Synonyms
Double-stranded RNA-activated protein kinase; dsRNA-activated inhibitor (DAI); Eukaryotic initiation factor 2α (EIF2α) protein kinase 2 (EIF2AK2); Interferon-inducible EIF2α kinase; Interferon-inducible RNA-dependent protein kinase; P1/eIF2A protein kinase; p68 kinase; Protein kinase interferon-induced double-stranded RNA-activated (PRKR); Protein kinase RNA-activated (PKR)
Historical Background
Protein kinase R (PKR) was identified through its function in regulating host protein synthesis during virus infection (Farrell et al. 1977; Metz and Esteban 1972). This regulation is enacted through phosphorylation of the eukaryotic initiation factor 2α (EIF2α), marking PKR as a member of a small kinase family that constitutes this universal stress response pathway in eukaryotes (Roberts et al. 1976). A number of additional protein substrates for PKR have been identified, although the consequence of this is not well characterized. The transcript’s cDNA was cloned and the genetic...
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abraham N, Stojdl DF, Duncan PI, Methot N, Ishii T, Dube M, et al. Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase PKR. J Biol Chem. 1999;274(9):5953–62.
Barber GN, Edelhoff S, Katze MG, Disteche CM. Chromosomal assignment of the interferon-inducible double-stranded RNA-dependent protein kinase (PRKR) to human chromosome 2p21-p22 and mouse chromosome 17 E2. Genomics. 1993;16(3):765–7.
Ben-Asouli Y, Banai Y, Pel-Or Y, Shir A, Kaempfer R. Human interferon-gamma mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR. Cell. 2002;108(2):221–32.
Blalock WL, Piazzi M, Bavelloni A, Raffini M, Faenza I, D’Angelo A, et al. Identification of the PKR nuclear interactome reveals roles in ribosome biogenesis, mRNA processing and cell division. J Cell Physiol. 2014;229(8):1047–60.
Bommer UA, Borovjagin AV, Greagg MA, Jeffrey IW, Russell P, Laing KG, et al. The mRNA of the translationally controlled tumor protein P23/TCTP is a highly structured RNA, which activates the dsRNA-dependent protein kinase PKR. RNA. 2002;8(4):478–96.
Bonnet MC, Weil R, Dam E, Hovanessian AG, Meurs EF. PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex. Mol Cell Biol. 2000;20(13):4532–42.
Clerzius G, Shaw E, Daher A, Burugu S, Gelinas JF, Ear T, et al. The PKR activator, PACT, becomes a PKR inhibitor during HIV-1 replication. Retrovirology. 2013;10:96.
Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE. 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. 1999;18(17):2690–702.
Dar AC, Dever TE, Sicheri F. Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR. Cell. 2005;122(6):887–900.
de la Cruz-Herrera CF, Campagna M, Garcia MA, Marcos-Villar L, Lang V, Baz-Martinez M, et al. Activation of the double-stranded RNA-dependent protein kinase PKR by small ubiquitin-like modifier (SUMO). J Biol Chem. 2014;289(38):26357–67.
Deb A, Zamanian-Daryoush M, Xu Z, Kadereit S, Williams BR. Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3. EMBO J. 2001;20(10):2487–96.
Delgado Andre N, De Lucca FL. Non-coding transcript in T cells (NTT): antisense transcript activates PKR and NF-kappaB in human lymphocytes. Blood Cells Mol Dis. 2008;40(2):227–32.
Dey M, Cao C, Dar AC, Tamura T, Ozato K, Sicheri F, et al. Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition. Cell. 2005;122(6):901–13.
Dickerman BK, White CL, Kessler PM, Sadler AJ, Williams BR, Sen GC. The protein activator of protein kinase R, PACT/RAX, negatively regulates protein kinase R during mouse anterior pituitary development. FEBS J. 2015;282(24):4766–81.
Donze O, Abbas-Terki T, Picard D. The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR. EMBO J. 2001;20(14):3771–80.
Farrell PJ, Balkow K, Hunt T, Jackson RJ, Trachsel H. Phosphorylation of initiation factor elF-2 and the control of reticulocyte protein synthesis. Cell. 1977;11(1):187–200.
Fasciano S, Hutchins B, Handy I, Patel RC. Identification of the heparin-binding domains of the interferon-induced protein kinase, PKR. FEBS J. 2005;272(6):1425–39.
Gil J, Esteban M, Roth D. In vivo regulation of the dsRNA-dependent protein kinase PKR by the cellular glycoprotein p67. Biochemistry. 2000;39(51):16016–25.
Gil J, Garcia MA, Gomez-Puertas P, Guerra S, Rullas J, Nakano H, et al. TRAF family proteins link PKR with NF-kappa B activation. Mol Cell Biol. 2004;24(10):4502–12.
Han AP, Fleming MD, Chen JJ. Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Invest. 2005;115(6):1562–70.
Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099–108.
Horng T, Barton GM, Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol. 2001;2(9):835–41.
Irving AT, Wang D, Vasilevski O, Latchoumanin O, Kozer N, Clayton AH, et al. Regulation of actin dynamics by protein kinase R control of gelsolin enforces basal innate immune defense. Immunity. 2012;36(5):795–806.
Katze MG, Wambach M, Wong ML, Garfinkel M, Meurs E, Chong K, et al. Functional expression and RNA binding analysis of the interferon-induced, double-stranded RNA-activated, 68,000-Mr protein kinase in a cell-free system. Mol Cell Biol. 1991;11(11):5497–505.
Kumar A, Yang YL, Flati V, Der S, Kadereit S, Deb A, et al. Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-kappaB. EMBO J. 1997;16(2):406–16.
Kumar KU, Srivastava SP, Kaufman RJ. Double-stranded RNA-activated protein kinase (PKR) is negatively regulated by 60S ribosomal subunit protein L18. Mol Cell Biol. 1999;19(2):1116–25.
Langland JO, Kao PN, Jacobs BL. Nuclear factor-90 of activated T-cells: a double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR. Biochemistry. 1999;38(19):6361–8.
Li H, Chen J, Qi Y, Dai L, Zhang M, Frank JA, et al. Deficient PKR in RAX/PKR association ameliorates ethanol-induced neurotoxicity in the developing cerebellum. Cerebellum. 2015;14(4):386–97.
Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundback P, et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature. 2012;488(7413):670–4.
Metz DH, Esteban M. Interferon inhibits viral protein synthesis in L cells infected with vaccinia virus. Nature. 1972;238(5364):385–8.
Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, et al. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell. 1990;62(2):379–90.
Mittelstadt M, Frump A, Khuu T, Fowlkes V, Handy I, Patel CV, et al. Interaction of human tRNA-dihydrouridine synthase-2 with interferon-induced protein kinase PKR. Nucleic Acids Res. 2008;36(3):998–1008.
Mundschau LJ, Faller DV. Endogenous inhibitors of the dsRNA-dependent eIF-2 alpha protein kinase PKR in normal and ras-transformed cells. Biochimie. 1994;76(8):792–800.
Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, et al. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell. 2010;140(3):338–48.
Nanduri S, Carpick BW, Yang Y, Williams BR, Qin J. Structure of the double-stranded RNA-binding domain of the protein kinase PKR reveals the molecular basis of its dsRNA-mediated activation. EMBO J. 1998;17(18):5458–65.
Okumura F, Okumura AJ, Uematsu K, Hatakeyama S, Zhang DE, Kamura T. Activation of double-stranded RNA-activated protein kinase (PKR) by interferon-stimulated gene 15 (ISG15) modification down-regulates protein translation. J Biol Chem. 2013;288(4):2839–47.
Oner R, Agarwal S, Dimovski AJ, Efremov GD, Petkov GH, Altay C, et al. The G----A mutation at position +22 3′ to the Cap site of the beta-globin gene as a possible cause for a beta-thalassemia. Hemoglobin. 1991;15(1–2):67–76.
Osman F, Jarrous N, Ben-Asouli Y, Kaempfer R. A cis-acting element in the 3′-untranslated region of human TNF-alpha mRNA renders splicing dependent on the activation of protein kinase PKR. Genes Dev. 1999;13(24):3280–93.
Pang Q, Christianson TA, Keeble W, Koretsky T, Bagby GC. The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC. J Biol Chem. 2002;277(51):49638–43.
Pang Q, Christianson TA, Koretsky T, Carlson H, David L, Keeble W, et al. Nucleophosmin interacts with and inhibits the catalytic function of eukaryotic initiation factor 2 kinase PKR. J Biol Chem. 2003;278(43):41709–17.
Park H, Davies MV, Langland JO, Chang HW, Nam YS, Tartaglia J, et al. TAR RNA-binding protein is an inhibitor of the interferon-induced protein kinase PKR. Proc Natl Acad Sci USA. 1994;91(11):4713–7.
Patel RC, Sen GC. PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J. 1998;17(15):4379–90.
Peel AL, Rao RV, Cottrell BA, Hayden MR, Ellerby LM, Bredesen DE. Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington’s disease (HD) transcripts and is activated in HD tissue. Hum Mol Genet. 2001;10(15):1531–8.
Perkins DJ, Qureshi N, Vogel SN. A Toll-like receptor-responsive kinase, protein kinase R, is inactivated in endotoxin tolerance through differential K63/K48 ubiquitination. MBio. 2010;1(5) e00239-10.
Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9(8):e1003709.
Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG. The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity. J Biol Chem. 1996;271(3):1702–7.
Roberts WK, Hovanessian A, Brown RE, Clemens MJ, Kerr IM. Interferon-mediated protein kinase and low-molecular-weight inhibitor of protein synthesis. Nature. 1976;264(5585):477–80.
Sadler AJ, Latchoumanin O, Hawkes D, Mak J, Williams BR. An antiviral response directed by PKR phosphorylation of the RNA helicase A. PLoS Pathog. 2009;5(2):e1000311.
Saelens X, Kalai M, Vandenabeele P. Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation. J Biol Chem. 2001;276(45):41620–8.
Shen S, Niso-Santano M, Adjemian S, Takehara T, Malik SA, Minoux H, et al. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol Cell. 2012;48(5):667–80.
Silva AM, Whitmore M, Xu Z, Jiang Z, Li X, Williams BR. Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. J Biol Chem. 2004;279(36):37670–6.
Singh M, Patel RC. Increased interaction between PACT molecules in response to stress signals is required for PKR activation. J Cell Biochem. 2012;113(8):2754–64.
Talloczy Z, Jiang W, Virgin HW, Leib DA, Scheuner D, Kaufman RJ, et al. Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci USA. 2002;99(1):190–5.
Tan SL, Tareen SU, Melville MW, Blakely CM, Katze MG. The direct binding of the catalytic subunit of protein phosphatase 1 to the PKR protein kinase is necessary but not sufficient for inactivation and disruption of enzyme dimer formation. J Biol Chem. 2002;277(39):36109–17.
Toth AM, Zhang P, Das S, George CX, Samuel CE. Interferon action and the double-stranded RNA-dependent enzymes ADAR1 adenosine deaminase and PKR protein kinase. Prog Nucleic Acid Res Mol Biol. 2006;81:369–434.
Visvanathan KV, Goodbourn S. Double-stranded RNA activates binding of NF-kappa B to an inducible element in the human beta-interferon promoter. EMBO J. 1989;8(4):1129–38.
Watanabe S, Yamashita T, Taira H. A new double-stranded RNA binding protein (DRBP-120) is associated with double-stranded RNA-activated protein kinase (PKR). Biosci Biotechnol Biochem. 2006;70(7):1717–23.
Wen Z, Zhong Z, Darnell Jr JE. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82(2):241–50.
Wong AH, Tam NW, Yang YL, Cuddihy AR, Li S, Kirchhoff S, et al. Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways. EMBO J. 1997;16(6):1291–304.
Xu Z, Williams BR. The B56alpha regulatory subunit of protein phosphatase 2A is a target for regulation by double-stranded RNA-dependent protein kinase PKR. Mol Cell Biol. 2000;20(14):5285–99.
Yang YL, Reis LF, Pavlovic J, Aguzzi A, Schafer R, Kumar A, et al. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 1995;14(24):6095–106.
Yang X, Nath A, Opperman MJ, Chan C. The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells. Mol Biol Cell. 2010;21(19):3449–58.
Yim HC, Wang D, Yu L, White CL, Faber PW, Williams BR, et al. The kinase activity of PKR represses inflammasome activity. Cell Res. 2016;26(3):367–79.
Yin Z, Haynie J, Williams BR, Yang YC. C114 is a novel IL-11-inducible nuclear double-stranded RNA-binding protein that inhibits protein kinase R. J Biol Chem. 2003;278(25):22838–45.
Yoon CH, Lee ES, Lim DS, Bae YS. PKR, a p53 target gene, plays a crucial role in the tumor-suppressor function of p53. Proc Natl Acad Sci USA. 2009;106(19):7852–7.
Yoshida K, Okamura H, Amorim BR, Ozaki A, Tanaka H, Morimoto H, et al. Double-stranded RNA-dependent protein kinase is required for bone calcification in MC3T3-E1 cells in vitro. Exp Cell Res. 2005;311(1):117–25.
Zamanian-Daryoush M, Mogensen TH, DiDonato JA, Williams BR. NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaB-inducing kinase and IkappaB kinase. Mol Cell Biol. 2000;20(4):1278–90.
Zhu PJ, Huang W, Kalikulov D, Yoo JW, Placzek AN, Stoica L, et al. Suppression of PKR promotes network excitability and enhanced cognition by interferon-gamma-mediated disinhibition. Cell. 2011;147(6):1384–96.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this entry
Cite this entry
Sadler, A.J. (2018). PKR. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_51
Download citation
DOI: https://doi.org/10.1007/978-3-319-67199-4_51
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-67198-7
Online ISBN: 978-3-319-67199-4
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences