.1136/bmj.38415.708634.F7 Faubert, 2013, AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo, Cell Metab., 17, 113, 10.1016/j.cmet.2012.12.001 Phoenix, 2012, AMPKalpha2 suppresses murine embryonic fibroblast transformation and tumorigenesis, Genes Cancer, 3, 51, 10.1177/1947601912452883 Jeon, 2012, AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress, Nature, 485, 661, 10.1038/nature11066 Kwiatkowski, 2002, 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, 10.1093/hmg/11.5.525 Castets, 2013, MTORC1 determines autophagy through ULK1 regulation in skeletal muscle, Autophagy, 9, 1435, 10.4161/auto.25722 Wu, 2014, iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions, J. Clin. Invest., 124, 1685, 10.1172/JCI69780 Malhowski, 2011, Smooth muscle protein-22-mediated deletion of Tsc1 results in cardiac hypertrophy that is mTORC1-mediated and reversed by rapamycin, Hum. Mol. Genet., 20, 1290, 10.1093/hmg/ddq570 Mori, 2009, Critical role for hypothalamic mTOR activity in energy balance, Cell Metab., 9, 362, 10.1016/j.cmet.2009.03.005 Zeng, 2008, Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex, Ann. Neurol., 63, 444, 10.1002/ana.21331 Kobayashi, 1999, Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice, Cancer Res., 59, 1206 Yuan, 2012, Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features, Hum. Mol. Genet., 21, 4286, 10.1093/hmg/dds262 Tartarin, 2012, Inactivation of AMPKalpha1 induces asthenozoospermia and alters spermatozoa morphology, Endocrinology, 153, 3468, 10.1210/en.2011-1911 Dzamko, 2010, AMPK beta1 deletion reduces appetite, preventing obesity and hepatic insulin resistance, J. Biol. Chem., 285, 115, 10.1074/jbc.M109.056762 Steinberg, 2010, Whole body deletion of AMP-activated protein kinase {beta}2 reduces muscle AMPK activity and exercise capacity, J. Biol. Chem., 285, 37198, 10.1074/jbc.M110.102434 Thomas, 2014, Muscle-specific AMPK beta1beta2-null mice display a myopathy due to loss of capillary density in nonpostural muscles, FASEB J., 28, 2098, 10.1096/fj.13-238972 Ma, 2009, Molecular mechanisms of mTOR-mediated translational control, Nat. Rev. Mol. Cell Biol., 10, 307, 10.1038/nrm2672 Hay, 2004, Upstream and downstream of mTOR, Genes Dev., 18, 1926, 10.1101/gad.1212704 Zhang, 2014, Coordinated regulation of protein synthesis and degradation by mTORC1, Nature, 513, 440, 10.1038/nature13492 Richter, 2005, Regulation of cap-dependent translation by eIF4E inhibitory proteins, Nature, 433, 477, 10.1038/nature03205 Mamane, 2004, eIF4E — from translation to transformation, Oncogene, 23, 3172, 10.1038/sj.onc.1207549 Tsukiyama-Kohara, 2001, Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1, Nat. Med., 7, 1128, 10.1038/nm1001-1128 Le Bacquer, 2007, Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2, J. Clin. Invest., 117, 387, 10.1172/JCI29528 Olson, 2009, Impaired myelopoiesis in mice lacking the repressors of translation initiation, 4E-BP1 and 4E-BP2, Immunology, 128, e376, 10.1111/j.1365-2567.2008.02981.x Wendel, 2004, Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy, Nature, 428, 332, 10.1038/nature02369 Petroulakis, 2009, p53-dependent translational control of senescence and transformation via 4E-BPs, Cancer Cell, 16, 439, 10.1016/j.ccr.2009.09.025 She, 2010, 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors, Cancer Cell, 18, 39, 10.1016/j.ccr.2010.05.023 Grove, 1991, Cloning and expression of two human p70 S6 kinase polypeptides differing only at their amino termini, Mol. Cell. Biol., 11, 5541, 10.1128/MCB.11.11.5541 Reinhard, 1992, A single gene encodes two isoforms of the p70 S6 kinase: activation upon mitogenic stimulation, Proc. Natl. Acad. Sci. U. S. A., 89, 4052, 10.1073/pnas.89.9.4052 Shima, 1998, Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase, EMBO J., 17, 6649, 10.1093/emboj/17.22.6649 Pende, 2004, S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway, Mol. Cell. Biol., 24, 3112, 10.1128/MCB.24.8.3112-3124.2004 Pende, 2000, Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice, Nature, 408, 994, 10.1038/35050135 Um, 2004, Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity, Nature, 431, 200, 10.1038/nature02866 Um, 2006, Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1, Cell Metab., 3, 393, 10.1016/j.cmet.2006.05.003 Hsu, 2011, The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling, Science, 332, 1317, 10.1126/science.1199498 Yu, 2011, Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling, Science, 332, 1322, 10.1126/science.1199484 Ye, 2011, Regulation of cholesterol and fatty acid synthesis, Cold Spring Harb. Perspect. Biol., 3, 10.1101/cshperspect.a004754 Duvel, 2010, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol. Cell, 39, 171, 10.1016/j.molcel.2010.06.022 Shao, 2012, Expanding roles for SREBP in metabolism, Cell Metab., 16, 414, 10.1016/j.cmet.2012.09.002 Peterson, 2011, mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway, Cell, 146, 408, 10.1016/j.cell.2011.06.034 Brown, 1997, The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, Cell, 89, 331, 10.1016/S0092-8674(00)80213-5 Shimano, 1997, Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene, J. Clin. Invest., 100, 2115, 10.1172/JCI119746 Liang, 2002, Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c, J. Biol. Chem., 277, 9520, 10.1074/jbc.M111421200 Shimano, 1996, Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a, J. Clin. Invest., 98, 1575, 10.1172/JCI118951 Shimano, 1997, Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells, J. Clin. Invest., 99, 846, 10.1172/JCI119248 Menendez, 2007, Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis, Nat. Rev. Cancer, 7, 763, 10.1038/nrc2222 Freed-Pastor, 2012, Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway, Cell, 148, 244, 10.1016/j.cell.2011.12.017 Bolender, 1973, A morphometric study of the removal of phenobarbital-induced membranes from hepatocytes after cessation of threatment, J. Cell Biol., 56, 746, 10.1083/jcb.56.3.746 Jewell, 2013, Amino acid signalling upstream of mTOR, Nat. Rev. Mol. Cell Biol., 14, 133, 10.1038/nrm3522 Yang, 2010, Eaten alive: a history of macroautophagy, Nat. Cell Biol., 12, 814, 10.1038/ncb0910-814 Koren, 2010, DAP1, a novel substrate of mTOR, negatively regulates autophagy, Curr. Biol., 20, 1093, 10.1016/j.cub.2010.04.041 Martina, 2012, MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB, Autophagy, 8, 903, 10.4161/auto.19653 Steingrimsson, 1998, The bHLH-Zip transcription factor Tfeb is essential for placental vascularization, Development, 125, 4607, 10.1242/dev.125.23.4607 Kundu, 2008, Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation, Blood, 112, 1493, 10.1182/blood-2008-02-137398 Qu, 2003, Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene, J. Clin. Invest., 112, 1809, 10.1172/JCI20039 Amaravadi, 2007, Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma, J. Clin. Invest., 117, 326, 10.1172/JCI28833 Horton, 2002, SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver, J. Clin. Invest., 109, 1125, 10.1172/JCI0215593 Ferron, 2013, A RANKL-PKCbeta-TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts, Genes Dev., 27, 955, 10.1101/gad.213827.113 Manning, 2007, AKT/PKB signaling: navigating downstream, Cell, 129, 1261, 10.1016/j.cell.2007.06.009 Hay, 2005, The Akt-mTOR tango and its relevance to cancer, Cancer Cell, 8, 179, 10.1016/j.ccr.2005.08.008 Toker, 2006, Akt signaling and cancer: surviving but not moving on, Cancer Res., 66, 3963, 10.1158/0008-5472.CAN-06-0743 Konishi, 1995, Molecular cloning and characterization of a new member of the RAC protein kinase family: association of the pleckstrin homology domain of three types of RAC protein kinase with protein kinase C subspecies and beta gamma subunits of G proteins, Biochem. Biophys. Res. Commun., 216, 526, 10.1006/bbrc.1995.2654 Fayard, 2005, Protein kinase B/Akt at a glance, J. Cell Sci., 118, 5675, 10.1242/jcs.02724 Toker, 2012, Achieving specificity in Akt signaling in cancer, Adv. Biol. Regul., 52, 78, 10.1016/j.advenzreg.2011.09.020 Alessi, 1997, Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha, Curr. Biol., 7, 261, 10.1016/S0960-9822(06)00122-9 Sarbassov, 2005, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex, Science, 307, 1098, 10.1126/science.1106148 Gonzalez, 2009, The Akt kinases: isoform specificity in metabolism and cancer, Cell Cycle, 8, 2502, 10.4161/cc.8.16.9335 Manning, 2002, 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, 10.1016/S1097-2765(02)00568-3 Liu, 2014, Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus, Nature, 508, 541, 10.1038/nature13079 Cho, 2001, Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice, J. Biol. Chem., 276, 38349, 10.1074/jbc.C100462200 Cho, 2001, Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta), Science, 292, 1728, 10.1126/science.292.5522.1728 Easton, 2005, Role for Akt3/protein kinase Bgamma in attainment of normal brain size, Mol. Cell. Biol., 25, 1869, 10.1128/MCB.25.5.1869-1878.2005 Chen, 2001, Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene, Genes Dev., 15, 2203, 10.1101/gad.913901 Garofalo, 2003, Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta, J. Clin. Invest., 112, 197, 10.1172/JCI16885 Tschopp, 2005, Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis, Development, 132, 2943, 10.1242/dev.01864 Yang, 2005, Dosage-dependent effects of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice, Mol. Cell. Biol., 25, 10407, 10.1128/MCB.25.23.10407-10418.2005 Peng, 2003, Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2, Genes Dev., 17, 1352, 10.1101/gad.1089403 Dummler, 2006, Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies, Mol. Cell. Biol., 26, 8042, 10.1128/MCB.00722-06 Carpten, 2007, A transforming mutation in the pleckstrin homology domain of AKT1 in cancer, Nature, 448, 439, 10.1038/nature05933 Campbell, 2004, Mutation of the PIK3CA gene in ovarian and breast cancer, Cancer Res., 64, 7678, 10.1158/0008-5472.CAN-04-2933 Samuels, 2004, High frequency of mutations of the PIK3CA gene in human cancers, Science, 304, 554, 10.1126/science.1096502 Lee, 2005, PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas, Oncogene, 24, 1477, 10.1038/sj.onc.1208304 Levine, 2005, Frequent mutation of the PIK3CA gene in ovarian and breast cancers, Clin. Cancer Res., 11, 2875, 10.1158/1078-0432.CCR-04-2142 Cantley, 1999, New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway, Proc. Natl. Acad. Sci. U. S. A., 96, 4240, 10.1073/pnas.96.8.4240 Banerji, 2012, Sequence analysis of mutations and translocations across breast cancer subtypes, Nature, 486, 405, 10.1038/nature11154 Maroulakou, 2007, Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice, Cancer Res., 67, 167, 10.1158/0008-5472.CAN-06-3782 Dillon, 2009, Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression, Cancer Res., 69, 5057, 10.1158/0008-5472.CAN-08-4287 Parker, 2004, PKC at a glance, J. Cell Sci., 117, 131, 10.1242/jcs.00982 Meier, 2009, Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice, Diabetologia, 52, 765, 10.1007/s00125-009-1278-y Chen, 2001, Opposing cardioprotective actions and parallel hypertrophic effects of delta PKC and epsilon PKC, Proc. Natl. Acad. Sci. U. S. A., 98, 11114, 10.1073/pnas.191369098 Menne, 2004, Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice, Diabetes, 53, 2101, 10.2337/diabetes.53.8.2101 Leitges, 1996, Immunodeficiency in protein kinase cbeta-deficient mice, Science, 273, 788, 10.1126/science.273.5276.788 Abeliovich, 1993, Modified hippocampal long-term potentiation in PKC gamma-mutant mice, Cell, 75, 1253, 10.1016/0092-8674(93)90613-U Abeliovich, 1993, PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning, Cell, 75, 1263, 10.1016/0092-8674(93)90614-V Mecklenbrauker, 2002, Protein kinase Cdelta controls self-antigen-induced B-cell tolerance, Nature, 416, 860, 10.1038/416860a Miyamoto, 2002, Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta, Nature, 416, 865, 10.1038/416865a Khasar, 1999, A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice, Neuron, 24, 253, 10.1016/S0896-6273(00)80837-5 Castrillo, 2001, Protein kinase Cepsilon is required for macrophage activation and defense against bacterial infection, J. Exp. Med., 194, 1231, 10.1084/jem.194.9.1231 Leitges, 2001, Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway, Mol. Cell, 8, 771, 10.1016/S1097-2765(01)00361-6 Martin, 2002, Role of zeta PKC in B-cell signaling and function, EMBO J., 21, 4049, 10.1093/emboj/cdf407 Sharif, 1999, Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell lines and primary tumor samples, Int. J. Oncol., 15, 237 Murray, 2004, Protein kinase Ciota is required for Ras transformation and colon carcinogenesis in vivo, J. Cell Biol., 164, 797, 10.1083/jcb.200311011 Stallings-Mann, 2006, A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells, Cancer Res., 66, 1767, 10.1158/0008-5472.CAN-05-3405 Nanjundan, 2007, Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer, Cancer Res., 67, 3074, 10.1158/0008-5472.CAN-06-2366 Liu, 2004, Protein kinase CbetaII regulates its own expression in rat intestinal epithelial cells and the colonic epithelium in vivo, J. Biol. Chem., 279, 45556, 10.1074/jbc.M407701200 Sledge, 2006, Protein kinase C-beta as a therapeutic target in breast cancer, Semin. Oncol., 33, S15, 10.1053/j.seminoncol.2006.03.019 Mochly-Rosen, 2012, Protein kinase C, an elusive therapeutic target?, Nat. Rev. Drug Discov., 11, 937, 10.1038/nrd3871 Iwamoto, 1992, Accelerated proliferation and interleukin-2 production of thymocytes by stimulation of soluble anti-CD3 monoclonal antibody in transgenic mice carrying a rabbit protein kinase C alpha, J. Biol. Chem., 267, 18644, 10.1016/S0021-9258(19)37009-7 Konopatskaya, 2010, Protein kinase Calpha: disease regulator and therapeutic target, Trends Pharmacol. Sci., 31, 8, 10.1016/j.tips.2009.10.006 Nasir, 2009, Relative resistance of SGK1 knockout mice against chemical carcinogenesis, IUBMB Life, 61, 768, 10.1002/iub.209 Kobayashi, 1999, Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase, Biochem. J., 344, 189, 10.1042/0264-6021:3440189 Lang, 2006, (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms, Physiol. Rev., 86, 1151, 10.1152/physrev.00050.2005 Wulff, 2002, Impaired renal Na(+) retention in the sgk1-knockout mouse, J. Clin. Invest., 110, 1263, 10.1172/JCI0215696 Grahammer, 2006, Renal function of gene-targeted mice lacking both SGK1 and SGK3, Am. J. Physiol. Regul. Integr. Comp. Physiol., 290, R945, 10.1152/ajpregu.00484.2005 Wang, 2010, SGK1-dependent intestinal tumor growth in APC-deficient mice, Cell. Physiol. Biochem., 25, 271, 10.1159/000276561 Towhid, 2013, Inhibition of colonic tumor growth by the selective SGK inhibitor EMD638683, Cell. Physiol. Biochem., 32, 838, 10.1159/000354486 Bruhn, 2010, Second AKT: the rise of SGK in cancer signalling, Growth Factors, 28, 394, 10.3109/08977194.2010.518616 Vasudevan, 2009, AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer, Cancer Cell, 16, 21, 10.1016/j.ccr.2009.04.012 Szmulewitz, 2012, Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers, Prostate, 72, 157, 10.1002/pros.21416 Abbruzzese, 2012, Determination of SGK1 mRNA in non-small cell lung cancer samples underlines high expression in squamous cell carcinomas, J. Exp. Clin. Cancer Res., 31, 4, 10.1186/1756-9966-31-4 Chu, 2002, FSH-regulated gene expression profiles in ovarian tumours and normal ovaries, Mol. Hum. Reprod., 8, 426, 10.1093/molehr/8.5.426 Chung, 2002, Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray, Mol. Cells, 14, 382 Hutchinson, 2004, Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion, Cancer Res., 64, 3171, 10.1158/0008-5472.CAN-03-3465 Kim, 2004, PKC-theta knockout mice are protected from fat-induced insulin resistance, J. Clin. Invest., 114, 823, 10.1172/JCI200422230 Sun, 2000, PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes, Nature, 404, 402, 10.1038/35006090 Yang, 2007, Expanding mTOR signaling, Cell Res., 17, 666, 10.1038/cr.2007.64 Klempner, 2013, What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway, Cancer Discov., 3, 1345, 10.1158/2159-8290.CD-13-0063 Shaw, 2006, Ras, PI(3)K and mTOR signalling controls tumour cell growth, Nature, 441, 424, 10.1038/nature04869 Cantley, 2002, The phosphoinositide 3-kinase pathway, Science, 296, 1655, 10.1126/science.296.5573.1655 Yuan, 2008, PI3K pathway alterations in cancer: variations on a theme, Oncogene, 27, 5497, 10.1038/onc.2008.245 Song, 2012, The functions and regulation of the PTEN tumour suppressor, Nat. Rev. Mol. Cell Biol., 13, 283, 10.1038/nrm3330 Long, 2005, Rheb binds and regulates the mTOR kinase, Curr. Biol., 15, 702, 10.1016/j.cub.2005.02.053 Sun, 2008, Phospholipase D1 is an effector of Rheb in the mTOR pathway, Proc. Natl. Acad. Sci. U. S. A., 105, 8286, 10.1073/pnas.0712268105 Toschi, 2009, Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin, Mol. Cell. Biol., 29, 1411, 10.1128/MCB.00782-08 Shaw, 2004, The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress, Proc. Natl. Acad. Sci. U. S. A., 101, 3329, 10.1073/pnas.0308061100 Hasumi, 2009, Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2, Proc. Natl. Acad. Sci. U. S. A., 106, 18722, 10.1073/pnas.0908853106 Dennis, 2014, REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling, Sci. Signal., 7, ra68, 10.1126/scisignal.2005103 Luo, 2003, Targeting the PI3K-Akt pathway in human cancer: rationale and promise, Cancer Cell, 4, 257, 10.1016/S1535-6108(03)00248-4 Harrison, 2009, Rapamycin fed late in life extends lifespan in genetically heterogeneous mice, Nature, 460, 392, 10.1038/nature08221 Neff, 2013, Rapamycin extends murine lifespan but has limited effects on aging, J. Clin. Invest., 123, 3272, 10.1172/JCI67674 Phung, 2006, Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin, Cancer Cell, 10, 159, 10.1016/j.ccr.2006.07.003 Sarbassov, 2006, Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB, Mol. Cell, 22, 159, 10.1016/j.molcel.2006.03.029 Motzer, 2008, Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial, Lancet, 372, 449, 10.1016/S0140-6736(08)61039-9 Blagosklonny, 2013, TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists, Cell Death Dis., 4, e964, 10.1038/cddis.2013.506 Ingels, 2014, Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts, Int. J. Cancer, 134, 2322, 10.1002/ijc.28579 Chresta, 2010, 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, 10.1158/0008-5472.CAN-09-1751 Pike, 2013, Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014, Bioorg. Med. Chem. Lett., 23, 1212, 10.1016/j.bmcl.2013.01.019 Zaytseva, 2012, mTOR inhibitors in cancer therapy, Cancer Lett., 319, 1, 10.1016/j.canlet.2012.01.005 Heckl, 2014, Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing, Nat. Biotechnol., 32, 941, 10.1038/nbt.2951 Kwong, 2012, Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma, Nat. Med., 18, 1503, 10.1038/nm.2941