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Gene Review

EIF2AK2  -  eukaryotic translation initiation factor 2...

Homo sapiens

Synonyms: EIF2AK1, Eukaryotic translation initiation factor 2-alpha kinase 2, Interferon-induced, double-stranded RNA-activated protein kinase, Interferon-inducible RNA-dependent protein kinase, P1/eIF-2A protein kinase, ...
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Disease relevance of EIF2AK2

  • TRBP and PKR are involved in the regulation of HIV-1 gene expression through their binding to TAR RNA [1].
  • Inhibition of PKR by NPM may be one mechanism by which neoplastic clones evolve in sporadic malignancies and in neoplastic cells arising in the context of the cancer predisposition syndrome, Fanconi anemia [2].
  • Additional coexpression of a dominant negative mutant of PKR or of adenovirus VA1 RNA suppressed this inhibition, indicating that it is mediated by PKR [3].
  • Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR [4].
  • Thus, PKR may play a critical role in mediating the subversive effects of HIV Tat resulting in IL-10 induction [5].

Psychiatry related information on EIF2AK2

  • Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue [6].
  • We also detected the accumulation of phosphorylated PKR in the nuclei of autopsied brain tissues in Alzheimer's disease [7].
  • Enhanced permissiveness of the transformed cells was linked to the inhibition of virus-induced activation (phosphorylation) of the double-stranded RNA-activated protein kinase (PKR), thereby allowing viral transcripts to be translated in these cells [8].
  • Ceramide-induced activation of double-stranded RNA-dependent protein kinase (PKR), a protein kinase important in anti-viral host defense mechanisms and recently implicated in cellular stress pathways, results in the inhibition of protein synthesis as a prelude to cell death [9].

High impact information on EIF2AK2

  • PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking [10].
  • The deduced amino acid sequence of the p68 kinase predicts a protein of 550 amino acids containing all of the conserved domains specific for members of the protein kinase family, including the catalytic domain characteristic of serine/threonine kinases [11].
  • Here it is shown that the HCV envelope protein E2 contains a sequence identical with phosphorylation sites of the interferon-inducible protein kinase PKR and the translation initiation factor eIF2alpha, a target of PKR [12].
  • E2 inhibited the kinase activity of PKR and blocked its inhibitory effect on protein synthesis and cell growth [12].
  • Unaided uptake into HeLa cells of 2-5A linked to an antisense oligonucleotide resulted in the selective ablation of messenger RNA for the double-stranded RNA (dsRNA)-dependent protein kinase PKR [13].

Chemical compound and disease context of EIF2AK2


Biological context of EIF2AK2

  • PKR, a member of the eukaryotic initiation-factor 2alpha (eIF-2alpha) kinase family, mediates the host antiviral response and is implicated in tumor suppression and apoptosis [19].
  • The PKR gene 5' flanking region was a functional promoter in interferon-treated, transfected cells as measured with chloramphenicol acetyltransferase as the reporter gene [20].
  • These studies also show, by immunodetection in tissue slices, that PKR is present in its activated form in both human Huntington autopsy material and brain tissue derived from Huntington yeast artificial chromosome transgenic mice [6].
  • The IFN-inducible dsRNA-activated protein kinase PKR regulates protein synthesis through phosphorylation of eukaryotic initiation factor-2alpha [21].
  • In normal cells the protein kinase PKR effects apoptosis in response to various extra and intracellular cues and can also function to suppress the neoplastic phenotype [2].

Anatomical context of EIF2AK2

  • Nuclear factor-90 of activated T-cells: A double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR [22].
  • We previously reported that PKR and p38 MAPK were required for dsRNA and viral induction of inflammatory cytokines in epithelial cells [23].
  • PKR and ASK1 showed predominant cytoplasmic localization in COS-1 cells transfected with both cDNAs, and coimmunoprecipitated from the cell extracts [24].
  • Transfection of either wild-type PKR or catalytically inactive PKR in PKR(0/0) mouse embryo fibroblasts resulted in the activation of the IKK complex [25].
  • Tumor suppressor p53 as a component of the tumor necrosis factor-induced, protein kinase PKR-mediated apoptotic pathway in human promonocytic U937 cells [26].

Associations of EIF2AK2 with chemical compounds

  • A short-term exposure of cells to the Hsp90 inhibitors GA or radicicol not only derepresses PKR, but also activates the Raf-MAPK pathway [19].
  • The IFN-gamma response can be blocked by 2',5'-oligoadenylate-linked antisense chimeras against PKR mRNA [21].
  • The double-stranded RNA activated protein kinase PKR is a serine/threonine kinase that modulates protein synthesis through the phosphorylation of translation initiation factor eIF-2alpha [27].
  • A full-length P23 transcript, but not a truncated version thereof, was able to bind to PKR in vitro and in vivo [3].
  • Double-stranded RNA-activated protein kinase (PKR), a serine/threonine kinase, is activated in virus-infected cells and acts as an antiviral machinery of type I interferons [24].

Physical interactions of EIF2AK2

  • Utilizing experimental approaches, which included coprecipitation or coselection of native and recombinant wild-type and mutant proteins, we found that P58 can efficiently complex with the PKR protein kinase [28].
  • Enhanced antiviral and antiproliferative properties of a STAT1 mutant unable to interact with the protein kinase PKR [29].
  • We found that NF-kappa B complexes induced by PKR are composed primarily of p50-p65 heterodimers and also of c-rel-p50 heterodimers [30].
  • Immunoprecipitation analysis revealed that PKR interacts with the IKK complex [30].
  • The PKR KCS element selectively bound nuclear proteins more efficiently than did the ADAR1 KCS-l element [31].

Enzymatic interactions of EIF2AK2

  • In addition, purified recombinant NPM was phosphorylated by activated PKR [2].
  • As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation [30].
  • OBJECTIVE: Protein kinase R (PKR) interacts with dsRNA and phosphorylates eukaryotic initiation factor-2 (eIF2alpha), which in turn inhibits host translation initiation as well as hepatitis C virus (HCV) translation [32].
  • In vitro kinase assays revealed that MKK6 was efficiently phosphorylated by PKR, and this could be inhibited by 2-aminopurine [33].
  • PKR phosphorylates eIF-2alpha on Ser(51), resulting in the suppression of protein synthesis [34].

Co-localisations of EIF2AK2


Regulatory relationships of EIF2AK2

  • These data, taken together, demonstrate that P58 inhibits PKR through a direct interaction, which is likely independent of the binding of double-stranded RNA to the protein kinase [28].
  • Kinase assays demonstrated that recombinant NPM inhibited PKR activation in a dose-dependent manner [2].
  • The promoter-proximal KCS element of the PKR kinase gene enhances transcription irrespective of orientation and position relative to the ISRE element and is functionally distinct from the KCS-like element of the ADAR deaminase Promoter [31].
  • The pathway of PKR-induced apoptosis involves FADD activation of caspase 8 by a mechanism independent of Fas and TNFR [36].
  • These data suggest that TRBP activates gene expression in PKR-dependent and PKR-independent manners [37].
  • Suppression of PKR promoted BCL2 phosphorylation with concomitant loss of B56alpha phosphorylation at serine 28 and inhibition of mitochondrial PP2A activity [38].

Other interactions of EIF2AK2

  • In these studies we show that a double-stranded RNA-binding protein, PKR, which has previously been linked to virally-induced and stress-mediated apoptosis, preferentially binds mutant huntingtin RNA transcripts immobilized on streptavidin columns that have been incubated with human brain extracts [6].
  • Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation [39].
  • These domains are conserved with the cis-acting transactivation response element (TAR)-binding protein (TRBP) and dsRNA-activated protein kinase (PKR) [1].
  • Furthermore, not all tetratricopeptide motifs were necessary for PKR-P58 interactions [28].
  • We also provide evidence that STAT1 functions as an inhibitor of PKR in vitro and in vivo [29].

Analytical, diagnostic and therapeutic context of EIF2AK2

  • Cellular expression of an epitope-tagged DRBP76 demonstrated its nuclear localization, and its co-immunoprecipitation with PKR demonstrated that the two proteins interact in vivo [40].
  • Using site-directed mutagenesis we show that PKR is specifically proteolysed at Asp(251) during cellular apoptosis [39].
  • Here we report the molecular cloning and characterization of several related cDNAs from which can be deduced the full-length p68 kinase sequence [11].
  • Here we report that PKR is involved in IFN- and dsRNA-signaling pathways by modulating the function of the signal transducer and activator of transcription STAT1 [41].
  • Flow cytometry in p53-null cells demonstrates that p53 plays only a marginal role in inducing HCV core-dependent G2/M phase accumulation that seems to be significantly affected by the functional inactivation of PKR [42].


  1. A Role of RNA Helicase A in cis-Acting Transactivation Response Element-mediated Transcriptional Regulation of Human Immunodeficiency Virus Type 1. Fujii, R., Okamoto, M., Aratani, S., Oishi, T., Ohshima, T., Taira, K., Baba, M., Fukamizu, A., Nakajima, T. J. Biol. Chem. (2001) [Pubmed]
  2. Nucleophosmin interacts with and inhibits the catalytic function of eukaryotic initiation factor 2 kinase PKR. Pang, Q., Christianson, T.A., Koretsky, T., Carlson, H., David, L., Keeble, W., Faulkner, G.R., Speckhart, A., Bagby, G.C. J. Biol. Chem. (2003) [Pubmed]
  3. The mRNA of the translationally controlled tumor protein P23/TCTP is a highly structured RNA, which activates the dsRNA-dependent protein kinase PKR. Bommer, U.A., Borovjagin, A.V., Greagg, M.A., Jeffrey, I.W., Russell, P., Laing, K.G., Lee, M., Clemens, M.J. RNA (2002) [Pubmed]
  4. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Knapp, S., Yee, L.J., Frodsham, A.J., Hennig, B.J., Hellier, S., Zhang, L., Wright, M., Chiaramonte, M., Graves, M., Thomas, H.C., Hill, A.V., Thursz, M.R. Genes Immun. (2003) [Pubmed]
  5. Mechanisms for HIV Tat upregulation of IL-10 and other cytokine expression: kinase signaling and PKR-mediated immune response. Li, J.C., Lee, D.C., Cheung, B.K., Lau, A.S. FEBS Lett. (2005) [Pubmed]
  6. Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue. Peel, A.L., Rao, R.V., Cottrell, B.A., Hayden, M.R., Ellerby, L.M., Bredesen, D.E. Hum. Mol. Genet. (2001) [Pubmed]
  7. An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease. Onuki, R., Bando, Y., Suyama, E., Katayama, T., Kawasaki, H., Baba, T., Tohyama, M., Taira, K. EMBO J. (2004) [Pubmed]
  8. Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1. Farassati, F., Yang, A.D., Lee, P.W. Nat. Cell Biol. (2001) [Pubmed]
  9. Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Ruvolo, P.P. Leukemia (2001) [Pubmed]
  10. PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking. Taylor, S.S., Haste, N.M., Ghosh, G. Cell (2005) [Pubmed]
  11. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Meurs, E., Chong, K., Galabru, J., Thomas, N.S., Kerr, I.M., Williams, B.R., Hovanessian, A.G. Cell (1990) [Pubmed]
  12. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Taylor, D.R., Shi, S.T., Romano, P.R., Barber, G.N., Lai, M.M. Science (1999) [Pubmed]
  13. Blockage of NF-kappa B signaling by selective ablation of an mRNA target by 2-5A antisense chimeras. Maran, A., Maitra, R.K., Kumar, A., Dong, B., Xiao, W., Li, G., Williams, B.R., Torrence, P.F., Silverman, R.H. Science (1994) [Pubmed]
  14. PKR gene expression and response to pegylated interferon plus ribavirin therapy in chronic hepatitis C. Gerotto, M., Dal Pero, F., Bortoletto, G., Realdon, S., Ferrari, A., Boccato, S., Alberti, A. Antivir. Ther. (Lond.) (2004) [Pubmed]
  15. The double-stranded RNA-activated kinase, PKR, can phosphorylate hepatitis D virus small delta antigen at functional serine and threonine residues. Chen, C.W., Tsay, Y.G., Wu, H.L., Lee, C.H., Chen, D.S., Chen, P.J. J. Biol. Chem. (2002) [Pubmed]
  16. The 58,000-dalton cellular inhibitor of the interferon-induced double-stranded RNA-activated protein kinase (PKR) is a member of the tetratricopeptide repeat family of proteins. Lee, T.G., Tang, N., Thompson, S., Miller, J., Katze, M.G. Mol. Cell. Biol. (1994) [Pubmed]
  17. Intrahepatic mRNA expression of interferon-inducible antiviral genes in liver diseases: dsRNA-dependent protein kinase overexpression and RNase L inhibitor suppression in chronic hepatitis C. Yu, S.H., Nagayama, K., Enomoto, N., Izumi, N., Marumo, F., Sato, C. Hepatology (2000) [Pubmed]
  18. Antiviral effects of geranylgeranylacetone: enhancement of MxA expression and phosphorylation of PKR during influenza virus infection. Unoshima, M., Iwasaka, H., Eto, J., Takita-Sonoda, Y., Noguchi, T., Nishizono, A. Antimicrob. Agents Chemother. (2003) [Pubmed]
  19. The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR. Donzé, O., Abbas-Terki, T., Picard, D. EMBO J. (2001) [Pubmed]
  20. Mechanism of interferon action: structure of the mouse PKR gene encoding the interferon-inducible RNA-dependent protein kinase. Tanaka, H., Samuel, C.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  21. RNA-dependent protein kinase PKR is required for activation of NF-kappa B by IFN-gamma in a STAT1-independent pathway. Deb, A., Haque, S.J., Mogensen, T., Silverman, R.H., Williams, B.R. J. Immunol. (2001) [Pubmed]
  22. Nuclear factor-90 of activated T-cells: A double-stranded RNA-binding protein and substrate for the double-stranded RNA-dependent protein kinase, PKR. Langland, J.O., Kao, P.N., Jacobs, B.L. Biochemistry (1999) [Pubmed]
  23. c-Jun N-terminal kinase negatively regulates dsRNA and RSV induction of tumor necrosis factor- alpha transcription in human epithelial cells. Stewart, M.J., Kulkarni, S.B., Meusel, T.R., Imani, F. J. Interferon Cytokine Res. (2006) [Pubmed]
  24. Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways. Takizawa, T., Tatematsu, C., Nakanishi, Y. Eur. J. Biochem. (2002) [Pubmed]
  25. PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex. Bonnet, M.C., Weil, R., Dam, E., Hovanessian, A.G., Meurs, E.F. Mol. Cell. Biol. (2000) [Pubmed]
  26. Tumor suppressor p53 as a component of the tumor necrosis factor-induced, protein kinase PKR-mediated apoptotic pathway in human promonocytic U937 cells. Yeung, M.C., Lau, A.S. J. Biol. Chem. (1998) [Pubmed]
  27. 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. Cuddihy, A.R., Wong, A.H., Tam, N.W., Li, S., Koromilas, A.E. Oncogene (1999) [Pubmed]
  28. The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity. Polyak, S.J., Tang, N., Wambach, M., Barber, G.N., Katze, M.G. J. Biol. Chem. (1996) [Pubmed]
  29. Enhanced antiviral and antiproliferative properties of a STAT1 mutant unable to interact with the protein kinase PKR. Wong, A.H., Durbin, J.E., Li, S., Dever, T.E., Decker, T., Koromilas, A.E. J. Biol. Chem. (2001) [Pubmed]
  30. Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex. Gil, J., Alcamí, J., Esteban, M. Oncogene (2000) [Pubmed]
  31. The promoter-proximal KCS element of the PKR kinase gene enhances transcription irrespective of orientation and position relative to the ISRE element and is functionally distinct from the KCS-like element of the ADAR deaminase Promoter. Ward, S.V., Markle, D., Das, S., Samuel, C.E. J. Interferon Cytokine Res. (2002) [Pubmed]
  32. Protein kinase R is increased and is functional in hepatitis C virus-related hepatocellular carcinoma. Hiasa, Y., Kamegaya, Y., Nuriya, H., Onji, M., Kohara, M., Schmidt, E.V., Chung, R.T. Am. J. Gastroenterol. (2003) [Pubmed]
  33. Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. Silva, A.M., Whitmore, M., Xu, Z., Jiang, Z., Li, X., Williams, B.R. J. Biol. Chem. (2004) [Pubmed]
  34. Caspase-mediated cleavage of eukaryotic translation initiation factor subunit 2alpha. Satoh, S., Hijikata, M., Handa, H., Shimotohno, K. Biochem. J. (1999) [Pubmed]
  35. The N-terminus of PKR is responsible for the activation of the NF-kappaB signaling pathway by interacting with the IKK complex. Bonnet, M.C., Daurat, C., Ottone, C., Meurs, E.F. Cell. Signal. (2006) [Pubmed]
  36. Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action. Gil, J., Esteban, M. Apoptosis (2000) [Pubmed]
  37. Two dimerization domains in the trans-activation response RNA-binding protein (TRBP) individually reverse the protein kinase R inhibition of HIV-1 long terminal repeat expression. Daher, A., Longuet, M., Dorin, D., Bois, F., Segeral, E., Bannwarth, S., Battisti, P.L., Purcell, D.F., Benarous, R., Vaquero, C., Meurs, E.F., Gatignol, A. J. Biol. Chem. (2001) [Pubmed]
  38. PKR regulates B56(alpha)-mediated BCL2 phosphatase activity in acute lymphoblastic leukemia-derived REH cells. Ruvolo, V.R., Kurinna, S.M., Karanjeet, K.B., Schuster, T.F., Martelli, A.M., McCubrey, J.A., Ruvolo, P.P. J. Biol. Chem. (2008) [Pubmed]
  39. Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation. Saelens, X., Kalai, M., Vandenabeele, P. J. Biol. Chem. (2001) [Pubmed]
  40. DRBP76, a double-stranded RNA-binding nuclear protein, is phosphorylated by the interferon-induced protein kinase, PKR. Patel, R.C., Vestal, D.J., Xu, Z., Bandyopadhyay, S., Guo, W., Erme, S.M., Williams, B.R., Sen, G.C. J. Biol. Chem. (1999) [Pubmed]
  41. Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways. Wong, A.H., Tam, N.W., Yang, Y.L., Cuddihy, A.R., Li, S., Kirchhoff, S., Hauser, H., Decker, T., Koromilas, A.E. EMBO J. (1997) [Pubmed]
  42. Thr 446 phosphorylation of PKR by HCV core protein deregulates G2/M phase in HCC cells. Alisi, A., Mele, R., Spaziani, A., Tavolaro, S., Palescandolo, E., Balsano, C. J. Cell. Physiol. (2005) [Pubmed]
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