Signaling crosstalk between the mTOR complexes

References

• Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003; 11:895 - 904; http://dx.doi.org/10.1016/S1097-2765(03)00114-X; PMID: 12718876
   PubMed Web of Science ®Google Scholar
• Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009; 137:873 - 86; http://dx.doi.org/10.1016/j.cell.2009.03.046; PMID: 19446321
   PubMed Web of Science ®Google Scholar
• Takai H, Wang RC, Takai KK, Yang H, de Lange T. Tel2 regulates the stability of PI3K-related protein kinases. Cell 2007; 131:1248 - 59; http://dx.doi.org/10.1016/j.cell.2007.10.052; PMID: 18160036
   PubMed Web of Science ®Google Scholar
• Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T, Mizushima N. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 2010; 285:20109 - 16; http://dx.doi.org/10.1074/jbc.M110.121699; PMID: 20427287
   PubMed Web of Science ®Google Scholar
• Ramírez-Rangel I, Bracho-Valdés I, Vázquez-Macías A, Carretero-Ortega J, Reyes-Cruz G, Vázquez-Prado J. Regulation of mTORC1 complex assembly and signaling by GRp58/ERp57. Mol Cell Biol 2011; 31:1657 - 71; http://dx.doi.org/10.1128/MCB.00824-10; PMID: 21321085
   PubMed Web of Science ®Google Scholar
• Saci A, Cantley LC, Carpenter CL. Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol Cell 2011; 42:50 - 61; http://dx.doi.org/10.1016/j.molcel.2011.03.017; PMID: 21474067
   PubMed Web of Science ®Google Scholar
• Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163 - 75; http://dx.doi.org/10.1016/S0092-8674(02)00808-5; PMID: 12150925
   PubMed Web of Science ®Google Scholar
• Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177 - 89; http://dx.doi.org/10.1016/S0092-8674(02)00833-4; PMID: 12150926
   PubMed Web of Science ®Google Scholar
• Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007; 25:903 - 15; http://dx.doi.org/10.1016/j.molcel.2007.03.003; PMID: 17386266
   PubMed Web of Science ®Google Scholar
• Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007; 9:316 - 23; http://dx.doi.org/10.1038/ncb1547; PMID: 17277771
   PubMed Web of Science ®Google Scholar
• Wang L, Harris TE, Roth RA, Lawrence JC Jr.. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 2007; 282:20036 - 44; http://dx.doi.org/10.1074/jbc.M702376200; PMID: 17510057
   PubMed Web of Science ®Google Scholar
• Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jenö P, Arrieumerlou C, Hall MN. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2007; 2:e1217; http://dx.doi.org/10.1371/journal.pone.0001217; PMID: 18030348
   PubMed Web of Science ®Google Scholar
• Fonseca BD, Smith EM, Lee VH, MacKintosh C, Proud CG. PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J Biol Chem 2007; 282:24514 - 24; http://dx.doi.org/10.1074/jbc.M704406200; PMID: 17604271
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14:1296 - 302; http://dx.doi.org/10.1016/j.cub.2004.06.054; PMID: 15268862
   PubMed Web of Science ®Google Scholar
• Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006; 127:125 - 37; http://dx.doi.org/10.1016/j.cell.2006.08.033; PMID: 16962653
   PubMed Web of Science ®Google Scholar
• Yang Q, Inoki K, Ikenoue T, Guan KL. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 2006; 20:2820 - 32; http://dx.doi.org/10.1101/gad.1461206; PMID: 17043309
   PubMed Web of Science ®Google Scholar
• Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006; 16:1865 - 70; http://dx.doi.org/10.1016/j.cub.2006.08.001; PMID: 16919458
   PubMed Web of Science ®Google Scholar
• Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 2007; 405:513 - 22; http://dx.doi.org/10.1042/BJ20070540; PMID: 17461779
   PubMed Web of Science ®Google Scholar
• Khanna N, Fang Y, Yoon MS, Chen J. XPLN is an endogenous inhibitor of mTORC2. Proc Natl Acad Sci U S A 2013; 110:15979 - 84; http://dx.doi.org/10.1073/pnas.1310434110; PMID: 24043828
   PubMed Web of Science ®Google Scholar
• Wang JQ, Chen JH, Chen YC, Chen MY, Hsieh CY, Teng SC, Wu KJ. Interaction between NBS1 and the mTOR/Rictor/SIN1 complex through specific domains. PLoS One 2013; 8:e65586; http://dx.doi.org/10.1371/journal.pone.0065586; PMID: 23762398
   PubMedGoogle Scholar
• Xu Y, Lai E, Liu J, Lin J, Yang C, Jia C, Li Y, Bai X, Li M. IKK interacts with rictor and regulates mTORC2. Cell Signal 2013; 25:2239 - 45; http://dx.doi.org/10.1016/j.cellsig.2013.07.008; PMID: 23872070
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22:159 - 68; http://dx.doi.org/10.1016/j.molcel.2006.03.029; PMID: 16603397
   PubMed Web of Science ®Google Scholar
• Zeng Z, Sarbassov D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 2007; 109:3509 - 12; http://dx.doi.org/10.1182/blood-2006-06-030833; PMID: 17179228
   PubMed Web of Science ®Google Scholar
• Barlow AD, Xie J, Moore CE, Campbell SC, Shaw JA, Nicholson ML, Herbert TP. Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2). Diabetologia 2012; 55:1355 - 65; http://dx.doi.org/10.1007/s00125-012-2475-7; PMID: 22314813
   PubMed Web of Science ®Google Scholar
• Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem 2005; 280:18717 - 27; http://dx.doi.org/10.1074/jbc.M414499200; PMID: 15772076
   PubMed Web of Science ®Google Scholar
• Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, Vazquez F, Carpenter CL, Kwiatkowski DJ. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest 2003; 112:1223 - 33; http://dx.doi.org/10.1172/JCI200317222; PMID: 14561707
   PubMed Web of Science ®Google Scholar
• Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 2003; 5:566 - 71; http://dx.doi.org/10.1038/ncb996; PMID: 12766776
   PubMed Web of Science ®Google Scholar
• Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003; 11:1457 - 66; http://dx.doi.org/10.1016/S1097-2765(03)00220-X; PMID: 12820960
   PubMed Web of Science ®Google Scholar
• Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002; 4:658 - 65; http://dx.doi.org/10.1038/ncb840; PMID: 12172554
   PubMed Web of Science ®Google Scholar
• Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10:151 - 62; http://dx.doi.org/10.1016/S1097-2765(02)00568-3; PMID: 12150915
   PubMed Web of Science ®Google Scholar
• Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 2002; 277:35364 - 70; http://dx.doi.org/10.1074/jbc.M205838200; PMID: 12167664
   PubMed Web of Science ®Google Scholar
• Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4:648 - 57; http://dx.doi.org/10.1038/ncb839; PMID: 12172553
   PubMed Web of Science ®Google Scholar
• Irvine RF, Letcher AJ, Heslop JP, Berridge MJ. The inositol tris/tetrakisphosphate pathway--demonstration of Ins(1,4,5)P3 3-kinase activity in animal tissues. Nature 1986; 320:631 - 4; http://dx.doi.org/10.1038/320631a0; PMID: 3010126
   PubMed Web of Science ®Google Scholar
• Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7:261 - 9; http://dx.doi.org/10.1016/S0960-9822(06)00122-9; PMID: 9094314
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307:1098 - 101; http://dx.doi.org/10.1126/science.1106148; PMID: 15718470
   PubMed Web of Science ®Google Scholar
• Subramaniam S, Napolitano F, Mealer RG, Kim S, Errico F, Barrow R, Shahani N, Tyagi R, Snyder SH, Usiello A. Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia. Nat Neurosci 2012; 15:191 - 3; http://dx.doi.org/10.1038/nn.2994; PMID: 22179112
   PubMed Web of Science ®Google Scholar
• Li H, Tsang CK, Watkins M, Bertram PG, Zheng XF. Nutrient regulates Tor1 nuclear localization and association with rDNA promoter. Nature 2006; 442:1058 - 61; http://dx.doi.org/10.1038/nature05020; PMID: 16900101
   PubMed Web of Science ®Google Scholar
• Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 2006; 25:6384 - 91; http://dx.doi.org/10.1038/sj.onc.1209883; PMID: 17041624
   PubMed Web of Science ®Google Scholar
• Kantidakis T, Ramsbottom BA, Birch JL, Dowding SN, White RJ. mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci U S A 2010; 107:11823 - 8; http://dx.doi.org/10.1073/pnas.1005188107; PMID: 20543138
   PubMed Web of Science ®Google Scholar
• Shor B, Wu J, Shakey Q, Toral-Barza L, Shi C, Follettie M, Yu K. Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells. J Biol Chem 2010; 285:15380 - 92; http://dx.doi.org/10.1074/jbc.M109.071639; PMID: 20233713
   PubMed Web of Science ®Google Scholar
• Tsang CK, Liu H, Zheng XF. mTOR binds to the promoters of RNA polymerase I- and III-transcribed genes. Cell Cycle 2010; 9:953 - 7; http://dx.doi.org/10.4161/cc.9.5.10876; PMID: 20038818
   PubMed Web of Science ®Google Scholar
• Iadevaia V, Zhang Z, Jan E, Proud CG. mTOR signaling regulates the processing of pre-rRNA in human cells. Nucleic Acids Res 2012; 40:2527 - 39; http://dx.doi.org/10.1093/nar/gkr1040; PMID: 22121221
   PubMed Web of Science ®Google Scholar
• Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 2012; 485:109 - 13; http://dx.doi.org/10.1038/nature11083; PMID: 22552098
   PubMed Web of Science ®Google Scholar
• Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012; 485:55 - 61; http://dx.doi.org/10.1038/nature10912; PMID: 22367541
   PubMed Web of Science ®Google Scholar
• Huo Y, Iadevaia V, Yao Z, Kelly I, Cosulich S, Guichard S, Foster LJ, Proud CG. Stable isotope-labelling analysis of the impact of inhibition of the mammalian target of rapamycin on protein synthesis. Biochem J 2012; 444:141 - 51; http://dx.doi.org/10.1042/BJ20112107; PMID: 22428559
   PubMed Web of Science ®Google Scholar
• Dowling RJ, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, Wang X, Larsson O, Selvaraj A, Liu Y, et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 2010; 328:1172 - 6; http://dx.doi.org/10.1126/science.1187532; PMID: 20508131
   PubMed Web of Science ®Google Scholar
• Larsson O, Morita M, Topisirovic I, Alain T, Blouin MJ, Pollak M, Sonenberg N. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc Natl Acad Sci U S A 2012; 109:8977 - 82; http://dx.doi.org/10.1073/pnas.1201689109; PMID: 22611195
   PubMed Web of Science ®Google Scholar
• Stumpf CR, Moreno MV, Olshen AB, Taylor BS, Ruggero D. The translational landscape of the mammalian cell cycle. Mol Cell 2013; 52:574 - 82; http://dx.doi.org/10.1016/j.molcel.2013.09.018; PMID: 24120665
   PubMed Web of Science ®Google Scholar
• Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 2009; 136:731 - 45; http://dx.doi.org/10.1016/j.cell.2009.01.042; PMID: 19239892
   PubMed Web of Science ®Google Scholar
• Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 2010; 11:113 - 27; http://dx.doi.org/10.1038/nrm2838; PMID: 20094052
   PubMed Web of Science ®Google Scholar
• Brunn GJ, Hudson CC, Sekulić A, Williams JM, Hosoi H, Houghton PJ, Lawrence JC Jr., Abraham RT. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997; 277:99 - 101; http://dx.doi.org/10.1126/science.277.5322.99; PMID: 9204908
   PubMed Web of Science ®Google Scholar
• Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 1999; 13:1422 - 37; http://dx.doi.org/10.1101/gad.13.11.1422; PMID: 10364159
   PubMed Web of Science ®Google Scholar
• Yang D, Brunn GJ, Lawrence JC Jr.. Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR. FEBS Lett 1999; 453:387 - 90; http://dx.doi.org/10.1016/S0014-5793(99)00762-0; PMID: 10405182
   PubMed Web of Science ®Google Scholar
• Mothe-Satney I, Brunn GJ, McMahon LP, Capaldo CT, Abraham RT, Lawrence JC Jr.. Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies. J Biol Chem 2000; 275:33836 - 43; http://dx.doi.org/10.1074/jbc.M006005200; PMID: 10942774
   PubMed Web of Science ®Google Scholar
• Mothe-Satney I, Yang D, Fadden P, Haystead TA, Lawrence JC Jr.. Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression. Mol Cell Biol 2000; 20:3558 - 67; http://dx.doi.org/10.1128/MCB.20.10.3558-3567.2000; PMID: 10779345
   PubMed Web of Science ®Google Scholar
• Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD, Wyslouch-Cieszynska A, Aebersold R, Sonenberg N. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 2001; 15:2852 - 64; PMID: 11691836
   PubMed Web of Science ®Google Scholar
• Chung J, Kuo CJ, Crabtree GR, Blenis J. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 1992; 69:1227 - 36; http://dx.doi.org/10.1016/0092-8674(92)90643-Q; PMID: 1377606
   PubMed Web of Science ®Google Scholar
• Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J 2004; 23:1761 - 9; http://dx.doi.org/10.1038/sj.emboj.7600193; PMID: 15071500
   PubMed Web of Science ®Google Scholar
• Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 2006; 314:467 - 71; http://dx.doi.org/10.1126/science.1130276; PMID: 17053147
   PubMed Web of Science ®Google Scholar
• Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005; 123:569 - 80; http://dx.doi.org/10.1016/j.cell.2005.10.024; PMID: 16286006
   PubMed Web of Science ®Google Scholar
• Harris TE, Chi A, Shabanowitz J, Hunt DF, Rhoads RE, Lawrence JC Jr.. mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin. EMBO J 2006; 25:1659 - 68; http://dx.doi.org/10.1038/sj.emboj.7601047; PMID: 16541103
   PubMed Web of Science ®Google Scholar
• Nairn AC, Bhagat B, Palfrey HC. Identification of calmodulin-dependent protein kinase III and its major Mr 100,000 substrate in mammalian tissues. Proc Natl Acad Sci U S A 1985; 82:7939 - 43; http://dx.doi.org/10.1073/pnas.82.23.7939; PMID: 3906654
   PubMed Web of Science ®Google Scholar
• Knebel A, Morrice N, Cohen P. A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. EMBO J 2001; 20:4360 - 9; http://dx.doi.org/10.1093/emboj/20.16.4360; PMID: 11500363
   PubMed Web of Science ®Google Scholar
• Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 2001; 20:4370 - 9; http://dx.doi.org/10.1093/emboj/20.16.4370; PMID: 11500364
   PubMed Web of Science ®Google Scholar
• Browne GJ, Proud CG. A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 2004; 24:2986 - 97; http://dx.doi.org/10.1128/MCB.24.7.2986-2997.2004; PMID: 15024086
   PubMed Web of Science ®Google Scholar
• Gan X, Wang J, Su B, Wu D. Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 2011; 286:10998 - 1002; http://dx.doi.org/10.1074/jbc.M110.195016; PMID: 21310961
   PubMed Web of Science ®Google Scholar
• Tato I, Bartrons R, Ventura F, Rosa JL. Amino acids activate mammalian target of rapamycin complex 2 (mTORC2) via PI3K/Akt signaling. J Biol Chem 2011; 286:6128 - 42; http://dx.doi.org/10.1074/jbc.M110.166991; PMID: 21131356
   PubMed Web of Science ®Google Scholar
• Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell 2011; 144:757 - 68; http://dx.doi.org/10.1016/j.cell.2011.02.014; PMID: 21376236
   PubMed Web of Science ®Google Scholar
• García-Martínez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008; 416:375 - 85; http://dx.doi.org/10.1042/BJ20081668; PMID: 18925875
   PubMed Web of Science ®Google Scholar
• Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J 2008; 27:1919 - 31; http://dx.doi.org/10.1038/emboj.2008.119; PMID: 18566587
   PubMed Web of Science ®Google Scholar
• Facchinetti V, Ouyang W, Wei H, Soto N, Lazorchak A, Gould C, Lowry C, Newton AC, Mao Y, Miao RQ, et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 2008; 27:1932 - 43; http://dx.doi.org/10.1038/emboj.2008.120; PMID: 18566586
   PubMed Web of Science ®Google Scholar
• Oh WJ, Wu CC, Kim SJ, Facchinetti V, Julien LA, Finlan M, Roux PP, Su B, Jacinto E. mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J 2010; 29:3939 - 51; http://dx.doi.org/10.1038/emboj.2010.271; PMID: 21045808
   PubMed Web of Science ®Google Scholar
• Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6:1122 - 8; http://dx.doi.org/10.1038/ncb1183; PMID: 15467718
   PubMed Web of Science ®Google Scholar
• Gulati N, Karsy M, Albert L, Murali R, Jhanwar-Uniyal M. Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility. Int J Oncol 2009; 35:731 - 40; PMID: 19724909
   PubMed Web of Science ®Google Scholar
• Liu L, Das S, Losert W, Parent CA. mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev Cell 2010; 19:845 - 57; http://dx.doi.org/10.1016/j.devcel.2010.11.004; PMID: 21145500
   PubMed Web of Science ®Google Scholar
• Rosner M, Fuchs C, Siegel N, Valli A, Hengstschläger M. Functional interaction of mammalian target of rapamycin complexes in regulating mammalian cell size and cell cycle. Hum Mol Genet 2009; 18:3298 - 310; http://dx.doi.org/10.1093/hmg/ddp271; PMID: 19505958
   PubMed Web of Science ®Google Scholar
• Wang T, Blumhagen R, Lao U, Kuo Y, Edgar BA. LST8 regulates cell growth via target-of-rapamycin complex 2 (TORC2). Mol Cell Biol 2012; 32:2203 - 13; http://dx.doi.org/10.1128/MCB.06474-11; PMID: 22493059
   PubMed Web of Science ®Google Scholar
• Stumpf CR, Moreno MV, Olshen AB, Taylor BS, Ruggero D. The translational landscape of the mammalian cell cycle. Mol Cell 2013; 52:574 - 82; http://dx.doi.org/10.1016/j.molcel.2013.09.018; PMID: 24120665
   PubMed Web of Science ®Google Scholar
• Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 2006; 11:583 - 9; http://dx.doi.org/10.1016/j.devcel.2006.08.013; PMID: 16962829
   PubMed Web of Science ®Google Scholar
• Matheny RW Jr., Lynch CM, Leandry LA. Enhanced Akt phosphorylation and myogenic differentiation in PI3K p110β-deficient myoblasts is mediated by PI3K p110α and mTORC2. Growth Factors 2012; 30:367 - 84; http://dx.doi.org/10.3109/08977194.2012.734507; PMID: 23137199
   PubMed Web of Science ®Google Scholar
• Esen E, Chen J, Karner CM, Okunade AL, Patterson BW, Long F. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab 2013; 17:745 - 55; http://dx.doi.org/10.1016/j.cmet.2013.03.017; PMID: 23623748
   PubMed Web of Science ®Google Scholar
• Yao Y, Suraokar M, Darnay BG, Hollier BG, Shaiken TE, Asano T, Chen CH, Chang BH, Lu Y, Mills GB, et al. BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation. Sci Signal 2013; 6:ra2; http://dx.doi.org/10.1126/scisignal.2003295; PMID: 23300339
   PubMed Web of Science ®Google Scholar
• Case N, Thomas J, Sen B, Styner M, Xie Z, Galior K, Rubin J. Mechanical regulation of glycogen synthase kinase 3β (GSK3β) in mesenchymal stem cells is dependent on Akt protein serine 473 phosphorylation via mTORC2 protein. J Biol Chem 2011; 286:39450 - 6; http://dx.doi.org/10.1074/jbc.M111.265330; PMID: 21956113
   PubMed Web of Science ®Google Scholar
• Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. 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 2006; 11:859 - 71; http://dx.doi.org/10.1016/j.devcel.2006.10.007; PMID: 17141160
   PubMed Web of Science ®Google Scholar
• Wang X, Paulin FE, Campbell LE, Gomez E, O’Brien K, Morrice N, Proud CG. Eukaryotic initiation factor 2B: identification of multiple phosphorylation sites in the epsilon-subunit and their functions in vivo. EMBO J 2001; 20:4349 - 59; http://dx.doi.org/10.1093/emboj/20.16.4349; PMID: 11500362
   PubMed Web of Science ®Google Scholar
• Gao D, Inuzuka H, Tan MK, Fukushima H, Locasale JW, Liu P, Wan L, Zhai B, Chin YR, Shaik S, et al. mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR. Mol Cell 2011; 44:290 - 303; http://dx.doi.org/10.1016/j.molcel.2011.08.030; PMID: 22017875
   PubMed Web of Science ®Google Scholar
• Huang J, Dibble CC, Matsuzaki M, Manning BD. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 2008; 28:4104 - 15; http://dx.doi.org/10.1128/MCB.00289-08; PMID: 18411301
   PubMed Web of Science ®Google Scholar
• Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 2012; 47:535 - 46; http://dx.doi.org/10.1016/j.molcel.2012.06.009; PMID: 22795129
   PubMed Web of Science ®Google Scholar
• Goncharova EA, Goncharov DA, Li H, Pimtong W, Lu S, Khavin I, Krymskaya VP. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol 2011; 31:2484 - 98; http://dx.doi.org/10.1128/MCB.01061-10; PMID: 21482669
   PubMed Web of Science ®Google Scholar
• Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, Park Y, Hay N. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell 2010; 18:592 - 604; http://dx.doi.org/10.1016/j.devcel.2010.03.008; PMID: 20412774
   PubMed Web of Science ®Google Scholar
• Peeters H, Debeer P, Bairoch A, Wilquet V, Huysmans C, Parthoens E, Fryns JP, Gewillig M, Nakamura Y, Niikawa N, et al. PA26 is a candidate gene for heterotaxia in humans: identification of a novel PA26-related gene family in human and mouse. Hum Genet 2003; 112:573 - 80; PMID: 12607115
   PubMed Web of Science ®Google Scholar
• Tanti JF, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol 2009; 9:753 - 62; http://dx.doi.org/10.1016/j.coph.2009.07.004; PMID: 19683471
   PubMed Web of Science ®Google Scholar
• Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431:200 - 5; http://dx.doi.org/10.1038/nature02866; PMID: 15306821
   PubMed Web of Science ®Google Scholar
• Kim SJ, DeStefano MA, Oh WJ, Wu CC, Vega-Cotto NM, Finlan M, Liu D, Su B, Jacinto E. mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8. Mol Cell 2012; 48:875 - 87; http://dx.doi.org/10.1016/j.molcel.2012.09.029; PMID: 23142081
   PubMed Web of Science ®Google Scholar
• Sarikas A, Xu X, Field LJ, Pan ZQ. The cullin7 E3 ubiquitin ligase: a novel player in growth control. Cell Cycle 2008; 7:3154 - 61; http://dx.doi.org/10.4161/cc.7.20.6922; PMID: 18927510
   PubMed Web of Science ®Google Scholar
• Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 2011; 332:1317 - 22; http://dx.doi.org/10.1126/science.1199498; PMID: 21659604
   PubMed Web of Science ®Google Scholar
• Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM, Villén J, Kubica N, Hoffman GR, Cantley LC, Gygi SP, et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 2011; 332:1322 - 6; http://dx.doi.org/10.1126/science.1199484; PMID: 21659605
   PubMed Web of Science ®Google Scholar
• Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012; 335:1638 - 43; http://dx.doi.org/10.1126/science.1215135; PMID: 22461615
   PubMed Web of Science ®Google Scholar
• Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 2009; 29:5657 - 70; http://dx.doi.org/10.1128/MCB.00735-09; PMID: 19720745
   PubMed Web of Science ®Google Scholar
• Boulbes D, Chen CH, Shaikenov T, Agarwal NK, Peterson TR, Addona TA, Keshishian H, Carr SA, Magnuson MA, Sabatini DM, et al. Rictor phosphorylation on the Thr-1135 site does not require mammalian target of rapamycin complex 2. Mol Cancer Res 2010; 8:896 - 906; http://dx.doi.org/10.1158/1541-7786.MCR-09-0409; PMID: 20501647
   PubMed Web of Science ®Google Scholar
• Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 2010; 30:908 - 21; http://dx.doi.org/10.1128/MCB.00601-09; PMID: 19995915
   PubMed Web of Science ®Google Scholar
• Treins C, Warne PH, Magnuson MA, Pende M, Downward J. Rictor is a novel target of p70 S6 kinase-1. Oncogene 2010; 29:1003 - 16; http://dx.doi.org/10.1038/onc.2009.401; PMID: 19935711
   PubMed Web of Science ®Google Scholar
• Gao D, Wan L, Inuzuka H, Berg AH, Tseng A, Zhai B, Shaik S, Bennett E, Tron AE, Gasser JA, et al. Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction. Mol Cell 2010; 39:797 - 808; http://dx.doi.org/10.1016/j.molcel.2010.08.016; PMID: 20832730
   PubMed Web of Science ®Google Scholar
• Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, Liu D, Wan L, Zhai B, Yu Y, et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol 2013; 15:1340 - 50; http://dx.doi.org/10.1038/ncb2860; PMID: 24161930
   PubMed Web of Science ®Google Scholar
• Humphrey SJ, Yang G, Yang P, Fazakerley DJ, Stöckli J, Yang JY, James DE. Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab 2013; 17:1009 - 20; http://dx.doi.org/10.1016/j.cmet.2013.04.010; PMID: 23684622
   PubMed Web of Science ®Google Scholar
• Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474:609 - 15; http://dx.doi.org/10.1038/nature10166; PMID: 21720365
   PubMed Web of Science ®Google Scholar
• Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov 2011; 1:248 - 59; http://dx.doi.org/10.1158/2159-8290.CD-11-0085; PMID: 22140653
   PubMed Web of Science ®Google Scholar
• Chaturvedi D, Gao X, Cohen MS, Taunton J, Patel TB. Rapamycin induces transactivation of the EGFR and increases cell survival. Oncogene 2009; 28:1187 - 96; http://dx.doi.org/10.1038/onc.2008.490; PMID: 19151764
   PubMed Web of Science ®Google Scholar
• Zhuang G, Yu K, Jiang Z, Chung A, Yao J, Ha C, Toy K, Soriano R, Haley B, Blackwood E, et al. Phosphoproteomic analysis implicates the mTORC2-FoxO1 axis in VEGF signaling and feedback activation of receptor tyrosine kinases. Sci Signal 2013; 6:ra25; http://dx.doi.org/10.1126/scisignal.2003572; PMID: 23592840
   PubMed Web of Science ®Google Scholar
• Dai N, Rapley J, Angel M, Yanik MF, Blower MD, Avruch J. mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. Genes Dev 2011; 25:1159 - 72; http://dx.doi.org/10.1101/gad.2042311; PMID: 21576258
   PubMed Web of Science ®Google Scholar
• Dai N, Christiansen J, Nielsen FC, Avruch J. mTOR complex 2 phosphorylates IMP1 cotranslationally to promote IGF2 production and the proliferation of mouse embryonic fibroblasts. Genes Dev 2013; 27:301 - 12; http://dx.doi.org/10.1101/gad.209130.112; PMID: 23388827
   PubMed Web of Science ®Google Scholar
• Zanchin NI, Roberts P, DeSilva A, Sherman F, Goldfarb DS. Saccharomyces cerevisiae Nip7p is required for efficient 60S ribosome subunit biogenesis. Mol Cell Biol 1997; 17:5001 - 15; PMID: 9271378
   PubMed Web of Science ®Google Scholar
• Chen CH, Kiyan V, Zhylkibayev AA, Kazyken D, Bulgakova O, Page KE, Bersimbaev RI, Spooner E, Sarbassov D. Autoregulation of the mechanistic target of rapamycin (mTOR) complex 2 integrity is controlled by an ATP-dependent mechanism. J Biol Chem 2013; 288:27019 - 30; http://dx.doi.org/10.1074/jbc.M113.498055; PMID: 23928304
   PubMed Web of Science ®Google Scholar
• Jewell JL, Guan KL. Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 2013; 38:233 - 42; http://dx.doi.org/10.1016/j.tibs.2013.01.004; PMID: 23465396
   PubMed Web of Science ®Google Scholar
• Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, et al. A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal 2012; 5:ra25; PMID: 22457331
   PubMed Web of Science ®Google Scholar
• Soliman GA, Acosta-Jaquez HA, Dunlop EA, Ekim B, Maj NE, Tee AR, Fingar DC. mTOR Ser-2481 autophosphorylation monitors mTORC-specific catalytic activity and clarifies rapamycin mechanism of action. J Biol Chem 2010; 285:7866 - 79; http://dx.doi.org/10.1074/jbc.M109.096222; PMID: 20022946
   PubMed Web of Science ®Google Scholar
• Manning BD. Comment on “A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation”: building a model of the mTOR signaling network with a potentially faulty tool. Sci Signal 2012; 5:lc3; author reply lc4.
   Google Scholar
• Völkers M, Konstandin MH, Doroudgar S, Toko H, Quijada P, Din S, Joyo A, Ornelas L, Samse K, Thuerauf DJ, et al. Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage. Circulation 2013; 128:2132 - 44; http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003638; PMID: 24008870
   PubMed Web of Science ®Google Scholar
• Völkers M, Toko H, Doroudgar S, Din S, Quijada P, Joyo AY, Ornelas L, Joyo E, Thuerauf DJ, Konstandin MH, et al. Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1. Proc Natl Acad Sci U S A 2013; 110:12661 - 6; http://dx.doi.org/10.1073/pnas.1301455110; PMID: 23842089
   PubMed Web of Science ®Google Scholar
• Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009; 37:217 - 22; http://dx.doi.org/10.1042/BST0370217; PMID: 19143635
   PubMed Web of Science ®Google Scholar