New insights into mTOR signaling: mTORC2 and beyond

Science Signaling

Volumn 2, Issue 67, 2009, Pages

  Alessi, Dario R ^a   Pearce, Laura R ^a   García Martínez, Juan M ^a  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

INITIATION FACTOR 4E BINDING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PHOSPHATASE; PROLINE; PROTEIN KINASE B; PROTEIN KINASE C; PROTEIN SERINE THREONINE KINASE; SERINE; SERUM AND GLUCOCORTICOID REGULATED KINASE 1; THREONINE; CRTC2 PROTEIN, HUMAN; IMMEDIATE EARLY PROTEIN; PROTEIN KINASE; SERUM GLUCOCORTICOID REGULATED KINASE; SERUM-GLUCOCORTICOID REGULATED KINASE; TRANSCRIPTION FACTOR;

CAENORHABDITIS ELEGANS; CANCER CELL; CELL GROWTH; CELL PROLIFERATION; CELL SURVIVAL; COMPLEX FORMATION; ENZYME ACTIVATION; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME SPECIFICITY; FIBROBLAST; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN CONFORMATION; PROTEIN MOTIF; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; AMINO ACID SEQUENCE; ANIMAL; ARTICLE; BIOLOGICAL MODEL; HUMAN; METABOLISM; PHOSPHORYLATION;

MAMMALIA;

AMINO ACID SEQUENCE; ANIMALS; CELL PROLIFERATION; HUMANS; IMMEDIATE-EARLY PROTEINS; MODELS, BIOLOGICAL; PHOSPHORYLATION; PROTEIN KINASES; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS C-AKT; SERINE; SIGNAL TRANSDUCTION; THREONINE; TRANSCRIPTION FACTORS;

EID: 70349239101     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.267pe27     Document Type: Review

References (49)

1. N. Hay, N. Sonenberg, Upstream and downstream of mTOR. Genes Dev. 18, 1926-1945 (2004). (Pubitemid 39071573)
2. Y. Sancak, C. C. Thoreen, T. R. Peterson, R. A. Lindquist, S. A. Kang, E. Spooner, S. A. Carr, D. M. Sabatini, PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903-915 (2007). (Pubitemid 46436534)
3. P. Nicklin, P. Bergman, B. Zhang, E. Triantafellow, H. Wang, B. Nyfeler, H. Yang, M. Hild, C. Kung, C. Wilson, V. E. Myer, J. P. MacKeigan, J. A. Porter, Y. K. Wang, L. C. Cantley, P. M. Finan, L. O. Murphy, Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521-534 (2009).
4. Y. Sancak, T. R. Peterson, Y. D. Shaul, R. A. Lindquist, C. C. Thoreen, L. Bar-Peled, D. M. Sabatini, The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496-1501 (2008); published online 21 May 2008 (10.1126/science.1157535). (Pubitemid 351929429)
5. E. Kim, P. Goraksha-Hicks, L. Li, T. P. Neufeld, K. L. Guan, Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935-945 (2008).
6. R. J. Shaw, LKB1 and AMPK control of mTOR signalling and growth. Acta Physiol. 196, 65-80 (2009).
7. E. Jacinto, R. Loewith, A. Schmidt, S. Lin, M. A. Ruegg, A. Hall, M. N. Hall, Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122-1128 (2004). (Pubitemid 39468014)
8. D. D. Sarbassov, S. M. Ali, D. H. Kim, D. A. Guertin, R. R. Latek, H. Erdjument-Bromage, P. Tempst, D. M. Sabatini, 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). (Pubitemid 38991819)
9. Q. Yang, K. Inoki, T. Ikenoue, K. L. Guan, Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20, 2820-2832 (2006). (Pubitemid 44771744)
10. A. Frias, C. C. Thoreen, J. D. Jaffe, W. Schroder, T. Sculley, S. A. Carr, D. M. Sabatini, mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16, 1865-1870 (2006). (Pubitemid 44354144)
11. E. Jacinto, V. Facchinetti, D. Liu, N. Soto, S. Wei, S. Y. Jung, Q. Huang, J. Qin, B. Su, SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125-137 (2006). (Pubitemid 44466632)
12. D. A. Guertin, D. M. Stevens, C. C. Thoreen, A. A. Burds, N. Y. Kalaany, J. Moffat, M. Brown, K. J. Fitzgerald, D. M. Sabatini, Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCa, but not S6K1. Dev. Cell 11, 859-871 (2006). (Pubitemid 44804279)
13. L. R. Pearce, X. Huang, J. Boudeau, R. Pawlowski, S. Wullschleger, M. Deak, A. F. Ibrahim, R. Gourlay, M. A. Magnuson, D. R. Alessi, Identification of Protor as a novel Rictorbinding component of mTOR complex-2. Biochem. J. 405, 513-522 (2007). (Pubitemid 47172049)
14. A. Mora, D. Komander, D. M. Van Aalten, D. R. Alessi, PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 15, 161-170 (2004). (Pubitemid 38251644)
15. D. H. Kim, D. D. Sarbassov, S. M. Ali, J. E. King, R. R. Latek, H. Erdjument-Bromage, P. Tempst, D. M. Sabatini, mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175 (2002). (Pubitemid 34876545)
16. Hara, Y. Maruki, X. Long, K. Yoshino, N. Oshiro, S. Hidayat, C. Tokunaga, J. Avruch, K. Yonezawa, Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177-189 (2002). (Pubitemid 34876546)
17. D. D. Sarbassov, D. A. Guertin, S. M. Ali, D. M. Sabatini, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101 (2005).
18. D. Parekh, W. Ziegler, K. Yonezawa, K. Hara, P. J. Parker, Mammalian TOR controls one of two kinase pathways acting upon nPKCd and nPKCe. J. Biol. Chem. 274, 34758-34764 (1999). (Pubitemid 129509518)
19. R. M. Biondi, Phosphoinositide-dependent protein kinase 1, a sensor of protein conformation. Trends Biochem. Sci. 29, 136-142 (2004). (Pubitemid 38314859)
20. J. M. García-Martínez, D. R. Alessi, mTOR com-plex-2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum and glucocorticoi induced protein kinase-1 (SGK1). Biochem. J. 416, 375-385 (2008).
21. K. T. Jones, E. R. Greer, D. Pearce, K. Ashrafi, Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol. 7, e60 (2009).
22. A. A. Soukas, E. A. Kane, C. E. Carr, J. A. Melo, G. Ruvkun, Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23, 496-511 (2009).
23. F. Lang, C. Bohmer, M. Palmada, G. Seebohm, N. Strutz-Seebohm, V. Vallon, (Patho)physiological significance of the serum- and glucocorticoidinducible kinase isoforms. Physiol. Rev. 86, 1151-1178 (2006). (Pubitemid 44521650)
24. M. Tessier, J. R. Woodgett, Serum and glucocorticoid- regulated protein kinases: Variations on a theme. J. Cell. Biochem. 98, 1391-1407 (2006). (Pubitemid 44141846)
25. C. Debonneville, S. Y. Flores, E. Kamynina, P. J. Plant, C. Tauxe, M. A. Thomas, C. Munster, A. Chraibi, J. H. Pratt, J. D. Horisberger, D. Pearce, J. Loffing, O. Staub, Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO J. 20, 7052-7059 (2001). (Pubitemid 34062297)
26. T. Ichimura, H. Yamamura, K. Sasamoto, Y. Tominaga, M. Taoka, K. Kakiuchi, T. Shinkawa, N. Takahashi, S. Shimada, T. Isobe, 14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase. J. Biol. Chem. 280, 13187-13194 (2005). (Pubitemid 40491144)
27. J. Loffing, S. Y. Flores, O. Staub, Sgk kinases and their role in epithelial transport. Annu. Rev. Physiol. 68, 461-490 (2006).
28. F. Hong, M. D. Larrea, C. Doughty, D. J. Kwiatkowski, R. Squillace, J. M. Slingerland, mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol. Cell 30, 701-711 (2008). (Pubitemid 351815130)
29. J. Park, M. L. Leong, P. Buse, A. C. Maiyar, G. L. Firestone, B. A. Hemmings, Serum and glucocorticoid- inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J. 18, 3024-3033 (1999). (Pubitemid 29255611)
30. M. Dehner, M. Hadjihannas, J. Weiske, O. Huber, J. Behrens, Wnt signaling inhibits Forkhead box O3ainduced transcription and apoptosis through up-regulation of serum- and glucocorticoid-inducible kinase 1. J. Biol. Chem. 283, 19201-19210 (2008).
31. L. Yan, V. Mieulet, R. F. Lamb, mTORC2 is the hydrophobic motif kinase for SGK1. Biochem. J. 416, e19-e21 (2008).
32. C. Hauge, T. L. Antal, D. Hirschberg, U. Doehn, K. Thorup, L. Idrissova, K. Hansen, O. N. Jensen, T. J. Jorgensen, R. M. Biondi, M. Frodin, Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation. EMBO J. 26, 2251-2261 (2007). (Pubitemid 46685864)
33. D. R. Alessi, M. Andjelkovic, B. Caudwell, P. Cron, N. Morrice, P. Cohen, B. A. Hemmings, Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15, 6541-6551 (1996). (Pubitemid 26413787)
34. D. R. Alessi, Discovery of PDK1, one of the missing links in insulin signal transduction. Biochem. Soc. Trans. 29, 1-14 (2001).
35. T. Ikenoue, K. Inoki, Q. Yang, X. Zhou, K. L. Guan, Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 27, 1919-1931 (2008).
36. V. Facchinetti, W. Ouyang, H. Wei, N. Soto, A. Lazorchak, C. Gould, C. Lowry, A. C. Newton, Y. Mao, R. Q. Miao, W. C. Sessa, J. Qin, P. Zhang, B. Su, E. Jacinto, The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J. 27, 1932-1943 (2008).
37. A. Balendran, G. R. Hare, A. Kieloch, M. R. Williams, D. R. Alessi, Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett. 484, 217-223 (2000). (Pubitemid 30457673)
38. M. Saitoh, N. Pullen, P. Brennan, D. Cantrell, P. B. Dennis, G. Thomas, Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site. J. Biol. Chem. 277, 20104-20112 (2002). (Pubitemid 34967534)
39. G. Manning, D. B. Whyte, R. Martinez, T. Hunter, S. Sudarsanam, The protein kinase complement of the human genome. Science 298, 1912-1934 (2002). (Pubitemid 35425239)
40. J. L. Crespo, M. N. Hall, Elucidating TOR signaling and rapamycin action: Lessons from Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 66, 579-591 (2002).
41. K. Hara, K. Yonezawa, Q. P. Weng, M. T. Kozlowski, C. Belham, J. Avruch, 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). (Pubitemid 28319170)
42. erratum: J. Biol. Chem. 273, 22160 (1998).
43. C. C. Thoreen, S. A. Kang, J. W. Chang, Q. Liu, J. Zhang, Y. Gao, L. J. Reichling, T. Sim, D. M. Sabatini, N. S. Gray, An ATP-competitive mTOR inhibitor reveals rapamycin-insensitive functions of mTORC1. J. Biol. Chem. 284, 8023-8032 (2009).
44. M. E. Feldman, B. Apsel, A. Uotila, R. Loewith, Z. A. Knight, D. Ruggero, K. M. Shokat, Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009).
45. P. E. Burnett, R. K. Barrow, N. A. Cohen, S. H. Snyder, D. M. Sabatini, RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl. Acad. Sci. U.S.A. 95, 1432-1437 (1998).
46. D. Yang, G. J. Brunn, J. C. Lawrence Jr., Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR. FEBS Lett. 453, 387-390 (1999). (Pubitemid 29326685)
47. A. C. Gingras, S. P. Gygi, B. Raught, R. D. Polakiewicz, R. T. Abraham, M. F. Hoekstra, R. Aebersold, N. Sonenberg, Regulation of 4E-BP1 phosphorylation: A novel two-step mechanism. Genes Dev. 13, 1422-1437 (1999). (Pubitemid 29270247)
48. G. J. Brunn, P. Fadden, T. A. Haystead, J. C. Lawrence Jr., The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)- Pro motif and is activated by antibodies to a region near its COOH terminus. J. Biol. Chem. 272, 32547-32550 (1997). (Pubitemid 28011942)
49. Research in the Alessi laboratory is supported by the Medical Research Council and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit.