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The eIF2α kinases: their structures and functions

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Abstract

Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2). Phosphorylation of eIF2α on serine 51 results in a severe decline in de novo protein synthesis and is an important strategy in the cell’s armory against stressful insults including viral infection, the accumulation of misfolded proteins, and starvation. The phosphorylation of eIF2α is carried out by a family of four kinases, PERK (PKR-like ER kinase), PKR (protein kinase double-stranded RNA-dependent), GCN2 (general control non-derepressible-2), and HRI (heme-regulated inhibitor). Each primarily responds to a distinct type of stress or stresses. Thus, while significant sequence similarity exists between the eIF2α kinases in their kinase domains, underlying their common role in phosphorylating eIF2α, additional unique features determine the regulation of these four proteins, that is, what signals activate them. This review will describe the structure of each eIF2α kinase and discuss how this is linked to their activation and function. In parallel to the general translational attenuation elicited by eIF2α kinase activation the translation of stress-induced mRNAs, most notably activating transcription factor 4 (ATF4) is enhanced and these set in motion cascades of gene expression constituting the integrated stress response (ISR), which seek to remediate stress and restore homeostasis. Depending on the cellular context and concurrent signaling pathways active, however, translational attenuation can also facilitate apoptosis. Accordingly, the role of the kinases in determining cell fate will also be discussed.

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References

  1. Abraham N, Stojdl DF, Duncan PI, Methot N, Ishii T, Dube M, Vanderhyden BC, Atkins HL, Gray DA, McBurney MW, Koromilas AE, Brown EG, Sonenberg N, Bell JC (1999) Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. J Biol Chem 274:5953–5962

    Article  PubMed  CAS  Google Scholar 

  2. Acharya P, Chen JJ, Correia MA (2010) Hepatic heme-regulated inhibitor (HRI) eukaryotic initiation factor 2alpha kinase: a protagonist of heme-mediated translational control of CYP2B enzymes and a modulator of basal endoplasmic reticulum stress tone. Mol Pharmacol 77:575–592

    Article  PubMed  CAS  Google Scholar 

  3. Acharya P, Engel JC, Correia MA (2009) Hepatic CYP3A suppression by high concentrations of proteasomal inhibitors: a consequence of endoplasmic reticulum (ER) stress induction, activation of RNA-dependent protein kinase-like ER-bound eukaryotic initiation factor 2alpha (eIF2alpha)-kinase (PERK) and general control nonderepressible-2 eIF2alpha kinase (GCN2), and global translational shutoff. Mol Pharmacol 76:503–515

    Article  PubMed  CAS  Google Scholar 

  4. Ameri K, Harris AL (2008) Activating transcription factor 4. Int J Biochem Cell Biol 40:14–21

    Article  PubMed  CAS  Google Scholar 

  5. Anderson E, Cole JL (2008) Domain stabilities in protein kinase R (PKR): evidence for weak interdomain interactions. Biochemistry 47:4887–4897

    Article  PubMed  CAS  Google Scholar 

  6. Anthony TG, McDaniel BJ, Byerley RL, McGrath BC, Cavener DR, McNurlan MA, Wek RC (2004) Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. J Biol Chem 279:36553–36561

    Article  PubMed  CAS  Google Scholar 

  7. Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP (2010) Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. J Biol Chem 285:6091–6100

    Article  PubMed  CAS  Google Scholar 

  8. Auch CJ, Saha RN, Sheikh FG, Liu X, Jacobs BL, Pahan K (2004) Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia. FEBS Lett 563:223–228

    Article  PubMed  CAS  Google Scholar 

  9. Back SH, Scheuner D, Han J, Song B, Ribick M, Wang J, Gildersleeve RD, Pennathur S, Kaufman RJ (2009) Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab 10:13–26

    Article  PubMed  CAS  Google Scholar 

  10. Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK, Archer DR, Barber GN (2000) Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13:129–141

    Article  PubMed  CAS  Google Scholar 

  11. Baltzis D, Pluquet O, Papadakis AI, Kazemi S, Qu LK, Koromilas AE (2007) The eIF2alpha kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasomal degradation of p53. J Biol Chem 282:31675–31687

    Article  PubMed  CAS  Google Scholar 

  12. Barber GN, Tomita J, Hovanessian AG, Meurs E, Katze MG (1991) Functional expression and characterization of the interferon-induced double-stranded RNA activated P68 protein kinase from Escherichia coli. Biochemistry 30:10356–10361

    Article  PubMed  CAS  Google Scholar 

  13. Bauer BN, Rafie-Kolpin M, Lu L, Han A, Chen JJ (2001) Multiple autophosphorylation is essential for the formation of the active and stable homodimer of heme-regulated eIF2alpha kinase. Biochemistry 40:11543–11551

    Article  PubMed  CAS  Google Scholar 

  14. Berlanga JJ, Ventoso I, Harding HP, Deng J, Ron D, Sonenberg N, Carrasco L, de Haro C (2006) Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses. EMBO J 25:1730–1740

    Article  PubMed  CAS  Google Scholar 

  15. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:326–332

    Article  PubMed  CAS  Google Scholar 

  16. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, Cavener D, Diehl JA (2010) PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 29:3881–3895

    Article  PubMed  CAS  Google Scholar 

  17. Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener DR, Thompson CB, Diehl JA (2008) PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation. Proc Natl Acad Sci USA 105:16314–16319

    Article  PubMed  CAS  Google Scholar 

  18. Bollo M, Paredes RM, Holstein D, Zheleznova N, Camacho P, Lechleiter JD (2010) Calcineurin interacts with PERK and dephosphorylates calnexin to relieve ER stress in mammals and frogs. PLoS ONE 5:e11925

    Article  PubMed  CAS  Google Scholar 

  19. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci USA 97:12625–12630

    Article  PubMed  CAS  Google Scholar 

  20. Bromati CR, Lellis-Santos C, Yamanaka TS, Nogueira TC, Leonelli M, Caperuto LC, Gorjao R, Leite AR, Anhe GF, Bordin S (2011) UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression. Am J Physiol Regul Integr Comp Physiol 300:R92–R100

    Article  PubMed  CAS  Google Scholar 

  21. Bruhat A, Jousse C, Wang XZ, Ron D, Ferrara M, Fafournoux P (1997) Amino acid limitation induces expression of CHOP, a CCAAT/enhancer binding protein-related gene, at both transcriptional and post-transcriptional levels. J Biol Chem 272:17588–17593

    Article  PubMed  CAS  Google Scholar 

  22. Brush MH, Weiser DC, Shenolikar S (2003) Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Mol Cell Biol 23:1292–1303

    Article  PubMed  CAS  Google Scholar 

  23. Cavener DR, Gupta S, McGrath BC (2010) PERK in beta cell biology and insulin biogenesis. Trends Endocrinol Metab 21:714–721

    Article  PubMed  CAS  Google Scholar 

  24. Chen JJ (2007) Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood 109:2693–2699

    PubMed  CAS  Google Scholar 

  25. Chen T, Ozel D, Qiao Y, Harbinski F, Chen L, Denoyelle S, He X, Zvereva N, Supko JG, Chorev M, Halperin JA, Aktas BH (2011) Chemical genetics identify eIF2alpha kinase heme-regulated inhibitor as an anticancer target. Nat Chem Biol 7:610–616

    Article  PubMed  CAS  Google Scholar 

  26. Chen YJ, Tan BC, Cheng YY, Chen JS, Lee SC (2010) Differential regulation of CHOP translation by phosphorylated eIF4E under stress conditions. Nucleic Acids Res 38:764–777

    Article  PubMed  CAS  Google Scholar 

  27. Cherkasova V, Qiu H, Hinnebusch AG (2010) Snf1 promotes phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 by activating Gcn2 and inhibiting phosphatases Glc7 and Sit4. Mol Cell Biol 30:2862–2873

    Article  PubMed  CAS  Google Scholar 

  28. Cherkasova VA, Hinnebusch AG (2003) Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. Genes Dev 17:859–872

    Article  PubMed  CAS  Google Scholar 

  29. Cheshire JL, Williams BR, Baldwin AS Jr (1999) Involvement of double-stranded RNA-activated protein kinase in the synergistic activation of nuclear factor-kappaB by tumor necrosis factor-alpha and gamma-interferon in preneuronal cells. J Biol Chem 274:4801–4806

    Article  PubMed  CAS  Google Scholar 

  30. Chu WM, Ostertag D, Li ZW, Chang L, Chen Y, Hu Y, Williams B, Perrault J, Karin M (1999) JNK2 and IKKbeta are required for activating the innate response to viral infection. Immunity 11:721–731

    Article  PubMed  CAS  Google Scholar 

  31. Cole JL (2007) Activation of PKR: an open and shut case? Trends Biochem Sci 32:57–62

    Article  PubMed  CAS  Google Scholar 

  32. Crosby JS, Lee K, London IM, Chen JJ (1994) Erythroid expression of the heme-regulated eIF-2 alpha kinase. Mol Cell Biol 14:3906–3914

    PubMed  CAS  Google Scholar 

  33. Cuddihy AR, Li S, Tam NW, Wong AH, Taya Y, Abraham N, Bell JC, Koromilas AE (1999) Double-stranded-RNA-activated protein kinase PKR enhances transcriptional activation by tumor suppressor p53. Mol Cell Biol 19:2475–2484

    PubMed  CAS  Google Scholar 

  34. Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE (1999) The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. Oncogene 18:2690–2702

    Article  PubMed  CAS  Google Scholar 

  35. Cui W, Li J, Ron D, Sha B (2011) The structure of the PERK kinase domain suggests the mechanism for its activation. Acta Crystallogr D Biol Crystallogr 67:423–428

    Article  PubMed  CAS  Google Scholar 

  36. Cullinan SB, Diehl JA (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317–332

    Article  PubMed  CAS  Google Scholar 

  37. D’Acquisto F, Ghosh S (2001) PACT and PKR: turning on NF-kappa B in the absence of virus. Sci STKE 2001: re1

  38. Dang Do AN, Kimball SR, Cavener DR, Jefferson LS (2009) eIF2alpha kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver. Physiological genomics 38:328–341

    Article  PubMed  CAS  Google Scholar 

  39. Dar AC, Dever TE, Sicheri F (2005) Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR. Cell 122:887–900

    Article  PubMed  CAS  Google Scholar 

  40. Deb A, Zamanian-Daryoush M, Xu Z, Kadereit S, Williams BR (2001) Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3. EMBO J 20:2487–2496

    Article  PubMed  CAS  Google Scholar 

  41. Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat Genet 25:406–409

    Article  PubMed  CAS  Google Scholar 

  42. Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D (2004) Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24:10161–10168

    Article  PubMed  CAS  Google Scholar 

  43. Deval C, Chaveroux C, Maurin AC, Cherasse Y, Parry L, Carraro V, Milenkovic D, Ferrara M, Bruhat A, Jousse C, Fafournoux P (2009) Amino acid limitation regulates the expression of genes involved in several specific biological processes through GCN2-dependent and GCN2-independent pathways. FEBS J 276:707–718

    Article  PubMed  CAS  Google Scholar 

  44. Dever TE, Hinnebusch AG (2005) GCN2 whets the appetite for amino acids. Mol Cell 18:141–142

    Article  PubMed  CAS  Google Scholar 

  45. Dey M, Cao C, Dar AC, Tamura T, Ozato K, Sicheri F, Dever TE (2005) Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition. Cell 122:901–913

    Article  PubMed  CAS  Google Scholar 

  46. Dey M, Trieselmann B, Locke EG, Lu J, Cao C, Dar AC, Krishnamoorthy T, Dong J, Sicheri F, Dever TE (2005) PKR and GCN2 kinases and guanine nucleotide exchange factor eukaryotic translation initiation factor 2B (eIF2B) recognize overlapping surfaces on eIF2alpha. Mol Cell Biol 25:3063–3075

    Article  PubMed  CAS  Google Scholar 

  47. Dey M, Velyvis A, Li JJ, Chiu E, Chiovitti D, Kay LE, Sicheri F, Dever TE (2011) Requirement for kinase-induced conformational change in eukaryotic initiation factor 2alpha (eIF2alpha) restricts phosphorylation of Ser51. Proc Natl Acad Sci USA 108:4316–4321

    Article  PubMed  CAS  Google Scholar 

  48. Dey S, Baird TD, Zhou D, Palam LR, Spandau DF, Wek RC (2010) Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. J Biol Chem 285:33165–33174

    Article  PubMed  CAS  Google Scholar 

  49. Dong J, Qiu H, Garcia-Barrio M, Anderson J, Hinnebusch AG (2000) Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol Cell 6:269–279

    Article  PubMed  CAS  Google Scholar 

  50. Donze O, Abbas-Terki T, Picard D (2001) The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR. EMBO J 20:3771–3780

    Article  PubMed  CAS  Google Scholar 

  51. Donze O, Jagus R, Koromilas AE, Hershey JW, Sonenberg N (1995) Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J 14:3828–3834

    PubMed  CAS  Google Scholar 

  52. DuRose JB, Tam AB, Niwa M (2006) Intrinsic capacities of molecular sensors of the unfolded protein response to sense alternate forms of endoplasmic reticulum stress. Mol Biol Cell 17:3095–3107

    Article  PubMed  CAS  Google Scholar 

  53. Fernandez BO, Lorkovic IM, Ford PC (2004) Mechanisms of ferriheme reduction by nitric oxide: nitrite and general base catalysis. Inorg Chem 43:5393–5402

    Article  PubMed  CAS  Google Scholar 

  54. Fonseca SG, Urano F, Burcin M, Gromada J (2010) Stress hypERactivation in the beta-cell. Islets 2:1–9

    Article  PubMed  Google Scholar 

  55. Frank CL, Ge X, Xie Z, Zhou Y, Tsai LH (2010) Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle progression and neurogenesis. J Biol Chem 285:33324–33337

    Article  PubMed  CAS  Google Scholar 

  56. Galluzzi L, Brenner C, Morselli E, Touat Z, Kroemer G (2008) Viral control of mitochondrial apoptosis. PLoS Pathog 4:e1000018

    Article  PubMed  CAS  Google Scholar 

  57. Garcia-Barrio M, Dong J, Cherkasova VA, Zhang X, Zhang F, Ufano S, Lai R, Qin J, Hinnebusch AG (2002) Serine 577 is phosphorylated and negatively affects the tRNA binding and eIF2alpha kinase activities of GCN2. J Biol Chem 277:30675–30683

    Article  PubMed  CAS  Google Scholar 

  58. Garcia MA, Meurs EF, Esteban M (2007) The dsRNA protein kinase PKR: virus and cell control. Biochimie 89:799–811

    Article  PubMed  CAS  Google Scholar 

  59. Georgescu MM (2010) PTEN tumor suppressor network in PI3 K-Akt pathway control. Genes Cancer 1:1170–1177

    Article  PubMed  CAS  Google Scholar 

  60. Gil J, Alcami J, Esteban M (1999) Induction of apoptosis by double-stranded-RNA-dependent protein kinase (PKR) involves the alpha subunit of eukaryotic translation initiation factor 2 and NF-kappaB. Mol Cell Biol 19:4653–4663

    PubMed  CAS  Google Scholar 

  61. Goh KC, de Veer MJ, Williams BR (2000) The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin. EMBO J 19:4292–4297

    Article  PubMed  CAS  Google Scholar 

  62. Gotoh T, Mori M (2006) Nitric oxide and endoplasmic reticulum stress. Arterioscler Thromb Vasc Biol 26:1439–1446

    Article  PubMed  CAS  Google Scholar 

  63. Grallert B, Boye E (2007) The Gcn2 kinase as a cell cycle regulator. Cell Cycle Georgetown Tex 6:2768–2772

    Article  CAS  Google Scholar 

  64. Guo F, Cavener DR (2007) The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 5:103–114

    Article  PubMed  CAS  Google Scholar 

  65. Gupta S, Cuffe L, Szegezdi E, Logue SE, Neary C, Healy S, Samali A (2010) Mechanisms of ER stress-mediated mitochondrial membrane permeabilization. Int J Cell Biol 2010:170215

    PubMed  Google Scholar 

  66. Gupta S, McGrath B, Cavener DR (2010) PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 59:1937–1947

    Article  PubMed  CAS  Google Scholar 

  67. Hai T, Curran T (1991) Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA 88:3720–3724

    Article  PubMed  CAS  Google Scholar 

  68. Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA (2005) PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell 16:5493–5501

    Article  PubMed  CAS  Google Scholar 

  69. Han AP, Fleming MD, Chen JJ (2005) Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Investig 115:1562–1570

    Article  PubMed  CAS  Google Scholar 

  70. Han AP, Yu C, Lu L, Fujiwara Y, Browne C, Chin G, Fleming M, Leboulch P, Orkin SH, Chen JJ (2001) Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. EMBO J 20:6909–6918

    Article  PubMed  CAS  Google Scholar 

  71. Hao S, Sharp JW, Ross-Inta CM, McDaniel BJ, Anthony TG, Wek RC, Cavener DR, McGrath BC, Rudell JB, Koehnle TJ, Gietzen DW (2005) Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307:1776–1778

    Article  PubMed  CAS  Google Scholar 

  72. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    Article  PubMed  CAS  Google Scholar 

  73. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163

    Article  PubMed  CAS  Google Scholar 

  74. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904

    Article  PubMed  CAS  Google Scholar 

  75. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  PubMed  CAS  Google Scholar 

  76. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633

    Article  PubMed  CAS  Google Scholar 

  77. He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J (2001) Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem 276:20858–20865

    Article  PubMed  CAS  Google Scholar 

  78. Healy SJ, Gorman AM, Mousavi-Shafaei P, Gupta S, Samali A (2009) Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur J Pharmacol 625:234–246

    Article  PubMed  CAS  Google Scholar 

  79. Heinicke LA, Wong CJ, Lary J, Nallagatla SR, Diegelman-Parente A, Zheng X, Cole JL, Bevilacqua PC (2009) RNA dimerization promotes PKR dimerization and activation. J Mol Biol 390:319–338

    Article  PubMed  CAS  Google Scholar 

  80. Hinnebusch AG (1984) Evidence for translational regulation of the activator of general amino acid control in yeast. Proc Natl Acad Sci USA 81:6442–6446

    Article  PubMed  CAS  Google Scholar 

  81. Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59:407–450

    Article  PubMed  CAS  Google Scholar 

  82. Hinnebusch AG, Natarajan K (2002) Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot Cell 1:22–32

    Article  PubMed  CAS  Google Scholar 

  83. Holcik M, Sonenberg N (2005) Translational control in stress and apoptosis. Nat Rev Mol Cell Biol 6:318–327

    Article  PubMed  CAS  Google Scholar 

  84. Hu P, Han Z, Couvillon AD, Exton JH (2004) Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J Biol Chem 279:49420–49429

    Article  PubMed  CAS  Google Scholar 

  85. Huang G, Yao J, Zeng W, Mizuno Y, Kamm KE, Stull JT, Harding HP, Ron D, Muallem S (2006) ER stress disrupts Ca2+-signaling complexes and Ca2+ regulation in secretory and muscle cells from PERK-knockout mice. J Cell Sci 119:153–161

    Article  PubMed  CAS  Google Scholar 

  86. Igarashi J, Sato A, Kitagawa T, Yoshimura T, Yamauchi S, Sagami I, Shimizu T (2004) Activation of heme-regulated eukaryotic initiation factor 2alpha kinase by nitric oxide is induced by the formation of a five-coordinate NO-heme complex: optical absorption, electron spin resonance, and resonance Raman spectral studies. J Biol Chem 279:15752–15762

    Article  PubMed  CAS  Google Scholar 

  87. Ito T, Yang M, May WS (1999) RAX, a cellular activator for double-stranded RNA-dependent protein kinase during stress signaling. J Biol Chem 274:15427–15432

    Article  PubMed  CAS  Google Scholar 

  88. Iwanaga T, Yamazaki T, Kominami S (1999) Kinetic studies on the successive reaction of neuronal nitric oxide synthase from l-arginine to nitric oxide and l-citrulline. Biochemistry 38:16629–16635

    Article  PubMed  CAS  Google Scholar 

  89. Iwawaki T, Akai R, Kohno K (2010) IRE1alpha disruption causes histological abnormality of exocrine tissues, increase of blood glucose level, and decrease of serum immunoglobulin level. PLoS ONE 5:e13052

    Article  PubMed  CAS  Google Scholar 

  90. Jackson RJ, Hellen CU, Pestova TV (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 11:113–127

    Article  PubMed  CAS  Google Scholar 

  91. Jiang HY, Wek RC (2005) GCN2 phosphorylation of eIF2alpha activates NF-kappaB in response to UV irradiation. Biochem J 385:371–380

    Article  PubMed  CAS  Google Scholar 

  92. Jiang HY, Wek RC (2005) Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. J Biol Chem 280:14189–14202

    Article  PubMed  CAS  Google Scholar 

  93. Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, Wang X, Ron D, Cavener DR, Wek RC (2004) Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 24:1365–1377

    Article  PubMed  CAS  Google Scholar 

  94. Jiang HY, Wek SA, McGrath BC, Scheuner D, Kaufman RJ, Cavener DR, Wek RC (2003) Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol Cell Biol 23:5651–5663

    Article  PubMed  CAS  Google Scholar 

  95. Jousse C, Bruhat A, Carraro V, Urano F, Ferrara M, Ron D, Fafournoux P (2001) Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5′UTR. Nucleic Acids Res 29:4341–4351

    Article  PubMed  CAS  Google Scholar 

  96. Kawagishi-Kobayashi M, Silverman JB, Ung TL, Dever TE (1997) Regulation of the protein kinase PKR by the vaccinia virus pseudosubstrate inhibitor K3L is dependent on residues conserved between the K3L protein and the PKR substrate eIF2alpha. Mol Cell Biol 17:4146–4158

    PubMed  CAS  Google Scholar 

  97. Kedersha NL, Gupta M, Li W, Miller I, Anderson P (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J Cell Biol 147:1431–1442

    Article  PubMed  CAS  Google Scholar 

  98. Kilberg MS, Pan YX, Chen H, Leung-Pineda V (2005) Nutritional control of gene expression: how mammalian cells respond to amino acid limitation. Annu Rev Nutr 25:59–85

    Article  PubMed  CAS  Google Scholar 

  99. Kim SH, Forman AP, Mathews MB, Gunnery S (2000) Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR. Oncogene 19:3086–3094

    Article  PubMed  CAS  Google Scholar 

  100. Kim SH, Gunnery S, Choe JK, Mathews MB (2002) Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR. Oncogene 21:8741–8748

    Article  PubMed  CAS  Google Scholar 

  101. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud RM, Walter P (2009) The unfolded protein response signals through high-order assembly of Ire1. Nature 457:687–693

    Article  PubMed  CAS  Google Scholar 

  102. Koumenis C (2006) ER stress, hypoxia tolerance and tumor progression. Curr Mol Med 6:55–69

    Article  PubMed  CAS  Google Scholar 

  103. Krishnamoorthy J, Mounir Z, Raven JF, Koromilas AE (2008) The eIF2alpha kinases inhibit vesicular stomatitis virus replication independently of eIF2alpha phosphorylation. Cell cycle Georgetown Tex 7:2346–2351

    CAS  Google Scholar 

  104. Kumar A, Haque J, Lacoste J, Hiscott J, Williams BR (1994) Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc Natl Acad Sci USA 91:6288–6292

    Article  PubMed  CAS  Google Scholar 

  105. Kumar R, Azam S, Sullivan JM, Owen C, Cavener DR, Zhang P, Ron D, Harding HP, Chen JJ, Han A, White BC, Krause GS, DeGracia DJ (2001) Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. J Neurochem 77:1418–1421

    Article  PubMed  CAS  Google Scholar 

  106. Langland JO, Cameron JM, Heck MC, Jancovich JK, Jacobs BL (2006) Inhibition of PKR by RNA and DNA viruses. Virus Res 119:100–110

    Article  PubMed  CAS  Google Scholar 

  107. Lee ES, Yoon CH, Kim YS, Bae YS (2007) The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis. FEBS Lett 581:4325–4332

    Article  PubMed  CAS  Google Scholar 

  108. Lee J, Ryu H, Ferrante RJ, Morris SM Jr, Ratan RR (2003) Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA 100:4843–4848

    Article  PubMed  CAS  Google Scholar 

  109. Lee JH, Park EJ, Kim OS, Kim HY, Joe EH, Jou I (2005) Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells. Glia 50:66–79

    Article  PubMed  Google Scholar 

  110. Lee YY, Cevallos RC, Jan E (2009) An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation. J Biol Chem 284:6661–6673

    Article  PubMed  CAS  Google Scholar 

  111. Lemaire PA, Tessmer I, Craig R, Erie DA, Cole JL (2006) Unactivated PKR exists in an open conformation capable of binding nucleotides. Biochemistry 45:9074–9084

    Article  PubMed  CAS  Google Scholar 

  112. Li G, Mongillo M, Chin KT, Harding H, Ron D, Marks AR, Tabas I (2009) Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol 186:783–792

    Article  PubMed  CAS  Google Scholar 

  113. Li G, Scull C, Ozcan L, Tabas I (2010) NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol 191:1113–1125

    Article  PubMed  CAS  Google Scholar 

  114. Liao M, Pabarcus MK, Wang Y, Hefner C, Maltby DA, Medzihradszky KF, Salas-Castillo SP, Yan J, Maher JJ, Correia MA (2007) Impaired dexamethasone-mediated induction of tryptophan 2,3-dioxygenase in heme-deficient rat hepatocytes: translational control by a hepatic eIF2alpha kinase, the heme-regulated inhibitor. J Pharma Exp Ther 323:979–989

    Article  CAS  Google Scholar 

  115. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM, Walter P (2007) IRE1 signaling affects cell fate during the unfolded protein response. Science 318:944–949

    Article  PubMed  CAS  Google Scholar 

  116. Lin JH, Li H, Zhang Y, Ron D, Walter P (2009) Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE 4:e4170

    Article  PubMed  CAS  Google Scholar 

  117. Liu S, Bhattacharya S, Han A, Suragani RN, Zhao W, Fry RC, Chen JJ (2008) Heme-regulated eIF2alpha kinase is necessary for adaptive gene expression in erythroid precursors under the stress of iron deficiency. Br J Haematol 143:129–137

    Article  PubMed  CAS  Google Scholar 

  118. Liu S, Suragani RN, Han A, Zhao W, Andrews NC, Chen JJ (2008) Deficiency of heme-regulated eIF2alpha kinase decreases hepcidin expression and splenic iron in HFE−/− mice. Haematologica 93:753–756

    Article  PubMed  CAS  Google Scholar 

  119. Liu S, Suragani RN, Wang F, Han A, Zhao W, Andrews NC, Chen JJ (2007) The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation. J Clin Investig 117:3296–3305

    Article  PubMed  CAS  Google Scholar 

  120. Liu Y, Laszlo C, Liu W, Chen X, Evans SC, Wu S (2010) Regulation of G(1) arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2alpha phosphorylation. Neoplasia 12:61–68

    PubMed  CAS  Google Scholar 

  121. Lo SC, Li X, Henzl MT, Beamer LJ, Hannink M (2006) Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 25:3605–3617

    Article  PubMed  CAS  Google Scholar 

  122. Lozon TI, Eastman AJ, Matute-Bello G, Chen P, Hallstrand TS, Altemeier WA (2011) PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 300:L422–L429

    Article  PubMed  CAS  Google Scholar 

  123. Lu L, Han AP, Chen JJ (2001) Translation initiation control by heme-regulated eukaryotic initiation factor 2alpha kinase in erythroid cells under cytoplasmic stresses. Mol Cell Biol 21:7971–7980

    Article  PubMed  CAS  Google Scholar 

  124. Ma Y, Brewer JW, Diehl JA, Hendershot LM (2002) Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 318:1351–1365

    Article  PubMed  CAS  Google Scholar 

  125. Malzer E, Daly ML, Moloney A, Sendall TJ, Thomas SE, Ryder E, Ryoo HD, Crowther DC, Lomas DA, Marciniak SJ (2010) Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response. J Cell Sci 123:2892–2900

    Article  PubMed  CAS  Google Scholar 

  126. Maurin AC, Jousse C, Averous J, Parry L, Bruhat A, Cherasse Y, Zeng H, Zhang Y, Harding HP, Ron D, Fafournoux P (2005) The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metab 1:273–277

    Article  PubMed  CAS  Google Scholar 

  127. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21:1249–1259

    Article  PubMed  CAS  Google Scholar 

  128. Mellor H, Proud CG (1991) A synthetic peptide substrate for initiation factor-2 kinases. Biochem Biophys Res Commun 178:430–437

    Article  PubMed  CAS  Google Scholar 

  129. Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, Hovanessian AG (1990) Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62:379–390

    Article  PubMed  CAS  Google Scholar 

  130. Mounir Z, Krishnamoorthy JL, Robertson GP, Scheuner D, Kaufman RJ, Georgescu MM, Koromilas AE (2009) Tumor suppression by PTEN requires the activation of the PKR-eIF2alpha phosphorylation pathway. Sci Signal 2:ra85

    Google Scholar 

  131. Mounir Z, Krishnamoorthy JL, Wang S, Papadopoulou B, Campbell S, Muller WJ, Hatzoglou M, Koromilas AE (2011) Akt determines cell fate through inhibition of the PERK-eIF2alpha phosphorylation pathway. Sci Signal 4: ra62

  132. Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS (2010) Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140:338–348

    Article  PubMed  CAS  Google Scholar 

  133. Nanduri S, Rahman F, Williams BR, Qin J (2000) A dynamically tuned double-stranded RNA binding mechanism for the activation of antiviral kinase PKR. EMBO J 19:5567–5574

    Article  PubMed  CAS  Google Scholar 

  134. Narasimhan J, Staschke KA, Wek RC (2004) Dimerization is required for activation of eIF2 kinase Gcn2 in response to diverse environmental stress conditions. J Biol Chem 279:22820–22832

    Article  PubMed  CAS  Google Scholar 

  135. Naugler WE, Karin M (2008) NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev 18:19–26

    Article  PubMed  CAS  Google Scholar 

  136. Neznanov N, Dragunsky EM, Chumakov KM, Neznanova L, Wek RC, Gudkov AV, Banerjee AK (2008) Different effect of proteasome inhibition on vesicular stomatitis virus and poliovirus replication. PLoS ONE 3:e1887

    Article  PubMed  CAS  Google Scholar 

  137. Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295

    Article  PubMed  CAS  Google Scholar 

  138. Niture SK, Kaspar JW, Shen J, Jaiswal AK (2010) Nrf2 signaling and cell survival. Toxicol Appl Pharmacol 244:37–42

    Article  PubMed  CAS  Google Scholar 

  139. Novoa I, Zeng H, Harding HP, Ron D (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 153:1011–1022

    Article  PubMed  CAS  Google Scholar 

  140. Novoa I, Zhang Y, Zeng H, Jungreis R, Harding HP, Ron D (2003) Stress-induced gene expression requires programmed recovery from translational repression. EMBO J 22:1180–1187

    Article  PubMed  CAS  Google Scholar 

  141. Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 24:1243–1255

    Article  PubMed  CAS  Google Scholar 

  142. Onuki R, Bando Y, Suyama E, Katayama T, Kawasaki H, Baba T, Tohyama M, Taira K (2004) An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer’s disease. EMBO J 23:959–968

    Article  PubMed  CAS  Google Scholar 

  143. Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389

    Article  PubMed  CAS  Google Scholar 

  144. Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18:6853–6866

    Article  PubMed  CAS  Google Scholar 

  145. Palam LR, Baird TD, Wek RC (2011) Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J Biol Chem 286:10939–10949

    Article  PubMed  CAS  Google Scholar 

  146. Pang Q, Christianson TA, Koretsky T, Carlson H, David L, Keeble W, Faulkner GR, Speckhart A, Bagby GC (2003) Nucleophosmin interacts with and inhibits the catalytic function of eukaryotic initiation factor 2 kinase PKR. J Biol Chem 278:41709–41717

    Article  PubMed  CAS  Google Scholar 

  147. Pataer A, Swisher SG, Roth JA, Logothetis CJ, Corn PG (2009) Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity. Cancer Biol Ther 8:245–252

    Article  PubMed  CAS  Google Scholar 

  148. Pataer A, Vorburger SA, Barber GN, Chada S, Mhashilkar AM, Zou-Yang H, Stewart AL, Balachandran S, Roth JA, Hunt KK, Swisher SG (2002) Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase (PKR). Cancer Res 62:2239–2243

    PubMed  CAS  Google Scholar 

  149. Pataer A, Vorburger SA, Chada S, Balachandran S, Barber GN, Roth JA, Hunt KK, Swisher SG (2005) Melanoma differentiation-associated gene-7 protein physically associates with the double-stranded RNA-activated protein kinase PKR. Mol Ther 11:717–723

    Article  PubMed  CAS  Google Scholar 

  150. Patel CV, Handy I, Goldsmith T, Patel RC (2000) PACT, a stress-modulated cellular activator of interferon-induced double-stranded RNA-activated protein kinase, PKR. J Biol Chem 275:37993–37998

    Article  PubMed  CAS  Google Scholar 

  151. Patel RC, Sen GC (1998) PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J 17:4379–4390

    Article  PubMed  CAS  Google Scholar 

  152. Perkins DJ, Barber GN (2004) Defects in translational regulation mediated by the alpha subunit of eukaryotic initiation factor 2 inhibit antiviral activity and facilitate the malignant transformation of human fibroblasts. Mol Cell Biol 24:2025–2040

    Article  PubMed  CAS  Google Scholar 

  153. Pervin S, Tran AH, Zekavati S, Fukuto JM, Singh R, Chaudhuri G (2008) Increased susceptibility of breast cancer cells to stress-mediated inhibition of protein synthesis. Cancer Res 68:4862–4874

    Article  PubMed  CAS  Google Scholar 

  154. Peters GA, Hartmann R, Qin J, Sen GC (2001) Modular structure of PACT: distinct domains for binding and activating PKR. Mol Cell Biol 21:1908–1920

    Article  PubMed  CAS  Google Scholar 

  155. Pomar N, Berlanga JJ, Campuzano S, Hernández G, Elías M, de Haro C (2003) Functional characterization of Drosophila melanogaster PERK eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Eur J Biochem 270:293–306

    Article  PubMed  CAS  Google Scholar 

  156. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349

    Article  PubMed  CAS  Google Scholar 

  157. Rafie-Kolpin M, Chefalo PJ, Hussain Z, Hahn J, Uma S, Matts RL, Chen JJ (2000) Two heme-binding domains of heme-regulated eukaryotic initiation factor-2alpha kinase. N terminus and kinase insertion. J Biol Chem 275:5171–5178

    Article  PubMed  CAS  Google Scholar 

  158. Rafie-Kolpin M, Han AP, Chen JJ (2003) Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI. Biochemistry 42:6536–6544

    Article  PubMed  CAS  Google Scholar 

  159. Rahman M, Lem C, Muaddi H, Koromilas AE (2009) PKR is not a universal target of tumor suppressor p53 in response to genotoxic stress. Cell cycle Georgetown Tex 8:3598–3599

    Google Scholar 

  160. Raine DA, Jeffrey IW, Clemens MJ (1998) Inhibition of the double-stranded RNA-dependent protein kinase PKR by mammalian ribosomes. FEBS Lett 436:343–348

    Article  PubMed  CAS  Google Scholar 

  161. Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, Stark GR (2000) Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. EMBO J 19:263–272

    Article  PubMed  CAS  Google Scholar 

  162. Ramelot TA, Cort JR, Yee AA, Liu F, Goshe MB, Edwards AM, Smith RD, Arrowsmith CH, Dever TE, Kennedy MA (2002) Myxoma virus immunomodulatory protein M156R is a structural mimic of eukaryotic translation initiation factor eIF2alpha. J Mol Biol 322:943–954

    Article  PubMed  CAS  Google Scholar 

  163. Ranganathan AC, Ojha S, Kourtidis A, Conklin DS, Aguirre-Ghiso JA (2008) Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. Cancer Res 68:3260–3268

    Article  PubMed  CAS  Google Scholar 

  164. Romano PR, Garcia-Barrio MT, Zhang X, Wang Q, Taylor DR, Zhang F, Herring C, Mathews MB, Qin J, Hinnebusch AG (1998) Autophosphorylation in the activation loop is required for full kinase activity in vivo of human and yeast eukaryotic initiation factor 2alpha kinases PKR and GCN2. Mol Cell Biol 18:2282–2297

    PubMed  CAS  Google Scholar 

  165. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120:127–141

    Article  PubMed  CAS  Google Scholar 

  166. Rutkowski DT, Kang SW, Goodman AG, Garrison JL, Taunton J, Katze MG, Kaufman RJ, Hegde RS (2007) The role of p58IPK in protecting the stressed endoplasmic reticulum. Mol Biol Cell 18:3681–3691

    Article  PubMed  CAS  Google Scholar 

  167. Ruvolo PP, Gao F, Blalock WL, Deng X, May WS (2001) Ceramide regulates protein synthesis by a novel mechanism involving the cellular PKR activator RAX. J Biol Chem 276:11754–11758

    Article  PubMed  CAS  Google Scholar 

  168. Rzymski T, Milani M, Pike L, Buffa F, Mellor HR, Winchester L, Pires I, Hammond E, Ragoussis I, Harris AL (2010) Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene 29:4424–4435

    Article  PubMed  CAS  Google Scholar 

  169. Sanderson TH, Deogracias MP, Nangia KK, Wang J, Krause GS, Kumar R (2010) PKR-like endoplasmic reticulum kinase (PERK) activation following brain ischemia is independent of unfolded nascent proteins. Neuroscience 169:1307–1314

    Article  PubMed  CAS  Google Scholar 

  170. Scheuner D, Patel R, Wang F, Lee K, Kumar K, Wu J, Nilsson A, Karin M, Kaufman RJ (2006) Double-stranded RNA-dependent protein kinase phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 mediates apoptosis. J Biol Chem 281:21458–21468

    Article  PubMed  CAS  Google Scholar 

  171. Schrier SL (1994) Thalassemia: pathophysiology of red cell changes. Annu Rev Med 45:211–218

    Article  PubMed  CAS  Google Scholar 

  172. Sevier CS, Kaiser CA (2008) Ero1 and redox homeostasis in the endoplasmic reticulum. Biochim Biophys Acta 1783:549–556

    Article  PubMed  CAS  Google Scholar 

  173. Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D (2003) Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev 29:297–307

    Article  PubMed  CAS  Google Scholar 

  174. Sharp TV, Witzel JE, Jagus R (1997) Homologous regions of the alpha subunit of eukaryotic translational initiation factor 2 (eIF2alpha) and the vaccinia virus K3L gene product interact with the same domain within the dsRNA-activated protein kinase (PKR). Eur J Biochem 250:85–91

    Article  PubMed  CAS  Google Scholar 

  175. Shimizu Y, Hendershot LM (2009) Oxidative folding: cellular strategies for dealing with the resultant equimolar production of reactive oxygen species. Antioxid Redox Signal 11:2317–2331

    Article  PubMed  CAS  Google Scholar 

  176. Singh M, Castillo D, Patel CV, Patel RC (2011) Stress-induced phosphorylation of PACT reduces its interaction with TRBP and leads to PKR activation. Biochemistry 50:4550–4560

    Article  PubMed  CAS  Google Scholar 

  177. Singh M, Fowlkes V, Handy I, Patel CV, Patel RC (2009) Essential role of PACT-mediated PKR activation in tunicamycin-induced apoptosis. J Mol Biol 385:457–468

    Article  PubMed  CAS  Google Scholar 

  178. Sonenberg N, Dever TE (2003) Eukaryotic translation initiation factors and regulators. Curr Opin Struct Biol 13:56–63

    Article  PubMed  CAS  Google Scholar 

  179. Sood R, Porter AC, Ma K, Quilliam LA, Wek RC (2000) Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. Biochem J 346(Pt 2):281–293

    Article  PubMed  CAS  Google Scholar 

  180. Srivastava SP, Kumar KU, Kaufman RJ (1998) Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J Biol Chem 273:2416–2423

    Article  PubMed  CAS  Google Scholar 

  181. Stojdl DF, Abraham N, Knowles S, Marius R, Brasey A, Lichty BD, Brown EG, Sonenberg N, Bell JC (2000) The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus. J Virol 74:9580–9585

    Article  PubMed  CAS  Google Scholar 

  182. Su N, Kilberg MS (2008) C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. J Biol Chem 283:35106–35117

    Article  PubMed  CAS  Google Scholar 

  183. Su Q, Wang S, Baltzis D, Qu LK, Wong AH, Koromilas AE (2006) Tyrosine phosphorylation acts as a molecular switch to full-scale activation of the eIF2alpha RNA-dependent protein kinase. Proc Natl Acad Sci USA 103:63–68

    Article  PubMed  CAS  Google Scholar 

  184. Su Q, Wang S, Gao HQ, Kazemi S, Harding HP, Ron D, Koromilas AE (2008) Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation. J Biol Chem 283:469–475

    Article  PubMed  CAS  Google Scholar 

  185. Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885

    Article  PubMed  CAS  Google Scholar 

  186. Taylor DR, Lee SB, Romano PR, Marshak DR, Hinnebusch AG, Esteban M, Mathews MB (1996) Autophosphorylation sites participate in the activation of the double-stranded-RNA-activated protein kinase PKR. Mol Cell Biol 16:6295–6302

    PubMed  CAS  Google Scholar 

  187. Thireos G, Penn MD, Greer H (1984) 5′ untranslated sequences are required for the translational control of a yeast regulatory gene. Proc Natl Acad Sci USA 81:5096–5100

    Article  PubMed  CAS  Google Scholar 

  188. Thomas MG, Loschi M, Desbats MA, Boccaccio GL (2011) RNA granules: the good, the bad and the ugly. Cell Signal 23:324–334

    Article  PubMed  CAS  Google Scholar 

  189. Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA (2006) S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441:513–517

    Article  PubMed  CAS  Google Scholar 

  190. Uetani K, Der SD, Zamanian-Daryoush M, de La Motte C, Lieberman BY, Williams BR, Erzurum SC (2000) Central role of double-stranded RNA-activated protein kinase in microbial induction of nitric oxide synthase. J Immunol 165:988–996

    PubMed  CAS  Google Scholar 

  191. Ung TL, Cao C, Lu J, Ozato K, Dever TE (2001) Heterologous dimerization domains functionally substitute for the double-stranded RNA binding domains of the kinase PKR. EMBO J 20:3728–3737

    Article  PubMed  CAS  Google Scholar 

  192. van Huizen R, Martindale JL, Gorospe M, Holbrook NJ (2003) P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. J Biol Chem 278:15558–15564

    Article  PubMed  Google Scholar 

  193. VanOudenhove J, Anderson E, Krueger S, Cole JL (2009) Analysis of PKR structure by small-angle scattering. J Mol Biol 387:910–920

    Article  PubMed  CAS  Google Scholar 

  194. Vattem KM, Staschke KA, Wek RC (2001) Mechanism of activation of the double-stranded-RNA-dependent protein kinase, PKR: role of dimerization and cellular localization in the stimulation of PKR phosphorylation of eukaryotic initiation factor-2 (eIF2). Eur J Biochem 268:3674–3684

    Article  PubMed  CAS  Google Scholar 

  195. Vazquez de Aldana CR, Dever TE, Hinnebusch AG (1993) Mutations in the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2 alpha) that overcome the inhibitory effect of eIF-2 alpha phosphorylation on translation initiation. Proc Natl Acad Sci USA 90:7215–7219

    Article  PubMed  CAS  Google Scholar 

  196. Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, Ye Y (2009) ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc Natl Acad Sci USA 106:2200–2205

    Article  PubMed  CAS  Google Scholar 

  197. Wei CL, Wu Q, Vega VB, Chiu KP, Ng P, Zhang T, Shahab A, Yong HC, Fu Y, Weng Z, Liu J, Zhao XD, Chew JL, Lee YL, Kuznetsov VA, Sung WK, Miller LD, Lim B, Liu ET, Yu Q, Ng HH, Ruan Y (2006) A global map of p53 transcription-factor binding sites in the human genome. Cell 124:207–219

    Article  PubMed  CAS  Google Scholar 

  198. Wethmar K, Smink JJ, Leutz A (2010) Upstream open reading frames: molecular switches in (patho)physiology. BioEssays 32:885–893

    Article  PubMed  CAS  Google Scholar 

  199. Williams BR (1999) PKR; a sentinel kinase for cellular stress. Oncogene 18:6112–6120

    Article  PubMed  CAS  Google Scholar 

  200. Wu S, Kaufman RJ (1997) A model for the double-stranded RNA (dsRNA)-dependent dimerization and activation of the dsRNA-activated protein kinase PKR. J Biol Chem 272:1291–1296

    Article  PubMed  CAS  Google Scholar 

  201. Xu WM, Liu LZ (1998) Nitric oxide: from a mysterious labile factor to the molecule of the Nobel Prize. Recent progress in nitric oxide research. Cell Res 8:251–258

    Article  PubMed  CAS  Google Scholar 

  202. Yamaguchi H, Wang HG (2004) CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279:45495–45502

    Article  PubMed  CAS  Google Scholar 

  203. Yan W, Gale MJ Jr, Tan SL, Katze MG (2002) Inactivation of the PKR protein kinase and stimulation of mRNA translation by the cellular co-chaperone P58(IPK) does not require J domain function. Biochemistry 41:4938–4945

    Article  PubMed  CAS  Google Scholar 

  204. Yang R, Wek SA, Wek RC (2000) Glucose limitation induces GCN4 translation by activation of Gcn2 protein kinase. Mol Cell Biol 20:2706–2717

    Article  PubMed  CAS  Google Scholar 

  205. Yang YL, Reis LF, Pavlovic J, Aguzzi A, Schafer R, Kumar A, Williams BR, Aguet M, Weissmann C (1995) Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J 14:6095–6106

    PubMed  CAS  Google Scholar 

  206. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl JA, Ron D, Koumenis C (2010) The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J 29:2082–2096

    Article  PubMed  CAS  Google Scholar 

  207. Yerlikaya A, Kimball SR, Stanley BA (2008) Phosphorylation of eIF2alpha in response to 26S proteasome inhibition is mediated by the heme-regulated inhibitor (HRI) kinase. Biochem J 412:579–588

    Article  PubMed  CAS  Google Scholar 

  208. Yeung MC, Liu J, Lau AS (1996) An essential role for the interferon-inducible, double-stranded RNA-activated protein kinase PKR in the tumor necrosis factor-induced apoptosis in U937 cells. Proc Natl Acad Sci USA 93:12451–12455

    Article  PubMed  CAS  Google Scholar 

  209. Yoon CH, Lee ES, Lim DS, Bae YS (2009) PKR, a p53 target gene, plays a crucial role in the tumor-suppressor function of p53. Proc Natl Acad Sci USA 106:7852–7857

    Article  PubMed  CAS  Google Scholar 

  210. Zhang F, Hamanaka RB, Bobrovnikova-Marjon E, Gordan JD, Dai MS, Lu H, Simon MC, Diehl JA (2006) Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest. J Biol Chem 281:30036–30045

    Article  PubMed  CAS  Google Scholar 

  211. Zhang P, McGrath BC, Reinert J, Olsen DS, Lei L, Gill S, Wek SA, Vattem KM, Wek RC, Kimball SR, Jefferson LS, Cavener DR (2002) The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Mol Cell Biol 22:6681–6688

    Article  PubMed  CAS  Google Scholar 

  212. Zhang S, Yu D (2010) PI(3)king apart PTEN’s role in cancer. Clin Cancer Res 16:4325–4330

    Article  PubMed  CAS  Google Scholar 

  213. Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener DR (2006) PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab 4:491–497

    Article  PubMed  CAS  Google Scholar 

  214. Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, Wek RC (2008) Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem 283:7064–7073

    Article  PubMed  CAS  Google Scholar 

  215. Zhu S, Wek RC (1998) Ribosome-binding domain of eukaryotic initiation factor-2 kinase GCN2 facilitates translation control. J Biol Chem 273:1808–1814

    Article  PubMed  CAS  Google Scholar 

  216. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Our research is supported by Science Foundation Ireland (09/RFP/BIC2371; 09/RFP/BMT2153), the Health Research Board (HRA/2009/59) and Breast Cancer Campaign (2008NovPhD21; 2010NovPR13).

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  1. Neysan Donnelly

    Present address: Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, Munich, 82152, Germany

Authors and Affiliations

  1. Apoptosis Research Center, National University of Ireland, Galway, Ireland

    Neysan Donnelly, Adrienne M. Gorman, Sanjeev Gupta & Afshin Samali

  2. School of Natural Sciences, National University of Ireland, Galway, Ireland

    Neysan Donnelly, Adrienne M. Gorman & Afshin Samali

  3. School of Medicine, National University of Ireland, Galway, Ireland

    Sanjeev Gupta

Authors
  1. Neysan Donnelly
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  2. Adrienne M. Gorman
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  3. Sanjeev Gupta
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  4. Afshin Samali
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Correspondence to Afshin Samali.

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Donnelly, N., Gorman, A.M., Gupta, S. et al. The eIF2α kinases: their structures and functions. Cell. Mol. Life Sci. 70, 3493–3511 (2013). https://doi.org/10.1007/s00018-012-1252-6

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  • DOI: https://doi.org/10.1007/s00018-012-1252-6

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