ER stress inhibits mTORC2 and Akt signaling through GSK-3β-mediated phosphorylation of rictor

Science Signaling

Volumn 4, Issue 161, 2011, Pages

  Chen, Chien Hung ^a,b   Shaikenov, Tattym ^a   Peterson, Timothy R ^c,d   Aimbetov, Rakhan ^a,e   Bissenbaev, Amangeldy K ^e   Lee, Szu Wei ^a,b   Wu, Juan ^a   Lin, Hui Kuan ^a,b   Sarbassov, Dos D ^a,b  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF TEXAS   (United States)

^c WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

^d MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^e AL FARABI KAZAKH NATIONAL UNIVERSITY   (Kazakhstan)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOSE; GLYCOGEN SYNTHASE KINASE 3BETA; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PROTEIN KINASE B; SERINE; CARRIER PROTEIN; CRTC2 PROTEIN, HUMAN; GLYCOGEN SYNTHASE KINASE 3; GLYCOGEN SYNTHASE KINASE 3 BETA; RICTOR PROTEIN, HUMAN; TRANSCRIPTION FACTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL PROLIFERATION; CONTROLLED STUDY; CYTOLYSIS; ENDOPLASMIC RETICULUM STRESS; ENZYME ACTIVITY; ENZYME ASSAY; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; GLUCOSE METABOLISM; GLYCOGEN SYNTHESIS; HUMAN; HUMAN CELL; IMMUNOBLOTTING; MOUSE; MUTAGENESIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN MODIFICATION; TUMOR GROWTH; CHEMISTRY; ENDOPLASMIC RETICULUM; ENZYME ACTIVATION; ENZYME SPECIFICITY; METABOLISM; PHOSPHORYLATION; PHYSIOLOGICAL STRESS;

EUKARYOTA; MAMMALIA;

CARRIER PROTEINS; ENDOPLASMIC RETICULUM; ENZYME ACTIVATION; GLYCOGEN SYNTHASE KINASE 3; HUMANS; PHOSPHORYLATION; PROTO-ONCOGENE PROTEINS C-AKT; SERINE; STRESS, PHYSIOLOGICAL; SUBSTRATE SPECIFICITY; TRANSCRIPTION FACTORS;

EID: 79952119614     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.2001731     Document Type: Article

References (46)

1. R. J. Shaw, L. C. Cantley, Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424-430 (2006).
2. A. J. Levine, Z. Feng, T. W. Mak, H. You, S. Jin, Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev. 20, 267-275 (2006).
3. G. S. Hotamisligil, Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900-917 (2010).
4. D. L. Eizirik, A. K. Cardozo, M. Cnop, The role for endoplasmic reticulum stress in diabetes mellitus. Endocr. Rev. 29, 42-61 (2008).
5. C. Xu, B. Bailly-Maitre, J. C. Reed, Endoplasmic reticulum stress: Cell life and death decisions. J. Clin. Invest. 115, 2656-2664 (2005).
6. L. R. Pearce, D. Komander, D. R. Alessi, The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 11, 9-22 (2010).
7. W. L. Yang, J. Wang, C. H. Chan, S. W. Lee, A. D. Campos, B. Lamothe, L. Hur, B. C. Grabiner, X. Lin, B. G. Darnay, H. K. Lin, The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325, 1134-1138 (2009).
8. D. R. Alessi, S. R. James, C. P. Downes, A. B. Holmes, P. R. Gaffney, C. B. Reese, P. Cohen, Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Ba. Curr. Biol. 7, 261-269 (1997).
9. L. Stephens,K.Anderson, D. Stokoe, H. Erdjument-Bromage, G. F. Painter,A. B. Holmes, P. R. Gaffney, C. B. Reese, F. McCormick, P. Tempst, J. Coadwell, P. T. Hawkins, Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate- dependent activation of protein kinase B. Science 279, 710-714 (1998).
10. 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).
11. C. Shiota, J. T. Woo, J. Lindner, K. D. Shelton, M. A. Magnuson, Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev. Cell 11, 583-589 (2006).
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).
13. 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).
14. 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).
15. L. Bozulic, B. Surucu, D. Hynx, B. A. Hemmings, PKBa/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol. Cell 30, 203-213 (2008).
16. S. M. Ali, D. M. Sabatini, Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site. J. Biol. Chem. 280, 19445-19448 (2005).
17. J. M. Garcia-Martinez, D. R. Alessi, 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).
18. 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).
19. W. A. Schroder, M. Buck, N. Cloonan, J. F. Hancock, A. Suhrbier, T. Sculley, G. Bushell, Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling. Cell. Signal. 19, 1279-1289 (2007).
20. C. C. Dibble, J. M. Asara, B. D. Manning, Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol. Cell. Biol. 29, 5657-5670 (2009).
21. L. A. Julien, A. Carriere, J. Moreau, P. P.Roux, mTORC1-activated S6K1 phosphorylates rictor on threonine 1135 and regulates mTORC2 signaling. Mol. Cell. Biol. 30, 908-921 (2010).
22. C. Treins, P. H. Warne, M. A. Magnuson, M. Pende, J. Downward, Rictor is a novel target of p70 S6 kinase-1. Oncogene 29, 1003-1016 (2010).
23. D. Boulbes, C. H. Chen, T. Shaikenov, N. K. Agarwal, T. R. Peterson, T. A. Addona, H. Keshishian, S. A. Carr, M. A. Magnuson, D. M. Sabatini, D. D. Sarbassov, Rictor phosphorylation on the Thr-1135 site does not require mammalian target of rapamycin complex 2. Mol. Cancer Res. 8, 896-906 (2010).
24. T. H. Lee, A. D. Linstedt, Osmotically induced cell volume changes alter anterograde and retrograde transport, Golgi structure, and COPI dissociation. Mol. Biol. Cell 10, 1445-1462 (1999).
25. K. Zhang, R. J. Kaufman, Identification and characterization of endoplasmic reticulum stress-induced apoptosis in vivo. Methods Enzymol. 442, 395-419 (2008).
26. L. Song, P. De Sarno, R. S. Jope, Central role of glycogen synthase kinase-3b in endoplasmic reticulum stress-induced caspase-3 activation. J. Biol. Chem. 277, 44701-44708 (2002).
27. P. Viatour, E. Dejardin, M. Warnier, F. Lair, E. Claudio, F. Bureau, J. C. Marine, M. P. Merville, U. Maurer, D. Green, J. Piette, U. Siebenlist, V. Bours, A. Chariot, GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol. Cell 16, 35-45 (2004).
28. K. Hughes, E. Nikolakaki, S. E. Plyte, N. F. Totty, J. R.Woodgett, Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 12, 803-808 (1993).
29. Q. M. Wang, C. J. Fiol, A. A. DePaoli-Roach, P. J. Roach, Glycogen synthase kinase-3b is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. J. Biol. Chem. 269, 14566-14574 (1994).
30. P. Polychronopoulos, P. Magiatis, A. L. Skaltsounis, V. Myrianthopoulos, E. Mikros, A. Tarricone, A. Musacchio, S. M. Roe, L. Pearl, M. Leost, P. Greengard, L. Meijer, Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J. Med. Chem. 47, 935-946 (2004).
31. K. Inoki, Y. Li, T. Zhu, J. Wu, K. L. Guan, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648-657 (2002).
32. B. D. Manning, A. R. Tee, M. N. Logsdon, J. Blenis, L. C. Cantley, 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).
33. P. Cohen, M. Goedert, GSK3 inhibitors: Development and therapeutic potential. Nat. Rev. Drug Discov. 3, 479-487 (2004).
34. R. Mussmann, M. Geese, F. Harder, S. Kegel, U. Andag, A. Lomow, U. Burk, D. Onichtchouk, C. Dohrmann, M. Austen, Inhibition of GSK3 promotes replication and survival of pancreatic b cells. J. Biol. Chem. 282, 12030-12037 (2007).
35. D. B. Ring, K. W. Johnson, E. J. Henriksen, J. M. Nuss, D. Goff, T. R. Kinnick, S. T. Ma, J. W. Reeder, I. Samuels, T. Slabiak, A. S. Wagman, M. E. Hammond, S. D. Harrison, Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52, 588-595 (2003).
36. K. P. Hoeflich, J. Luo, E. A. Rubie, M. S. Tsao, O. Jin, J. R. Woodgett, Requirement for glycogen synthase kinase-3b in cell survival and NF-κB activation. Nature 406, 86-90 (2000).
37. L. Ruel, M. Bourouis, P. Heitzler, V. Pantesco, P. Simpson, Drosophila shaggy kinase and rat glycogen synthase kinase-3 have conserved activities and act downstream of Notch. Nature 362, 557-560 (1993).
38. H. C. Lee, J. N. Tsai,P.Y. Liao, W. Y. Tsai,K.Y. Lin,C.C.Chuang, C. K. Sun,W. C. Chang, H. J. Tsai, Glycogen synthase kinase 3a and 3b have distinct functions during cardiogenesis of zebrafish embryo. BMC Dev. Biol. 7, 93 (2007).
39. G. V. Rayasam, V. K. Tulasi, R. Sodhi, J. A. Davis, A. Ray, Glycogen synthase kinase 3: More than a namesake. Br. J. Pharmacol. 156, 885-898 (2009).
40. C. Xu, N. G. Kim, B. M. Gumbiner, Regulation of protein stability by GSK3 mediated phosphorylation. Cell Cycle 8, 4032-4039 (2009).
41. D. A. Cross, D. R. Alessi, P. Cohen, M. Andjelkovich, B. A. Hemmings, Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785-789 (1995).
42. S. Srinivasan, M. Ohsugi, Z. Liu, S. Fatrai, E. Bernal-Mizrachi, M. A. Permutt, Endoplasmic reticulum stress-induced apoptosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3b in mouse insulinoma cells. Diabetes 54, 968-975 (2005).
43. K. Tanabe, Z. Liu, S. Patel, B. W. Doble, L. Li, C. Cras-Méneur, S. C. Martinez, C. M. Welling, M. F. White, E. Bernal-Mizrachi, J. R. Woodgett, M. A. Permutt, Genetic deficiency of glycogen synthase kinase-3β corrects diabetes in mouse models of insulin resistance. PLoS Biol. 6, e37 (2008).
44. N. J. Bryant, R. Govers, D. E. James, Regulated transport of the glucose transporter GLUT4. Nat. Rev. Mol. Cell Biol. 3, 267-277 (2002).
45. H. Cho, J. Mu, J. K. Kim, J. L. Thorvaldsen, Q. Chu, E. B. Crenshaw III, K. H. Kaestner, M. S. Bartolomei, G. I. Shulman, M. J. Birnbaum, Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBb). Science 292, 1728-1731 (2001).
46. 1235 rictor antibodies and S.-C. J. Yeung for help with the statistical analysis. We gratefully acknowledge D. M. Sabatini for the critical reading and editing of our manuscript. Funding: This work was supported by the M. D. Anderson Trust Fellow Fund and NIH grant CA133522 (D.D.S.). T.R.P. was supported by the Ludwig Cancer Center Fellowship and the American Diabetes Association. Author contributions: C.-H.C., T.R.P., and D.D.S. conceived the project. C.-H.C. and D.D.S. designed the experiments and analyzed the data. C.-H.C. performed most of the experiments. T.S. set up in vitro kinase studies. R.A. and A.K.B. performed the rictor mutagenesis and established the stable cell lines. S.-W.L., J.W., and H.-K.L. performed in vivo studies. T.R.P. and D.D.S. wrote the manuscript. Competing interests: The authors declare that they have no competing interests.